Public perceptions of comparative effectiveness research and use of evidence in healthcare decision-making.

PubMed

Cornwell, Derekh; Hu, Mindy; Esposito, Dominick

2014-11-01

This study elaborates on the public's understanding of comparative effectiveness research (CER) or patient-centered outcomes research (PCOR), attitudes toward CER/PCOR and use of evidence in healthcare decision-making. We conducted six focus groups with the general public - three with individuals actively engaged in healthcare decision-making and three with individuals more passive in their approach. The general public has little knowledge of CER/PCOR, and its perceptions of certain CER/PCOR concepts are inconsistent with those of researchers and policy-makers. Active healthcare consumers value information more than passive consumers and are likely to use evidence in decision-making. Providers are an important source for disseminating and communicating CER/PCOR evidence to active and passive consumers.

Data for Cancer Comparative Effectiveness Research: Past, Present, and Future Potential

PubMed Central

Meyer, Anne-Marie; Carpenter, William R; Abernethy, Amy P.; Stürmer, Til; Kosorok, Michael R.

2012-01-01

Background Comparative effectiveness research (CER) can efficiently and rapidly generate new scientific evidence and address knowledge gaps, reduce clinical uncertainty, and guide health care choices. Much of the potential in CER is driven by the application of novel methods to analyze existing data. Despite its potential, several challenges must be identified and overcome so that CER may be improved, accelerated, and expeditiously implemented into the broad spectrum of cancer care and clinical practice. Methods To identify and characterize the challenges to cancer CER, we reviewed the literature and conducted semi-structured interviews with 41 cancer CER researchers at the Agency for Healthcare Research and Quality (AHRQ)'s Developing Evidence to Inform Decisions about Effectiveness (DEcIDE) Cancer CER Consortium. Results A number of datasets for cancer CER were identified and differentiated into an ontology of eight categories, and characterized in terms of strengths, weaknesses, and utility. Several themes emerged during development of this ontology and discussions with CER researchers. Dominant among them was accelerating cancer CER and promoting the acceptance of findings, which will necessitate transcending disciplinary silos to incorporate diverse perspectives and expertise. Multidisciplinary collaboration is required including those with expertise in non-experimental data, outcomes research, clinical trials, epidemiology, generalist and specialty medicine, survivorship, informatics, data, and methods, among others. Conclusions Recommendations highlight the systematic, collaborative identification of critical measures; application of more rigorous study design and sampling methods; policy-level resolution of issues in data ownership, governance, access, and cost; and development and application of consistent standards for data security, privacy, and confidentiality. PMID:22517505

Data for cancer comparative effectiveness research: past, present, and future potential.

PubMed

Meyer, Anne-Marie; Carpenter, William R; Abernethy, Amy P; Stürmer, Til; Kosorok, Michael R

2012-11-01

Comparative effectiveness research (CER) can efficiently and rapidly generate new scientific evidence and address knowledge gaps, reduce clinical uncertainty, and guide health care choices. Much of the potential in CER is driven by the application of novel methods to analyze existing data. Despite its potential, several challenges must be identified and overcome so that CER may be improved, accelerated, and expeditiously implemented into the broad spectrum of cancer care and clinical practice. To identify and characterize the challenges to cancer CER, the authors reviewed the literature and conducted semistructured interviews with 41 cancer CER researchers at the Agency for Healthcare Research and Quality's Developing Evidence to Inform Decisions about Effectiveness (DEcIDE) Cancer CER Consortium. Several data sets for cancer CER were identified and differentiated into an ontology of 8 categories and were characterized in terms of strengths, weaknesses, and utility. Several themes emerged during the development of this ontology and discussions with CER researchers. Dominant among them was accelerating cancer CER and promoting the acceptance of findings, which will necessitate transcending disciplinary silos to incorporate diverse perspectives and expertise. Multidisciplinary collaboration is required, including those with expertise in nonexperimental data, statistics, outcomes research, clinical trials, epidemiology, generalist and specialty medicine, survivorship, informatics, data, and methods, among others. Recommendations highlight the systematic, collaborative identification of critical measures; application of more rigorous study design and sampling methods; policy-level resolution of issues in data ownership, governance, access, and cost; and development and application of consistent standards for data security, privacy, and confidentiality. Copyright © 2012 American Cancer Society.

Stakeholder participation in comparative effectiveness research: defining a framework for effective engagement

PubMed Central

Deverka, Patricia A; Lavallee, Danielle C; Desai, Priyanka J; Esmail, Laura C; Ramsey, Scott D; Veenstra, David L; Tunis, Sean R

2012-01-01

Aims Stakeholder engagement is fundamental to comparative effectiveness research (CER), but lacks consistent terminology. This paper aims to define stakeholder engagement and present a conceptual model for involving stakeholders in CER. Materials & methods The definitions and model were developed from a literature search, expert input and experience with the Center for Comparative Effectiveness Research in Cancer Genomics, a proof-of-concept platform for stakeholder involvement in priority setting and CER study design. Results Definitions for stakeholder and stakeholder engagement reflect the target constituencies and their role in CER. The ‘analytic-deliberative’ conceptual model for stakeholder engagement illustrates the inputs, methods and outputs relevant to CER. The model differentiates methods at each stage of the project; depicts the relationship between components; and identifies outcome measures for evaluation of the process. Conclusion While the definitions and model require testing before being broadly adopted, they are an important foundational step and will be useful for investigators, funders and stakeholder groups interested in contributing to CER. PMID:22707880

Stakeholder participation in comparative effectiveness research: defining a framework for effective engagement.

PubMed

Deverka, Patricia A; Lavallee, Danielle C; Desai, Priyanka J; Esmail, Laura C; Ramsey, Scott D; Veenstra, David L; Tunis, Sean R

2012-03-01

AIMS: Stakeholder engagement is fundamental to comparative effectiveness research (CER), but lacks consistent terminology. This paper aims to define stakeholder engagement and present a conceptual model for involving stakeholders in CER. MATERIALS #ENTITYSTARTX00026; METHODS: The definitions and model were developed from a literature search, expert input and experience with the Center for Comparative Effectiveness Research in Cancer Genomics, a proof-of-concept platform for stakeholder involvement in priority setting and CER study design. RESULTS: Definitions for stakeholder and stakeholder engagement reflect the target constituencies and their role in CER. The 'analytic-deliberative' conceptual model for stakeholder engagement illustrates the inputs, methods and outputs relevant to CER. The model differentiates methods at each stage of the project; depicts the relationship between components; and identifies outcome measures for evaluation of the process. CONCLUSION: While the definitions and model require testing before being broadly adopted, they are an important foundational step and will be useful for investigators, funders and stakeholder groups interested in contributing to CER.

Future directions for cardiovascular disease comparative effectiveness research: report of a workshop sponsored by the National Heart, Lung, and Blood Institute.

PubMed

Hlatky, Mark A; Douglas, Pamela S; Cook, Nakela L; Wells, Barbara; Benjamin, Emelia J; Dickersin, Kay; Goff, David C; Hirsch, Alan T; Hylek, Elaine M; Peterson, Eric D; Roger, Véronique L; Selby, Joseph V; Udelson, James E; Lauer, Michael S

2012-08-14

Comparative effectiveness research (CER) aims to provide decision makers with the evidence needed to evaluate the benefits and harms of alternative clinical management strategies. CER has become a national priority, with considerable new research funding allocated. Cardiovascular disease is a priority area for CER. This workshop report provides an overview of CER methods, with an emphasis on practical clinical trials and observational treatment comparisons. The report also details recommendations to the National Heart, Lung, and Blood Institute for a new framework for evidence development to foster cardiovascular CER, and specific studies to address 8 clinical issues identified by the Institute of Medicine as high priorities for cardiovascular CER. Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Evaluation of Pharmacy and Therapeutic (P&T) Committee member knowledge, attitudes and ability regarding the use of comparative effectiveness research (CER) in health care decision-making.

PubMed

Tang, D H; Warholak, T L; Hines, L E; Hurwitz, J; Brown, M; Taylor, A M; Brixner, D; Malone, D C

2014-01-01

Comparative effectiveness research (CER) is a constellation of research methods designed to improve health care decision making. Educational programs that improve health care decision makers' CER knowledge and awareness may ultimately lead to more cost-effective use of health care resources. This study was conducted to evaluate changes in CER knowledge, attitudes, and ability among Pharmacy and Therapeutics (P&T) Committee members and support staff after attending a tailored educational program. Physicians and pharmacists from two professional societies and the Indian Health Service who participated in the P&T process were invited via email to participate in this study. Participants completed a questionnaire, designed specifically for this study, prior to and following the 4-hour live, educational program on CER to determine the impact on their related knowledge, attitudes, and ability to use CER in decision-making. Rasch analysis was used to assess validity and reliability of subsections of the questionnaire and regression analysis was used to assess programmatic impact on CER knowledge, attitude, and ability. One hundred and forty of the 199 participants completed both the pre- and post-CER session questionnaires (response rate = 70.4%). Most participants (>75%) correctly answered eight of the ten knowledge items after attending the educational session. More than 60% of the respondents had a positive attitude toward CER both before and after the program. Compared to baseline (pretest), participants reported significant improvements in their perceived ability to use CER after attending the session in these areas: using CER reviews, knowledge of CER methods, identifying problems with randomized controlled trials, identifying threats to validity, understanding of evidence synthesis approaches, and evaluating the quality of CER (all P values < 0.001). The questionnaire demonstrated acceptable reliability and validity evidence (limited evidence of construct under-representation and construct irrelevant variance). The CER educational program was effective in increasing participants' CER knowledge and self-perceived ability to evaluate relevant evidence. Improving knowledge and awareness of CER and its applicability is a critical first step in improving its use in health care decision making. Copyright © 2014 Elsevier Inc. All rights reserved.

The impact of comparative effectiveness research on health and health care spending☆, ☆☆

PubMed Central

Basu, Anirban; Jena, Anupam B.; Philipson, Tomas J.

2011-01-01

Comparative effectiveness research (CER) is thought to identify what works and does not work in health care. We interpret CER as infusing evidence on product quality into markets, shifting the relative demand for products in CER studies. We analyze how shifts in demand affect health and health care spending and demonstrate that CER may raise or lower overall health when treatments have heterogeneous effects, but payers respond with product-specific coverage policies. Among patients with schizophrenia, we calibrate that subsidy policies based on the clinical trial CATIE may have reduced overall health by inducing some patients to switch away from schizophrenia treatments that were effective for them towards winners of the CER. PMID:21696840

75 FR 990 - HHS Intent To Publish Grant and Contract Solicitations for Comparative Effectiveness Research...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-07

... Publish Grant and Contract Solicitations for Comparative Effectiveness Research (CER) Projects With Funds... input, the Comparative Effectiveness Research- Coordination Implementation Team, the Federal Coordinating Council for Comparative Effectiveness Research (FCC), and the Institute of Medicine Report on CER...

The Economics of Comparative Effectiveness Studies

PubMed Central

Meltzer, David; Basu, Anirban; Conti, Rena

2013-01-01

Comparative effectiveness research (CER) can provide valuable information for patients, providers and payers. These stakeholders differ in their incentives to invest in CER. To maximize benefits from public investments in CER, it is important to understand the value of CER from the perspectives of these stakeholders and how that affects their incentives to invest in CER. This article provides a conceptual framework for valuing CER, and illustrates the potential benefits of such studies from a number of perspectives using several case studies. We examine cases in which CER provides value by identifying when one treatment is consistently better than others, when different treatments are preferred for different subgroups, and when differences are small enough that decisions can be made based on price. We illustrate these findings using value-of-information techniques to assess the value of research, and by examining changes in pharmaceutical prices following publication of a comparative effectiveness study. Our results suggest that CER may have high societal value but limited private return to providers or payers. This suggests the importance of public efforts to promote the production of CER. We also conclude that value-of-information tools may help inform policy decisions about how much public funds to invest in CER and how to prioritize the use of available public funds for CER, in particular targeting public CER spending to areas where private incentives are low relative to social benefits. PMID:20831292

Can CER be an effective tool for change in the development and assessment of new drugs and technologies?

PubMed

Brixner, Diana I; Watkins, John B

2012-06-01

Comparative effectiveness research (CER) has been proposed in the United States as a way to compare new drugs and technologies with established alternatives and determine not just whether a therapy works, but how well it works compared to other options. To define the current use of CER in the development of new drugs and technologies and explore what is needed for this research approach to reduce or stabilize health care costs in the United States. In 2010, the Patient-Centered Outcomes Research Institute (PCORI) was established by the Patient Protection and Affordable Care Act (PPACA) to coordinate federally funded CER and recommend research priorities. Hochman and McCormick's (2010) evaluation of 328 randomized trials, observational studies, and meta-analyses involving medications published between June 2008 and September 2009 in 6 key journals showed that most published research did not fulfill the criteria of CER (defined as comparison to active treatment) and that most study design is driven by FDA requirements rather than the need to develop evidence to facilitates election of the most effective therapy. Since PPACA provides alternative funding for CER, it could encourage funding more studies to help determine which treatment delivers the best value per unit of investment from clinical, humanistic, and economic perspectives. Manufacturers may avoid CER because it increases product development costs, but a drug proven more effective is more likely to be accepted by formulary committees, increasing the drug's market share, whereas payers may reject or limit use of a new drug that performs less effectively in comparative studies. CER may not directly reduce expenditures for drugs and medical technologies. The results may vary widely from case to case; however, despite often significantly higher prices for new drugs, it is important to look beyond product costs to the overall impact on health care costs, including medical cost offsets that may occur through improved health or decreased morbidity. To truly decrease cost and improve quality, cost-effectiveness will have to be integrated into CER with the objective of prioritizing efficient therapies in the real-world health care system. If the methods and output of CER improve, the resulting cost-effectiveness ratios will also be more useful to the payer. CER should ultimately, therefore, be a useful tool to help patients, providers, and decision makers provide the most effective and most cost-effective interventions.

CER Hub: An informatics platform for conducting comparative effectiveness research using multi-institutional, heterogeneous, electronic clinical data.

PubMed

Hazlehurst, Brian L; Kurtz, Stephen E; Masica, Andrew; Stevens, Victor J; McBurnie, Mary Ann; Puro, Jon E; Vijayadeva, Vinutha; Au, David H; Brannon, Elissa D; Sittig, Dean F

2015-10-01

Comparative effectiveness research (CER) requires the capture and analysis of data from disparate sources, often from a variety of institutions with diverse electronic health record (EHR) implementations. In this paper we describe the CER Hub, a web-based informatics platform for developing and conducting research studies that combine comprehensive electronic clinical data from multiple health care organizations. The CER Hub platform implements a data processing pipeline that employs informatics standards for data representation and web-based tools for developing study-specific data processing applications, providing standardized access to the patient-centric electronic health record (EHR) across organizations. The CER Hub is being used to conduct two CER studies utilizing data from six geographically distributed and demographically diverse health systems. These foundational studies address the effectiveness of medications for controlling asthma and the effectiveness of smoking cessation services delivered in primary care. The CER Hub includes four key capabilities: the ability to process and analyze both free-text and coded clinical data in the EHR; a data processing environment supported by distributed data and study governance processes; a clinical data-interchange format for facilitating standardized extraction of clinical data from EHRs; and a library of shareable clinical data processing applications. CER requires coordinated and scalable methods for extracting, aggregating, and analyzing complex, multi-institutional clinical data. By offering a range of informatics tools integrated into a framework for conducting studies using EHR data, the CER Hub provides a solution to the challenges of multi-institutional research using electronic medical record data. Copyright © 2015. Published by Elsevier Ireland Ltd.

Patient and clinician views on comparative effectiveness research and engagement in research.

PubMed

Forsythe, Laura P; Frank, Lori; Walker, Kara Odom; Anise, Ayodola; Wegener, Natalie; Weisman, Harlan; Hunt, Gail; Beal, Anne

2015-01-01

Describe and compare patient and primary care clinician attitudes about comparative effectiveness research (CER) and inclusion of patients and clinicians as partners in clinical research. Online survey of patients (n = 900) and primary care clinicians (n = 750) from opt-in survey panels. Nearly half (45%) of clinicians were not familiar with CER, but after reviewing a definition of CER, most (76%) agreed that it can improve patient care. Patients and clinicians indicated interest in engagement as research partners (66% and 55%, respectively). Lack of time was the most commonly endorsed barrier. Attitudes toward CER and engagement in clinical research were generally favorable. Identified facilitators and barriers point to strategies for enhancing patient and clinician engagement in research.

[Overview of design, implementation and analysis of comparative effectiveness research].

PubMed

Liao, Xing; Xie, Yan-Ming; Tian, Feng; Shen, Hao

2013-03-01

Comparative effectiveness research (CER) has been regarded as a hot topic in health care recently. Many medicalresearchers currently deem CER as a potential powerful instrument for improving the quality of healthcare and cut medical cost. However, in the past, classic efficacy studies are always focusing on comparing one new intervention with placebo under complete controlled environment. Now CER turns to comparing different interventions directly in real world of routine practice. This article reviewed a series of literature about the design, implementation and analysis of CER in order to give a clue for Chinese medicine researchers in future.

Comparative effectiveness research and its utility in In-clinic practice

PubMed Central

Dang, Amit; Kaur, Kirandeep

2016-01-01

One of the important components of patient-centered healthcare is comparative effectiveness research (CER), which aims at generating evidence from the real-life setting. The primary purpose of CER is to provide comparative information to the healthcare providers, patients, and policy makers about the standard of care available. This involves research on clinical questions unanswered by the explanatory trials during the regulatory approval process. Main methods of CER involve randomized controlled trials and observational methods. The limitations of these two methods have been overcome with the help of new statistical methods. After the evidence generation, it is equally important to communicate the results to all the interested organizations. CER is beginning to have its impact in the clinical practice as its results become part of the clinical practice guidelines. CER will have far-reaching scientific and financial impact. CER will make both the treating physician and the patient equally responsible for the treatment offered. PMID:26955571

Which research is needed to support clinical decision-making on integrative medicine?- Can comparative effectiveness research close the gap?

PubMed

Witt, Claudia M; Huang, Wen-jing; Lao, Lixing; Bm, Berman

2012-10-01

In clinical research on complementary and integrative medicine, experts and scientists have often pursued a research agenda in spite of an incomplete understanding of the needs of end users. Consequently, the majority of previous clinical trials have mainly assessed the efficacy of interventions. Scant data is available on their effectiveness. Comparative effectiveness research (CER) promises to support decision makers by generating evidence that compares the benefits and harms of the best care options. This evidence, more generalizable than the evidence generated by traditional randomized controlled trials (RCTs), is better suited to inform real-world care decisions. An emphasis on CER supports the development of the evidence base for clinical and policy decision-making. Whereas in most areas of complementary and integrative medicine data on comparative effectiveness is scarce, available acupuncture research already contributes to CER evidence. This paper will introduce CER and make suggestions for future research.

Comparative Effectiveness Research: A Roadmap for Physical Activity and Lifestyle

PubMed Central

Jakicic, John M.; Sox, Harold; Blair, Steven N.; Bensink, Mark; Johnson, William G.; King, Abby C.; Lee, I-Min; Nahum-Shani, Inbal; Sallis, James F.; Sallis, Robert E.; Craft, Lynette; Whitehead, James R.; Ainsworth, Barbara E.

2017-01-01

Purpose Comparative Effectiveness Research (CER) is designed to support informed decision making at both the individual, population, and policy levels. The American College of Sports Medicine and partners convened a conference with the focus of building an agenda for CER within the context of physical activity and non-pharmacological lifestyle approaches in the prevention and treatment of chronic disease. This report summarizes the conference content and consensus recommendations that culminated in a CER Roadmap for Physical Activity and Lifestyle approaches to reducing the risk of chronic disease. Methods This conference focused on presentations and discussion around the following topic areas: 1) defining CER, 2) identifying the current funding climate to support CER, 3) summarizing methods for conducting CER, and 4) identifying CER opportunities for physical activity. Results This conference resulted in consensus recommendations to adopt a CER Roadmap for Physical Activity and Lifestyle approaches to reducing the risk of chronic disease. In general, this roadmap provides a systematic framework by which CER for physical activity can move from a planning phase, to a phase of engagement in CER related to lifestyle factors with particular emphasis on physical activity, to a societal change phase that results in changes in policy, practice, and health. Conclusions It is recommended that physical activity researchers and healthcare providers use the roadmap developed from this conference as a method to systematically engage in and apply CER to the promotion of physical activity as a key lifestyle behavior that can be effective at impacting a variety of health-related outcomes. PMID:25426735

PCOR, CER, and CBPR: alphabet soup or complementary fields of health research?

PubMed

Burke, Jessica G; Jones, Jennifer; Yonas, Michael; Guizzetti, Lisa; Virata, Maria C; Costlow, Monica; Morton, Sally C; Elizabeth, Miller

2013-12-01

Comparative effectiveness research (CER) and community- based participatory research (CBPR) are two fields of research that do not have a history of strong collaboration. However, CER and CBPR researchers could benefit from interdisciplinary collaboration to design and implement relevant, timely, action-oriented research. This commentary explores field-specific definitions of stakeholders and then outlines various roles stakeholders might play within grant-funded research. Questions such as "What stakeholders should be involved?" and "How are stakeholders involved?" are addressed. The goal of this commentary is to highlight how the expertise and experiences of CBPR investigators can enhance the field of CER and to describe strategies for encouraging stakeholder involvement in CER research through the lens of CBPR. It is recommended that a team-based approach to conducting stakeholder-engaged CER encourages multiple stakeholders and "end users" to contribute their diverse expertise to the research process and contributes to the development of research with an increased likelihood of improving patient health and healthcare. © 2013 Wiley Periodicals, Inc.

Ceramide synthases in biomedical research.

PubMed

Cingolani, Francesca; Futerman, Anthony H; Casas, Josefina

2016-05-01

Sphingolipid metabolism consists of multiple metabolic pathways that converge upon ceramide, one of the key molecules among sphingolipids (SLs). In mammals, ceramide synthesis occurs via N-acylation of sphingoid backbones, dihydrosphingosine (dhSo) or sphingosine (So). The reaction is catalyzed by ceramide synthases (CerS), a family of enzymes with six different isoforms, with each one showing specificity towards a restricted group of acyl-CoAs, thus producing ceramides (Cer) and dihydroceramides (dhCer) with different fatty acid chain lengths. A large body of evidence documents the role of both So and dhSo as bioactive molecules, as well as the involvement of dhCer and Cer in physiological and pathological processes. In particular, the fatty acid composition of Cer has different effects in cell biology and in the onset and progression of different diseases. Therefore, modulation of CerS activity represents an attractive target in biomedical research and in finding new treatment modalities. In this review, we discuss functional, structural and biochemical features of CerS and examine CerS inhibitors that are currently available. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Building the Evidence Base for Decision-making in Cancer Genomic Medicine Using Comparative Effectiveness Research

PubMed Central

Goddard, Katrina A.B.; Knaus, William A.; Whitlock, Evelyn; Lyman, Gary H.; Feigelson, Heather Spencer; Schully, Sheri D.; Ramsey, Scott; Tunis, Sean; Freedman, Andrew N.; Khoury, Muin J.; Veenstra, David L.

2013-01-01

Background The clinical utility is uncertain for many cancer genomic applications. Comparative effectiveness research (CER) can provide evidence to clarify this uncertainty. Objectives To identify approaches to help stakeholders make evidence-based decisions, and to describe potential challenges and opportunities using CER to produce evidence-based guidance. Methods We identified general CER approaches for genomic applications through literature review, the authors’ experiences, and lessons learned from a recent, seven-site CER initiative in cancer genomic medicine. Case studies illustrate the use of CER approaches. Results Evidence generation and synthesis approaches include comparative observational and randomized trials, patient reported outcomes, decision modeling, and economic analysis. We identified significant challenges to conducting CER in cancer genomics: the rapid pace of innovation, the lack of regulation, the limited evidence for clinical utility, and the beliefs that genomic tests could have personal utility without having clinical utility. Opportunities to capitalize on CER methods in cancer genomics include improvements in the conduct of evidence synthesis, stakeholder engagement, increasing the number of comparative studies, and developing approaches to inform clinical guidelines and research prioritization. Conclusions CER offers a variety of methodological approaches to address stakeholders’ needs. Innovative approaches are needed to ensure an effective translation of genomic discoveries. PMID:22516979

Investigation of comparative effectiveness research in Asia, Europe, and North America.

PubMed

Patel, Isha; Rarus, Rachel; Tan, Xi; Lee, E K; Guy, Jason; Ahmad, Akram; Chang, Jongwha

2015-01-01

Comparative effectiveness research (CER) is an important branch of pharmacoeconomics that systematically studies and evaluates the cost-effectiveness of medical interventions. CER plays instrumental roles in guiding government public health policy programs and insurance. Countries throughout the world use different methods of CER to help make medical decisions based on providing optimal therapy at a reduced cost. Expenses to the healthcare system continue to rise, and CER is one-way in which expenses could be curbed in the future by applying cost-effectiveness evidence to clinical decisions. China, India, South Korea, and the United Kingdom are of essential focus because these country's economies and health care expenses continue to expand. The structures and use of CER are diverse throughout these countries, and each is of prime importance. By conducting this thorough comparison of CER in different nations, strategies and organizational setups from different countries can be applied to help guide public health and medical decision-making in order to continue to expand the establishment and role of CER programs. The patient-centered medical home has been created to help reduce costs in the primary care sector and to help improve the effectiveness of therapy. Barriers to CER are also important as many stakeholders need to be able to work together to provide the best CER evidence. The advancement of CER in multiple countries throughout the world provides a possible way of reducing costs to the healthcare system in an age of expanding expenses.

Insights from a conference on implementing comparative effectiveness research through shared decision-making

PubMed Central

Politi, Mary C; Clayman, Marla L; Fagerlin, Angela; Studts, Jamie L; Montori, Victor

2013-01-01

For decades, investigators have conducted innovative research on shared decision-making (SDM), helping patients and clinicians to discuss health decisions and balance evidence with patients' preferences for possible outcomes of options. In addition, investigators have developed and used rigorous methods for conducting comparative effectiveness research (CER), comparing the benefits and risks of different interventions in real-world settings with outcomes that matter to patients and other stakeholders. However, incorporating CER findings into clinical practice presents numerous challenges. In March 2012, we organized a conference at Washington University in St Louis (MO, USA) aimed at developing a network of researchers to collaborate in developing, conducting and disseminating research about the implementation of CER through SDM. Meeting attendees discussed conceptual similarities and differences between CER and SDM, challenges in implementing CER and SDM in practice, specific challenges when engaging SDM with unique populations and examples of ways to overcome these challenges. CER and SDM are related processes that emphasize examining the best clinical evidence and how it applies to real patients in real practice settings. SDM can provide one opportunity for clinicians to discuss CER findings with patients and engage in a dialog about how to manage uncertainty about evidence in order to make decisions on an individual patient level. This meeting highlighted key challenges and suggested avenues to pursue such that CER and SDM can be implemented into routine clinical practice. PMID:23430243

76 FR 70456 - Agency Information Collection Activities: Proposed Collection; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-14

... in developing mechanisms for reviewing and disseminating Comparative Effectiveness Research (CER) and... through its Effective Healthcare Program (EHCP). CER directly compares the benefits, potential risks, and... augment AHRQ's existing CER dissemination efforts performed by the Eisenberg Center and other initiatives...

Comparative Effectiveness Research in Lung Diseases and Sleep Disorders

PubMed Central

Lieu, Tracy A.; Au, David; Krishnan, Jerry A.; Moss, Marc; Selker, Harry; Harabin, Andrea; Connors, Alfred

2011-01-01

The Division of Lung Diseases of the National Heart, Lung, and Blood Institute (NHLBI) held a workshop to develop recommendations on topics, methodologies, and resources for comparative effectiveness research (CER) that will guide clinical decision making about available treatment options for lung diseases and sleep disorders. A multidisciplinary group of experts with experience in efficacy, effectiveness, implementation, and economic research identified (a) what types of studies the domain of CER in lung diseases and sleep disorders should include, (b) the criteria and process for setting priorities, and (c) current resources for and barriers to CER in lung diseases. Key recommendations were to (1) increase efforts to engage stakeholders in developing CER questions and study designs; (2) invest in further development of databases and other infrastructure, including efficient methods for data sharing; (3) make full use of a broad range of study designs; (4) increase the appropriate use of observational designs and the support of methodologic research; (5) ensure that committees that review CER grant applications include persons with appropriate perspective and expertise; and (6) further develop the workforce for CER by supporting training opportunities that focus on the methodologic and practical skills needed. PMID:21965016

Translating comparative effectiveness research into Medicaid payment policy: views from medical and pharmacy directors.

PubMed

Weissman, Joel S; Westrich, Kimberly; Hargraves, J Lee; Pearson, Steven D; Dubois, Robert; Emond, Sarah; Olufajo, Olubode A

2015-03-01

As the USA seeks to expand the conduct and dissemination of comparative effectiveness research (CER), views of key stakeholders will help guide the way. We surveyed 60 medical and pharmacy directors from 46 state Medicaid programs. Over 90% felt that CER would lead to better clinical decision-making and overall value within 5 years and were willing to consider cost-effectiveness in setting medical policy. However, perceived poor quality, inconclusive research, restrictive legislative mandates, lack of budget impact and coverage recommendations, and lack of an independent body to interpret study results were major barriers cited to using CER evidence. Given the significant resources being invested in CER, it is critical that these barriers are overcome to maximize its usefulness for stakeholders.

Unresolved tensions in consumer engagement in CER: a US research perspective.

PubMed

Workman, Thomas; Maurer, Maureen; Carman, Kristin

2013-03-01

Efforts to engage patients and consumers in comparative effectiveness research (CER) in the USA are still in the early stages, and the outcomes of these partnerships have yet to be fully understood or realized. Our work assisting federal agencies and national organizations who engage patients and consumers in CER reveal three unresolved tensions around the representation of the patient experience in the research process, the culture of research and capacity to partner with patients and consumers, and the conflict between the methodological approaches to CER and the outcomes of interest to patients and caregivers. Several approaches to address these tensions have emerged, yet resolving these tensions will require addressing many system-level challenges and building an evidence base for consumer engagement in CER.

Ability and Use of Comparative Effectiveness Research by P&T Committee Members and Support Staff: A 1-Year Follow-up.

PubMed

Augustine, Jill; Warholak, Terri L; Hines, Lisa E; Sun, Diana; Brown, Mary; Hurwitz, Jason; Taylor, Ann M; Brixner, Diana; Cobaugh, Daniel J; Schlaifer, Marissa; Malone, Daniel C

2016-06-01

In recent years, comparative effectiveness tools and methods have evolved to assist health care decision makers in identifying optimal therapies. In-person training programs on comparative effectiveness research may be helpful in understanding and applying this information. To provide a follow-up assessment of the use of comparative effectiveness research (CER) in the pharmacy and therapeutics (P&T) committee decision-making process, using information collected from participants 1 year after attending a live continuing education program, in which participants were taught about CER designs and how to access available CER resources through the Agency for Healthcare Research and Quality (AHRQ) Effective Health Care (EHC) Program. A retrospective, cross-sectional questionnaire was developed and mailed to 2 groups of individuals: CER workshop attendees and interested nonattendees (expressing an interest in attending a workshop but did not attend for unknown reasons). The questionnaire asked respondents to indicate personal and organizational use of CER in the decision-making process. Participants were asked to indicate whether their knowledge, ability, and use of CER studies increased since participating in the program. Data were analyzed using nonparametric tests to compare the responses of attendees and nonattendees, as well as overall reliability of the instrument. A total of 164 respondents completed the questionnaire (63 attendees and 101 nonattendees; overall response rate = 44%). The majority of respondents were pharmacists (n = 157, 95.7%) and were affiliated with a hospital (n = 106, 64.6%). Proportions of attendees and nonattendees differed significantly in the use of EHC research reviews/reports (45% and 28%, respectively; P = 0.02) and EHC executive summaries of research reviews/reports (48% and 29%, respectively; P = 0.01). At 1-year follow-up, the majority of attendees reported an increase ("somewhat" or "very much") in knowledge of CER (91.5%), ability to use CER (83.0%), and use of CER studies (58.7%). Health professionals attending a continuing education CER program reported higher use of EHC CER materials compared with nonattendees. Additionally, attendees reported increased use of CER in clinical decision making. A continuing education program such as this may provide an effective avenue for introducing CER methods and resources to the P&T committee and clinical decision-making processes. This project was supported by grant number R18HS019220 from the Agency of Healthcare Research and Quality. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency of Healthcare Research and Quality. Augustine has stock in Pfizer. The authors declared no other potential conflicts of interest associated with this study. Study concept and design were primarily contributed by Malone, along with Warholak, Hines, Brown, Hurwitz, and Taylor. Warholak, Hines, Brown, Hurwitz, and Taylor collected the data, assisted by Malone, Brixner, Cobaugh, and Schlaifer. Data interpretation was performed by Malone and Augustine, with assistance from the other authors. The manuscript was written primarily by Augustine, with assistance from Malone, Sun, Warholak, Hines, Brown, Hurwitz, and Taylor. Malone revised the manuscript, assisted by Warholak, Hines, Brown, Hurwitz, Taylor, Brixner, Cobaugh, and Schlaifer.

The politics of comparative effectiveness research: lessons from recent history.

PubMed

Sorenson, Corinna; Gusmano, Michael K; Oliver, Adam

2014-02-01

Efforts to support and use comparative effectiveness research (CER), some more successful than others, have been promulgated at various times over the last forty years. Following a resurgence of interest in CER, recent health care reforms provided substantial support to strengthen its role in US health care. While CER has generally captured bipartisan support, detractors have raised concerns that it will be used to ration services and heighten government control over health care. Such concerns almost derailed the initiative during passage of the health care reform legislation and are still present today. Given recent investments in CER and the debates surrounding its development, the time is ripe to reflect on past efforts to introduce CER in the United States. This article examines previous initiatives, highlighting their prescribed role in US health care, the reasons for their success or failure, and the political lessons learned. Current CER initiatives have corrected for many of the pitfalls experienced by previous efforts. However, past experiences point to a number of issues that must still be addressed to ensure the long-term success and sustainability of CER, including adopting realistic aims about its impact, demonstrating the impact of Patient-Centered Outcomes Research Institute (PCORI) and communicating the benefits of CER, and maintaining strong political and stakeholder support.

76 FR 1616 - Agency Information Collection Request; 60-Day Public Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-11

.... Proposed Project: Comparative Effectiveness Research Inventory--OMB No. 0990-New-Assistant Secretary for... directly to a web-based inventory of comparative effectiveness research (CER). The CER Inventory will...: Research, human & scientific capital (e.g., training/education, methods development), data infrastructure...

75 FR 80504 - Agency Information Collection Request. 60-Day Public Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-22

.... Proposed Project: Comparative Effectiveness Research Inventory--OMB No. 0990-New-Assistant Secretary for... directly to a web-based inventory of comparative effectiveness research (CER). The CER Inventory will...: research, human & scientific capital (e.g., training/education, methods development), data infrastructure...

Comparative Effectiveness Research in Oncology

PubMed Central

2013-01-01

Although randomized controlled trials represent the gold standard for comparative effective research (CER), a number of additional methods are available when randomized controlled trials are lacking or inconclusive because of the limitations of such trials. In addition to more relevant, efficient, and generalizable trials, there is a need for additional approaches utilizing rigorous methodology while fully recognizing their inherent limitations. CER is an important construct for defining and summarizing evidence on effectiveness and safety and comparing the value of competing strategies so that patients, providers, and policymakers can be offered appropriate recommendations for optimal patient care. Nevertheless, methodological as well as political and social challenges for CER remain. CER requires constant and sophisticated methodological oversight of study design and analysis similar to that required for randomized trials to reduce the potential for bias. At the same time, if appropriately conducted, CER offers an opportunity to identify the most effective and safe approach to patient care. Despite rising and unsustainable increases in health care costs, an even greater challenge to the implementation of CER arises from the social and political environment questioning the very motives and goals of CER. Oncologists and oncology professional societies are uniquely positioned to provide informed clinical and methodological expertise to steer the appropriate application of CER toward critical discussions related to health care costs, cost-effectiveness, and the comparative value of the available options for appropriate care of patients with cancer. PMID:23697601

Comparative effectiveness research in hand surgery.

PubMed

Johnson, Shepard P; Chung, Kevin C

2014-08-01

Comparative effectiveness research (CER) is a concept initiated by the Institute of Medicine and financially supported by the federal government. The primary objective of CER is to improve decision making in medicine. This research is intended to evaluate the effectiveness, benefits, and harmful effects of alternative interventions. CER studies are commonly large, simple, observational, and conducted using electronic databases. To date, there is little comparative effectiveness evidence within hand surgery to guide therapeutic decisions. To draw conclusions on effectiveness through electronic health records, databases must contain clinical information and outcomes relevant to hand surgery interventions, such as patient-related outcomes. Copyright © 2014 Elsevier Inc. All rights reserved.

Approaches to answering critical CER questions.

PubMed

Kinnier, Christine V; Chung, Jeanette W; Bilimoria, Karl Y

2015-01-01

While randomized controlled trials (RCTs) are the gold standard for research, many research questions cannot be ethically and practically answered using an RCT. Comparative effectiveness research (CER) techniques are often better suited than RCTs to address the effects of an intervention under routine care conditions, an outcome otherwise known as effectiveness. CER research techniques covered in this section include: effectiveness-oriented experimental studies such as pragmatic trials and cluster randomized trials, treatment response heterogeneity, observational and database studies including adjustment techniques such as sensitivity analysis and propensity score analysis, systematic reviews and meta-analysis, decision analysis, and cost effectiveness analysis. Each section describes the technique and covers the strengths and weaknesses of the approach.

Patient, caregiver and clinician use of comparative effectiveness research findings in care decisions: results from a national study.

PubMed

Frank, Lori B; Forsythe, Laura P; Workman, Thomas A; Hilliard, Tandrea; Lavelle, Mary; Harwell, Daniel; Fayish, Lauren

2017-05-01

To assess awareness, use and attitudes concerning comparative effectiveness research (CER) findings. Online surveys of patients and caregivers managing rare (n = 560 patients, n = 609 caregivers) or chronic conditions (n = 762 patients, n = 776 caregivers), and practicing clinicians (n = 638). Less than half of patients and caregivers reported exposure to any type of CER findings in the past 12 months. Of those, over half identify healthcare professionals as the information source, yet only 10% of clinicians indicated they were 'very familiar' with CER. Clinicians were concerned about the time required to find relevant evidence and the appropriateness of comparisons in available health research. Clinicians, patients and caregivers indicate unmet need for incorporating CER research findings into clinical decision-making.

An overview of methods for comparative effectiveness research.

PubMed

Meyer, Anne-Marie; Wheeler, Stephanie B; Weinberger, Morris; Chen, Ronald C; Carpenter, William R

2014-01-01

Comparative effectiveness research (CER) is a broad category of outcomes research encompassing many different methods employed by researchers and clinicians from numerous disciplines. The goal of cancer-focused CER is to generate new knowledge to assist cancer stakeholders in making informed decisions that will improve health care and outcomes of both individuals and populations. There are numerous CER methods that may be used to examine specific questions, including randomized controlled trials, observational studies, systematic literature reviews, and decision sciences modeling. Each has its strengths and weaknesses. To both inform and serve as a reference for readers of this issue of Seminars in Radiation Oncology as well as the broader oncology community, we describe CER and several of the more commonly used approaches and analytical methods. © 2013 Published by Elsevier Inc.

Comparative effectiveness research in the U.S.A.: when will there be an impact on healthcare decision-making?

PubMed

Westrich, Kimberly D; Wilhelm, Jess A; Schur, Claudia L

2016-03-01

Five annual surveys of healthcare decision-makers potentially affected by comparative effectiveness research (CER) indicate sustained recognition of its importance and potential impact. Initial expectations of immediate CER impact have over time turned to stakeholder assessments of little short-term impact. In successive surveys, they project a continuous horizon of 3-5 years for CER to have a moderate or substantial improvement in decision making. The prominence of Patient-Centered Outcomes Research Institute in CER is highlighted by stakeholders, but greater emphasis on translating and disseminating research findings is needed, a role in which Agency for Healthcare Research and Quality is expected to contribute. Stakeholders, including patients, must be engaged throughout to ensure that findings provide the flexibility for decision makers to apply them to their patient populations.

Cost, Coverage, and Comparative Effectiveness Research: The Critical Issues for Oncology

PubMed Central

Pearson, Steven D.

2012-01-01

A new national initiative in comparative effectiveness research (CER) is part of a broad and long-term evolution toward greater reliance on scientific evidence in clinical practice and medical policy. But CER has been controversial because of its high profile in the health care reform effort, its instantiation in a prominent new national research institute, and lingering concerns that the ultimate goal of CER is to empower the government and private insurers to reduce health care costs by restricting access to expensive new medical tests and treatments. This article presents an analysis of the policy development behind CER and focuses on its potential impact on insurance coverage and payment for oncology services. By itself, CER will not solve the tension that exists between the goal of innovative, personalized care and the eroding affordability of cancer treatment in the United States. But CER does offer an important opportunity for progress. Oncologists have taken important first steps in acknowledging their responsibility for addressing cost issues; as a professional society, they should now move forward to assume leadership in the effort to integrate clinical evidence with considerations of cost effectiveness to guide clinical practice and insurer policies. PMID:23071229

Recent controversies on comparative effectiveness research investigations: Challenges, opportunities, and pitfalls.

PubMed

Kirpalani, Haresh; Truog, William E; D'Angio, Carl T; Cotten, Michael

2016-10-01

The purpose of comparative effectiveness research (CER) is to improve health outcomes by developing and disseminating evidence-based information about which currently available interventions and practices are most effective for patients. Randomized Controlled Trials (RCT) are the hallmark of scientific proof, and have been used to compare interventions used in variable ways by different clinicians (comparative effectiveness RCTs, CER-RCTs). But such CER-RCTs have at times generated controversy. Usually the background for the CER-RCT is a range of "standard therapy" or "standard of care." This may have been adopted on observational data alone, or pilot data. At times, such prior data may derive from populations that differ from the population in which the widely variable standard approach is being applied. We believe that controversies related to these CER-RCTs result from confusing "accepted" therapies and "rigorously evaluated therapies." We first define evidence-based medicine and consider how well neonatology conforms to that definition. We then contrast the approach of testing new therapies and those already existing and widely adopted, as in CER-RCTs. We next examine a central challenge in incorporating the control arm within CER-RCTs and aspects of the "titrated" trial. We finally briefly consider some ethical issues that have arisen, and discuss the wide range of neonatology practices that could be tested by CER-RCTs or alternative CER-based strategies that might inform practice. Throughout, we emphasize the lack of awareness of the lay community, and indeed many researchers or commentators, in appreciating the wide variation of standard of care. There is a corresponding need to identify the best uses of available resources that will lead to the best outcomes for our patients. We conclude that CER-RCTs are an essential methodology in modern neonatology to address many unanswered questions and test unproven therapies in newborn care. Copyright © 2016 Elsevier Inc. All rights reserved.

76 FR 10366 - Agency Information Collection Request; 60-Day Public Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-24

...). Abstract: This research leverages best practices in behavior change, interaction design, and service innovation to increase the understanding and adoption of Comparative Effectiveness Research (CER) information..., translation, and adoption of evidence-based, outcomes- oriented CER findings. Comparative Effectiveness...

HETEROGENEITY IN TREATMENT EFFECT AND COMPARATIVE EFFECTIVENESS RESEARCH.

PubMed

Luo, Zhehui

2011-10-01

The ultimate goal of comparative effectiveness research (CER) is to develop and disseminate evidence-based information about which interventions are most effective for which patients under what circumstances. To achieve this goal it is crucial that researchers in methodology development find appropriate methods for detecting the presence and sources of heterogeneity in treatment effect (HTE). Comparing with the typically reported average treatment effect (ATE) in randomized controlled trials and non-experimental (i.e., observational) studies, identifying and reporting HTE better reflect the nature and purposes of CER. Methodologies of CER include meta-analysis, systematic review, design of experiments that encompasses HTE, and statistical correction of various types of estimation bias, which is the focus of this review.

Looking at CER from Medicare's perspective.

PubMed

Mohr, Penny

2012-05-01

Comparative effectiveness research (CER) is rapidly adding to the amount of data available to health care coverage and payment decision makers. Medicare's decisions have a large effect on coverage and reimbursement policies throughout the health insurance industry and will likely influence the entire U.S. health care system; thus, examining its role in integrating CER into policy is crucial. To describe the potential benefits of CER to support payment and coverage decisions in the Medicare program, limitations on its use,the role of the Centers for Medicare & Medicaid Services (CMS) in improving the infrastructure for CER, and to discuss challenges that must be addressed to integrate CER into CMS's decision-making process. A defining feature of CER is that it provides the type of evidence that will help decision makers, such as patients, clinicians, and payers,make more informed treatment and policy decisions. Because CMS is responsible for more than 47 million elderly and disabled beneficiaries, the way that Medicare uses CER has the potential to have a large impact on public and individual health. Currently many critical payment and coverage decisions within the Medicare program are made on the basis of poor quality evidence, and CER has the potential to greatly improve the quality of decision making. Despite common misconceptions, CMS is not prohibited by law from using CER apart from some reasonable limitations. CMS is,however, required to support the development of the CER infrastructure by making their data more readily available to researchers. While CER has substantial potential to improve the quality of the agency's policy decisions,challenges remain to integrate CER into Medicare's processes. These challenges include statutory ambiguities, lack of sufficient staff and internal resources to take advantage of CER, and the lack of an active voice in setting priorities for CER and study design. Although challenges exist, CER has the potential to greatly enhance CMS's ability to make decisions regarding coverage and payment that will benefit both the agency and their patient population.

Practice-Based Knowledge Discovery for Comparative Effectiveness Research: An Organizing Framework

PubMed Central

Lucero, Robert J.; Bakken, Suzanne

2014-01-01

Electronic health information systems can increase the ability of health-care organizations to investigate the effects of clinical interventions. The authors present an organizing framework that integrates outcomes and informatics research paradigms to guide knowledge discovery in electronic clinical databases. They illustrate its application using the example of hospital acquired pressure ulcers (HAPU). The Knowledge Discovery through Informatics for Comparative Effectiveness Research (KDI-CER) framework was conceived as a heuristic to conceptualize study designs and address potential methodological limitations imposed by using a single research perspective. Advances in informatics research can play a complementary role in advancing the field of outcomes research including CER. The KDI-CER framework can be used to facilitate knowledge discovery from routinely collected electronic clinical data. PMID:25278645

Looking at CER from the pharmaceutical industry perspective.

PubMed

Dubois, Robert W

2012-05-01

Comparative effectiveness research (CER) is increasing as an element of health care reform in the United States. By comparing drugs against other drugs or other therapies instead of just to placebo, CER has the potential to improve decisions about the appropriate treatment for patients. But the growth of CER also brings an array of questions and decisions for purchasers and policy makers that will not be easy to answer and which require significant dialogue to fully understand and address. To describe some of the impact, both positive and negative, that comparative effectiveness research (CER) may have on the pharmaceutical industry. As CER data proliferate, questions are being raised about who can access the data, who can discuss it, and in what forums. Regulations place different communication restrictions on the pharmaceutical industry than on other health care stakeholders, which creates a potential inequality. Another CER consideration will be the tendency to apply average results to individuals, even if not every individual experiences the average result. Policy makers should implement CER findings carefully with a goal toward accommodating flexibility. A final impact to consider is whether greater expectations for CER will have a negative or positive effect on incentives for drug innovation. In some cases, CER may increase development costs or decrease market size. In other cases, better targeting of trial populations could result in lower development costs. The rising expectations and growth in CER raise questions about information access, communication restrictions, flexible implementation policies, and incentives for innovation. Members of the pharmaceutical industry should be cognizant of the questions and should be participating in dialogues now to pave the way for future solutions.

The use of clinical trials in comparative effectiveness research on mental health.

PubMed

Blanco, Carlos; Rafful, Claudia; Olfson, Mark

2013-08-01

A large body of comparative effectiveness research (CER) focuses on the use of observational and quasi-experimental approaches. We sought to examine the use of clinical trials as a tool for CER, particularly in mental health. Examination of three ongoing randomized clinical trials in psychiatry addressing issues that would pose difficulties for nonexperimental CER methods. Existing statistical approaches to nonexperimental data appear insufficient to compensate for biases that may arise when the pattern of missing data cannot be properly modeled such as when there are no standards for treatment, when affected populations have limited access to treatment, or when there are high rates of treatment dropout. Clinical trials should retain an important role in CER, particularly in cases of high disorder prevalence, large expected effect sizes, difficult-to-reach populations, or when examining sequential treatments or stepped-care algorithms. Progress in CER on mental health will require careful consideration of appropriate selection between clinical trials and nonexperimental designs and on allocation of research resources to optimally inform key treatment decisions for each patient. Copyright © 2013 Elsevier Inc. All rights reserved.

Consensus of recommendations guiding comparative effectiveness research methods.

PubMed

Morton, Jacob B; McConeghy, Robert; Heinrich, Kirstin; Gatto, Nicolle M; Caffrey, Aisling R

2016-12-01

Because of an increasing demand for quality comparative effectiveness research (CER), methods guidance documents have been published, such as those from the Agency for Healthcare Research and Quality (AHRQ) and the Patient-Centered Outcomes Research Institute (PCORI). Our objective was to identify CER methods guidance documents and compare them to produce a summary of important recommendations which could serve as a consensus of CER method recommendations. We conducted a systematic literature review to identify CER methods guidance documents published through 2014. Identified documents were analyzed for methods guidance recommendations. Individual recommendations were categorized to determine the degree of overlap. We identified nine methods guidance documents, which contained a total of 312 recommendations, 97% of which were present in two or more documents. All nine documents recommended transparency and adaptation for relevant stakeholders in the interpretation and dissemination of results. Other frequently shared CER methods recommendations included: study design and operational definitions should be developed a priori and allow for replication (n = 8 documents); focus on areas with gaps in current clinical knowledge that are relevant to decision-makers (n = 7); validity of measures, instruments, and data should be assessed and discussed (n = 7); outcomes, including benefits and harms, should be clinically meaningful, and objectively measured (n = 7). Assessment for and strategies to minimize bias (n = 6 documents), confounding (n = 6), and heterogeneity (n = 4) were also commonly shared recommendations between documents. We offer a field-consensus guide based on nine CER methods guidance documents that will aid researchers in designing CER studies and applying CER methods. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Evidence gaps in advanced cancer care: community-based clinicians' perspectives and priorities for CER.

PubMed

Lowry, Sarah J; Loggers, Elizabeth T; Bowles, Erin J A; Wagner, Edward H

2012-05-01

Although much effort has focused on identifying national comparative effectiveness research (CER) priorities, little is known about the CER priorities of community-based practitioners treating patients with advanced cancer. CER priorities of managed care-based clinicians may be valuable as reflections of both payer and provider research interests. We conducted mixed methods interviews with 10 clinicians (5 oncologists and 5 pharmacists) at 5 health plans within the Health Maintenance Organization Cancer Research Network. We asked, "What evidence do you most wish you had when treating patients with advanced cancer" and questioned participants on their impressions and knowledge of CER and pragmatic clinical trials (PCTs). We conducted qualitative analyses to identify themes across interviews. Ninety percent of participants had heard of CER, 20% had heard of PCTs, and all rated CER/PCTs as highly relevant to patient and health plan decision making. Each participant offered between 3 and 10 research priorities. Half (49%) involved head-to-head treatment comparisons; another 20% involved comparing different schedules or dosing regimens of the same treatment. The majority included alternative outcomes to survival (eg, toxicity, quality of life, noninferiority). Participants cited several limitations to existing evidence, including lack of generalizability, funding biases, and rapid development of new treatments. Head-to-head treatment comparisons remain a major evidence need among community- based oncology clinicians, and CER/PCTs are highly valued methods to address the limitations of traditional randomized trials, answer questions of cost-effectiveness or noninferiority, and inform data-driven dialogue and decision making by all stakeholders.

The use of clinical trials in comparative effectiveness research on mental health

PubMed Central

Blanco, Carlos; Rafful, Claudia; Olfson, Mark

2013-01-01

Objectives A large body of research on comparative effectiveness research (CER) focuses on the use of observational and quasi-experimental approaches. We sought to examine the use of clinical trials as a tool for CER, particularly in mental health. Study Design and Setting Examination of three ongoing randomized clinical trials in psychiatry that address issues which would pose difficulties for non-experimental CER methods. Results Existing statistical approaches to non-experimental data appear insufficient to compensate for biases that may arise when the pattern of missing data cannot be properly modeled such as when there are no standards for treatment, when affected populations have limited access to treatment, or when there are high rates of treatment dropout. Conclusions Clinical trials should retain an important role in CER, particularly in cases of high disorder prevalence, large expected effect sizes, difficult to reach populations or when examining sequential treatments or stepped-care algorithms. Progress in CER in mental health will require careful consideration of appropriate selection between clinical trials and non-experimental designs and on allocation of research resources to optimally inform key treatment decisions for each individual patient. PMID:23849150

Pre-study feasibility and identifying sensitivity analyses for protocol pre-specification in comparative effectiveness research.

PubMed

Girman, Cynthia J; Faries, Douglas; Ryan, Patrick; Rotelli, Matt; Belger, Mark; Binkowitz, Bruce; O'Neill, Robert

2014-05-01

The use of healthcare databases for comparative effectiveness research (CER) is increasing exponentially despite its challenges. Researchers must understand their data source and whether outcomes, exposures and confounding factors are captured sufficiently to address the research question. They must also assess whether bias and confounding can be adequately minimized. Many study design characteristics may impact on the results; however, minimal if any sensitivity analyses are typically conducted, and those performed are post hoc. We propose pre-study steps for CER feasibility assessment and to identify sensitivity analyses that might be most important to pre-specify to help ensure that CER produces valid interpretable results.

Health care decision makers' use of comparative effectiveness research: report from a series of focus groups.

PubMed

Villa, Lorenzo; Warholak, Terri L; Hines, Lisa E; Taylor, Ann M; Brown, Mary; Hurwitz, Jason; Brixner, Diana; Malone, Daniel C

2013-01-01

Comparative effectiveness research (CER) is a helpful approach to improve health outcomes by developing and disseminating evidence-based information to patients, clinicians, and other decision makers about the most effective interventions. To (a) identify the factors necessary to increase the use of the Agency for Healthcare Research and Quality's (AHRQ) CER reviews in hospitals and managed care organizations; (b) assess current awareness and implementation of CER materials in these facilities and organizations; and (c) inform development of content for a workshop on CER. Pharmacy and therapeutics (PT) committee members and supportive personnel were recruited to participate in focus groups conducted at national health professional meetings. Prior to the sessions, each participant completed a prefocus group questionnaire evaluating the organization and process of the respondent's PT committee, as well as the respondent's role in the PT committee and awareness of AHRQ CER reports. Each session consisted of a focused discussion about CER and sources of evidence for PT monographs, and each participant completed a ballot to rank topics of importance for inclusion in a CER workshop for health care professionals involved in the PT process. Overarching themes were later identified using qualitative analysis of the transcripts of the focus group sessions. Thirty-nine (68%) pharmacists and 18 (32%) physicians involved in the PT process participated in 1 of 7 focus groups. Almost half of the participants had 6-15 years experience with the PT process. Participants represented health plans, hospitals, and health care systems. Two-thirds indicated they were aware of AHRQ's Effective Health Care Program's CER reviews, yet only 26% reported using the reviews in their organizations. The overarching themes reflected the need for timely and conclusive CER information; the role of the pharmacist as central to evidence synthesis for the PT process; and the need for educational programs in online formats that are designed primarily for pharmacists. Health care decision makers identified timeliness as a key factor for facilitating the use of AHRQ CER reviews and guides in hospitals and managed care organizations. To facilitate integration of CER into the decision-making process, it is imperative that key stakeholders have access to comprehensive and timely information. While the majority of participants indicated that they were aware of AHRQ CER reviews, few had used them in the PT process.

Tensile Characterization of Injection-Molded Fuzzy Glass Fiber/Nylon Composite Material

DTIC Science & Technology

2016-05-01

enhanced reinforcement ( CER ) in a nylon matrix. A majority of the masterbatch CER material research is focused on electromagnetic shielding applications...however, the CER system, with the CNT network fixed to the host fiber, provides a novel approach of minimizing CNT agglomeration. Tensile specimens are...injection molded with varying weight percentages of CER to evaluate effect of the reinforcement on the mechanical properties. Tension testing showed

76 FR 28987 - Agency Information Collection Request; 30-Day Public Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-19

... diverse populations and clinical practice settings, that is, comparative effectiveness research (CER). The American Reinvestment and Recovery Act of 2009 (ARRA) expanded Federal resources devoted to CER by... also called for a report to Congress and the Secretary of HHS on priority CER topics by the Institute...

76 FR 59131 - Agency Information Collection Request; 60-Day Public Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-23

... related to comparative effectiveness research (CER) funded by the American Recovery and Reinvestment Act... CER. Approximately 25% of the $400 million allocated to the Office of the Secretary for Health and... longitudinal data on health services financed by both public and private payers to help facilitate CER...

PRIVATE MANUFACTURERS’ THRESHOLDS TO INVEST IN COMPARATIVE EFFECTIVENESS TRIALS

PubMed Central

Basu, Anirban; Meltzer, David

2015-01-01

The recent rush of enthusiasm for public investment in comparative effectiveness research (CER) in the United States has focused attention on these public investments. However, little attention has been given to how changing public investment in CER may affect private manufacturers’ incentives for CER, which has long been a major source of CER. In this work, based on a simple revenue maximizing economic framework, we generate predictions on thresholds to invest in CER for a private manufacturer that compares its own product to its competitor’s in head to head trials. Our analysis shows that private incentives to invest in CER are determined by how the results of CER may affect the price and quantity of the product sold and the duration over which resulting changes in revenue would accrue given the time required to complete CER and the time from the completion of CER to the time of patent expiration. We highlight the result that private incentives may often be less than public incentives to invest in CER and may even be negative if the likelihood of adverse findings is sufficient. We find that these incentives imply a number of predictions about patterns of CER and how they will be affected by changes in public financing of CER and CER methods. For example, these incentives imply that incumbent patent holders may be less likely to invest in CER than entrants and that public investments in CER may crowd out similar private investments. In contrast, newer designs and methods for CER, such as Bayesian adaptive trials, which can reduce ex-post risk of unfavorable results and shorten the time for the production of CER, may increase the expected benefits of CER and may tend to increase private investment in CER as long as the costs of such innovative designs are not excessive. Bayesian approaches to design also naturally highlight the dynamic aspects of CER, allowing less expensive initial studies to guide decisions about future investments and thereby encouraging greater initial investments in CER. However, whether the potential effects we highlight of public funding of CER and of Bayesian approaches to trial design actually produce changes in private investment in CER remains an empirical question. PMID:22901018

Private manufacturers' thresholds to invest in comparative effectiveness trials.

PubMed

Basu, Anirban; Meltzer, David

2012-10-01

The recent rush of enthusiasm for public investment in comparative effectiveness research (CER) in the US has focussed attention on these public investments. However, little attention has been given to how changing public investment in CER may affect private manufacturers' incentives for CER, which has long been a major source of CER. In this work, based on a simple revenue maximizing economic framework, we generate predictions on thresholds to invest in CER for a private manufacturer that compares its own product to a competitor's product in head-to-head trials. Our analysis shows that private incentives to invest in CER are determined by how the results of CER may affect the price and quantity of the product sold and the duration over which resulting changes in revenue would accrue, given the time required to complete CER and the time from the completion of CER to the time of patent expiration. We highlight the result that private incentives may often be less than public incentives to invest in CER and may even be negative if the likelihood of adverse findings is sufficient. We find that these incentives imply a number of predictions about patterns of CER and how they will be affected by changes in public financing of CER and CER methods. For example, these incentives imply that incumbent patent holders may be less likely to invest in CER than entrants and that public investments in CER may crowd out similar private investments. In contrast, newer designs and methods for CER, such as Bayesian adaptive trials, which can reduce ex post risk of unfavourable results and shorten the time for the production of CER, may increase the expected benefits of CER and may tend to increase private investment in CER as long as the costs of such innovative designs are not excessive. Bayesian approaches to design also naturally highlight the dynamic aspects of CER, allowing less expensive initial studies to guide decisions about future investments and thereby encouraging greater initial investments in CER. However, whether the potential effects we highlight of public funding of CER and of Bayesian approaches to trial design actually produce changes in private investment in CER remains an empirical question.

Use of comparative effectiveness research in drug coverage and pricing decisions: a six-country comparison.

PubMed

Sorenson, Corinna

2010-07-01

Comparative effectiveness research (CER) has assumed an increasing role in drug coverage and, in some cases, pricing decisions in Europe, as decision-makers seek to obtain better value for money. This issue brief comparatively examines the use of CER across six countries--Denmark, England, France, Germany, the Netherlands, and Sweden. With CER gaining traction in the United States, these international experiences offer insights and potential lessons. Investing in CER can help address the current gap in publicly available, credible, up-to-date, and scientifically based comparative information on the effectiveness of drugs and other health interventions. This information can be used to base coverage and pricing decisions on evidence of value, thereby facilitating access to and public and private investment in the most beneficial new drugs and technologies. In turn, use of CER creates incentives for more efficient, high-quality health care and encourages development of innovative products that offer measurable value to patients.

Comparative-effectiveness research in distributed health data networks.

PubMed

Toh, S; Platt, R; Steiner, J F; Brown, J S

2011-12-01

Comparative-effectiveness research (CER) can be conducted within a distributed health data network. Such networks allow secure access to separate data sets from different data partners and overcome many practical obstacles related to patient privacy, data security, and proprietary concerns. A scalable network architecture supports a wide range of CER activities and meets the data infrastructure needs envisioned by the Federal Coordinating Council for Comparative Effectiveness Research.

Nursing Research, CER, PICO and PCORI.

PubMed

Patel, Darpan I

2018-01-01

Community and public health nurse researchers encompass a unique cohort of nurse researchers that have the skills and capacity to lead projects and programs of science centered on improvement of patient outcomes through methods of comparative effectiveness research (CER). CER, as a general method, has been taught to all nurses in the form of the PICO question to improve evidence-based practices. As the climate for funding becomes more and more competitive, nurse researchers are primed to lead the change in improving patient outcomes through patient centered outcomes research (PCOR). However, the number of projects funded by agencies like the Patient Centered Outcomes Research Institute, fall well below the capabilities of the field. The purpose of this commentary is to promote the field of PCOR and encourage novice and experienced nurse researchers to apply for funding from the PCORI by introducing different methods for building capacity and promoting engagement in the national conversations of PCOR and CER.

Implementing CER: what will it take?

PubMed

Biskupiak, Joseph E; Dunn, Jeffrey D; Holtorf, Anke-Peggy

2012-06-01

Comparative effectiveness research (CER) is undeniably changing how drugs are developed, launched, priced, and reimbursed in the United States. But most organizations are still evaluating what CER can do for them and how and when they can utilize the data. A roundtable of stakeholders, including formulary decision makers, evaluated CER's possible effects on managed care organizations (MCOs) and what it may take to fully integrate CER into decision making. To examine the role of CER in current formulary decision making, compare CER to modeling, discuss ways CER may be used in the future, and describe CER funding sources. While decision makers from different types of organizations, such as pharmacy benefit management (PBM) companies and MCOs, may have varying definitions and expectations of CER, most thought leaders from a roundtable of stakeholders, including formulary decision makers, see value in CER's ability to enhance their formulary decision making. Formulary decision makers may be able to use CER to better inform their coverage decisions in areas such as benefit design, contracting, conditional reimbursement, pay for performance, and other alternative pricing arrangements. Real-world CER will require improvement in the health information technology infrastructure to better capture value-related information. The federal government is viewed as a key driver and funding source behind CER, especially for infrastructure and methods development, while industry will adapt the clinical development and create increasing CER evidence. CER then needs to be applied to determining value (or cost efficacy). It is expected that CER will continue to grow as a valuable component of formulary decision making. Future integration of CER into formulary decision making will require federal government and academic leadership, improvements in the health information technology infrastructure, ongoing funding, and improved and more consistent methodologies.

76 FR 6793 - Agency Information Collection Request. 60-Day Public Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-08

..., that is, comparative effectiveness research (CER). The American Reinvestment and Recovery Act of 2009 (ARRA) expanded Federal resources devoted to CER by directing $1.1 billion to the U.S. Department of... Secretary of HHS on priority CER topics by the Institute of Medicine (IOM). The report presented priority...

Increasing uptake of comparative effectiveness and patient-centered outcomes research among stakeholders: insights from conference discussion.

PubMed

Law, Ernest; Harrington, Rachel; Alexander, G Caleb; Saha, Soumi; Oehrlein, Elisabeth; Perfetto, Eleanor M

2018-02-01

The goal of comparative effectiveness research (CER) and patient-centered outcomes research (PCOR) is to improve health outcomes by providing stakeholders with evidence directly relevant to decision making. In January 2017, the Pharmaceutical Research and Manufacturers Association Foundation, alongside the Academy for Managed Care Pharmacy, organized a conference aimed at engaging experts and opinion leaders representing clinicians, patients and payers to identify and discuss barriers and strategies to enhancing uptake and use of CER/PCOR. This report summarizes the conference discussion in the following sections: preconference survey; summary of barriers and strategies to the uptake of CER/PCOR identified by conference attendees; and future perspectives on the field.

Practical guide to understanding Comparative Effectiveness Research (CER).

PubMed

Neely, J Gail; Sharon, Jeffrey D; Graboyes, Evan M; Paniello, Randal C; Nussenbaum, Brian; Grindler, David J; Dassopoulos, Themistocles

2013-12-01

"Comparative effectiveness research" (CER) is not a new concept; however, recently it has been popularized as a method to develop scientifically sound actionable data by which patients, physicians, payers, and policymakers may make informed health care decisions. Fundamental to CER is that the comparative data are derived from large diverse populations of patients assembled from point-of-care general primary care practices and that measured outcomes include patient value judgments. The challenge is to obtain scientifically valid data to be acted upon by decision-making stakeholders with potentially quite diversely different agenda. The process requires very thoughtful research designs modulated by complex statistical and analytic methods. This article is composed of a guiding narrative with an extensive set of tables outlining many of the details required in performing and understanding CER. It ends with short discussions of three example papers, limitations of the method, and how a practicing physician may view such reports.

The ARRA investment in CER: a description of the midstream evaluation and how the funds were allocated and CER priorities addressed.

PubMed

Esposito, Dominick; Yong, Pierre L; Rich, Eugene; Geonnotti, Kristin; Kimmey, Laura D

2014-11-01

To describe the evaluation design of the American Recovery and Reinvestment Act of 2009 comparative effectiveness research (CER) investment, how funds were allocated and how CER priorities were addressed. Primary and secondary data included information from redacted project proposals, an investigator survey and federal project officers, investigators and expert panel discussions. More than 420 projects (US$1.1 billion) were awarded. Those generating new or synthesizing existing CER made up the plurality (194, or US$524 million). Data infrastructure projects were the second-largest area (28%, US$302 million). More than three-fourths addressed at least one priority population, condition category or intervention category. These investments expanded the nation's CER activities and its future capacity to conduct CER.

A tall order on a tight timeframe: stakeholder perspectives on comparative effectiveness research using electronic clinical data.

PubMed

Holve, Erin; Lopez, Marianne Hamilton; Scott, Lisa; Segal, Courtney

2012-09-01

BACKGROUND & SIGNIFICANCE: The AcademyHealth Electronic Data Methods Forum aims to advance the national dialogue on the use of electronic clinical data (ECD) for comparative effectiveness research (CER), patient-centered outcomes research, and quality improvement by facilitating exchange and collaboration among eleven research projects and external stakeholders. AcademyHealth conducted a mixed-method needs assessment with the Electronic Data Methods Forum's key stakeholders to assess: stakeholder views on developing new infrastructure for CER using ECD; current gaps in knowledge with respect to CER; and expectations for a learning health system. AcademyHealth conducted 50 stakeholder interviews between August 2011 and November 2011 with participants from the following seven stakeholder groups: government, business/payer, industry, healthcare delivery, patient/consumer, nonprofit/policy and research. With input from key collaborators, AcademyHealth designed a semi-structured interview guide and a short survey. Reviewers used the qualitative data analysis software NVivo to code the transcripts and to identify and manage complex concepts. Quantitative data from the questionnaire has been integrated with the final analysis as relevant. The analysis of recurring concepts in the interviews focus on five central themes: stakeholders have substantial expectations for CER using ECD, both with respect to addressing the limitations of traditional research studies, and generating meaningful evidence for decision-making and improving patient outcomes; stakeholders are aware of many challenges related to implementing CER with ECD, including the need to develop appropriate governance, assess and manage data quality, and develop methods to address confounding in observational data; stakeholders continue to struggle to define 'patient-centeredness' in CER using ECD, adding complexity to attaining this goal; stakeholders express that improving translation and dissemination of CER, and how research can be 'useful' at the point of care, can help mitigate negative perceptions of the CER 'brand'; and stakeholders perceive a need for a substantial 'culture shift' to facilitate collaborative science and new ways of conducting biomedical and outcomes research. Many stakeholders proposed approaches or solutions they felt might address the challenges identified.

Dissemination and implementation of comparative effectiveness evidence: key informant interviews with Clinical and Translational Science Award institutions.

PubMed

Morrato, Elaine H; Concannon, Thomas W; Meissner, Paul; Shah, Nilay D; Turner, Barbara J

2013-03-01

To identify ongoing practices and opportunities for improving national comparative effectiveness research (CER) translation through dissemination and implementation (D&I) via NIH-funded Clinical and Translational Science Award (CTSA) institutions. Key informant interviews were conducted with 18 CTSA grantees sampled to represent a range of D&I efforts. The institutional representatives endorsed fostering CER translation nationally via the CTSA Consortium. However, five themes emerged from the interviews as barriers to CER D&I: lack of institutional awareness, insufficient capacity, lack of established D&I methods, confusion among stakeholders about what CER actually is and limited funding opportunities. Interviewees offered two key recommendations to improve CER translation: development of a centralized clearing house to facilitate the diffusion of CER D&I resources and methods across CTSA institutions; and formalization of the national CTSA network to leverage existing community engagement relationships and resources for the purpose of adapting and disseminating robust CER evidence locally with providers, patients and healthcare systems.

Dissemination and implementation of comparative effectiveness evidence: key informant interviews with Clinical and Translational Science Award institutions

PubMed Central

Morrato, Elaine H; Concannon, Thomas W; Meissner, Paul; Shah, Nilay D; Turner, Barbara J

2014-01-01

Aim To identify ongoing practices and opportunities for improving national comparative effectiveness research (CER) translation through dissemination and implementation (D&I) via NIH-funded Clinical and Translational Science Award (CTSA) institutions. Materials & methods Key informant interviews were conducted with 18 CTSA grantees sampled to represent a range of D&I efforts. Results & conclusions The institutional representatives endorsed fostering CER translation nationally via the CTSA Consortium. However, five themes emerged from the interviews as barriers to CER D&I: lack of institutional awareness, insufficient capacity, lack of established D&I methods, confusion among stakeholders about what CER actually is and limited funding opportunities. Interviewees offered two key recommendations to improve CER translation: development of a centralized clearing house to facilitate the diffusion of CER D&I resources and methods across CTSA institutions; and formalization of the national CTSA network to leverage existing community engagement relationships and resources for the purpose of adapting and disseminating robust CER evidence locally with providers, patients and healthcare systems. PMID:24236560

It is important to note that RWD will never replace the more traditional and more robust RCT data; however, the emerging trend is to incorporate data that are more generalizable. Introduction.

PubMed

Mullins, C Daniel; Sanchez, Robert J

2011-01-01

The Patient Protection and Affordable Care Act brought considerable attention to comparative effectiveness research (CER).   To (a) suggest best practices for conducting and reporting CER using "real-world data" (RWD), (b) describe some of the data and infrastructure requirements for conducting CER using RWD, (c) identify statistical challenges with the analysis of nonrandomized studies and suggest appropriate techniques to address those challenges, (d) recognize the value of patient-reported outcomes in CER, (e) encourage the incorporation of observational data into randomized controlled studies, and (f) highlight the importance of incorporating payers in industry-sponsored research.  The first article in this supplement, "Something old, something new…" provides a policy perspective on the recent evolution of CER. It reviews the historical context, discusses the "promise and fear" of CER, and then describes the new role of the Patient-Centered Outcomes Research Institute (PCORI) in defining and sponsoring CER. The second paper, "Ten Commandments," proposes a series of tenets for planning, conducting, and reporting CER done with RWD. Oriented for basic-to-intermediate researchers, it combines standard scientific research principles with considerations specific to nonrandomized, RWD studies. The third article, "Infrastructure Requirements," points out that effective use of secondary data requires addressing major methodological and infrastructural issues, including development of analytical tools to readily access and analyze data, formulation of guidelines to enhance quality and transparency, establishment of data standards, and creation of data warehouses that respect the privacy and confidentiality of patients. It identifies gaps that must be filled to address the underlying issues, with emphasis on data standards, data quality assurance, data warehouses, computing environment, and protection of privacy and confidentiality. The fourth paper, "Statistical Issues," discusses how the validity of analytic results from observational studies is adversely impacted by biases that may be introduced due to lack of randomization. It reviews some of the methodological challenges that arise in the analysis of data from nonrandomized studies, with particular emphasis on the limitations of traditional approaches and potential solutions from recent methodological developments. The fifth paper, "Considerations on the Use of Patient Reported Outcomes (PROs)," describes how PRO data can play a critical role in guiding patients, health care providers, payers, and policy makers in making informed decisions regarding patient-centered treatment from among alternative options and technologies and have been noted as such by PCORI. However, collection and interpretation of such data within the context of CER have not yet been fully established. It discusses some challenges with including PROs in CER initiatives, provides a framework for their effective use, and proposes several areas for future research. Lastly, "Developing a Collaborative Study Protocol…" indicates that there is the potential, the desire, and the capability for payers to be involved in CER studies, combining elements of their own observational data with prospective studies. It describes a case example of a payer, a pharmaceutical company, and a research organization collaborating on a prospective study to examine the effect of prior authorization for pregabalin on health care costs to the payer.   Researchers at Pfizer routinely conduct CER-type studies. In this supplement, we have proposed some approaches that we believe are useful in developing certain kinds of evidence and have described some of our experiences. Our experiences also make us acutely aware of the limitations of approaches and data sources that have been used for CER studies and suggest that there is a need to further develop methods that are most useful for answering CER questions.

PAYER PERSPECTIVES ON FUTURE ACCEPTABILITY OF COMPARATIVE EFFECTIVENESS AND RELATIVE EFFECTIVENESS RESEARCH.

PubMed

Moloney, Rachael; Mohr, Penny; Hawe, Emma; Shah, Koonal; Garau, Martina; Towse, Adrian

2015-01-01

Our objective was to gather perspectives from payers on how comparative effectiveness research (CER) in the United States and relative effectiveness (RE) research in Europe will impact evidentiary standards for access decisions of new drugs by 2020. We conducted semi-structured interviews with fourteen senior officials representing public and private payers, health technology assessment groups, and pricing and reimbursement bodies in the United States and Europe. An online survey assessed current use of CER/RE evidence and potential trends that might influence its use for decision making by 2020. A semi-structured interview elicited payers' definitions of CER/RE and was structured around four hypothetical cases resembling drugs expected to be more common or poised to create policy challenges by 2020. Topics included acceptance of study designs and analytic methods associated with CER/RE. A systematic content review was done to extract relevant information. According to key informants, randomization will remain an essential component for assessing comparative or relative effectiveness. They anticipate greater use of policy levers such as conditional reimbursement or prior authorization to manage diffusion of new drugs. Case studies provided important insights into situations when certain types of CER evidence may be acceptable (e.g., observational data when differences between drugs are largely convenience). Industry perceptions that CER/RE will change payers' evidentiary requirements in the future are consistent with our findings. Growing investment in payers' own data and increased reliance on policy tools to control diffusion of new drugs may also influence the type of evidence industry will be required to produce by 2020.

IMPACCT Kids’ Care: a real-world example of stakeholder involvement in comparative effectiveness research

PubMed Central

Likumahuwa-Ackman, Sonja; Angier, Heather; Sumic, Aleksandra; Harding, Rose L; Cottrell, Erika K; Cohen, Deborah J; Nelson, Christine A; Burdick, Timothy E; Wallace, Lorraine S; Gallia, Charles; DeVoe, Jennifer E

2015-01-01

The Patient-Centered Outcomes Research Institute has accelerated conversations about the importance of actively engaging stakeholders in all aspects of comparative effectiveness research (CER). Other scientific disciplines have a history of stakeholder engagement, yet few empirical examples exist of how these stakeholders can inform and enrich CER. Here we present a case study which includes the methods used to engage stakeholders, what we learned from them, and how we incorporated their ideas in a CER project. We selected stakeholders from key groups, built relationships with them and collected their feedback through interviews, observation and ongoing meetings during the four research process phases: proposal development, adapting study methods, understanding the context and information technology tool design and refinement. PMID:26274796

IMPACCT Kids' Care: a real-world example of stakeholder involvement in comparative effectiveness research.

PubMed

Likumahuwa-Ackman, Sonja; Angier, Heather; Sumic, Aleksandra; Harding, Rose L; Cottrell, Erika K; Cohen, Deborah J; Nelson, Christine A; Burdick, Timothy E; Wallace, Lorraine S; Gallia, Charles; DeVoe, Jennifer E

2015-08-01

The Patient-Centered Outcomes Research Institute has accelerated conversations about the importance of actively engaging stakeholders in all aspects of comparative effectiveness research (CER). Other scientific disciplines have a history of stakeholder engagement, yet few empirical examples exist of how these stakeholders can inform and enrich CER. Here we present a case study which includes the methods used to engage stakeholders, what we learned from them, and how we incorporated their ideas in a CER project. We selected stakeholders from key groups, built relationships with them and collected their feedback through interviews, observation and ongoing meetings during the four research process phases: proposal development, adapting study methods, understanding the context and information technology tool design and refinement.

Knowledge management and informatics considerations for comparative effectiveness research: a case-driven exploration.

PubMed

Embi, Peter J; Hebert, Courtney; Gordillo, Gayle; Kelleher, Kelly; Payne, Philip R O

2013-08-01

As clinical data are increasingly collected and stored electronically, their potential use for comparative effectiveness research (CER) grows. Despite this promise, challenges face those wishing to leverage such data. In this paper we aim to enumerate some of the knowledge management and informatics issues common to such data reuse. After reviewing the current state of knowledge regarding biomedical informatics challenges and best practices related to CER, we then present 2 research projects at our institution. We analyze these and highlight several common themes and challenges related to the conduct of CER studies. Finally, we represent these emergent themes. The informatics challenges commonly encountered by those conducting CER studies include issues related to data information and knowledge management (eg, data reuse, data preparation) as well as those related to people and organizational issues (eg, sociotechnical factors and organizational factors). Examples of these are described in further detail and a formal framework for describing these findings is presented. Significant challenges face researchers attempting to use often diverse and heterogeneous datasets for CER. These challenges must be understood in order to be dealt with successfully and can often be overcome with the appropriate use of informatics best practices. Many research and policy questions remain to be answered in order to realize the full potential of the increasingly electronic clinical data available for such research.

Dissemination and Adoption of Comparative Effectiveness Research Findings When Findings Challenge Current Practices

PubMed Central

Schneider, Eric C.; Timbie, Justin W.; Fox, D. Steven; Van Busum, Kristin R.; Caloyeras, John P.

2013-01-01

Abstract Insufficient evidence regarding the effectiveness of medical treatments has been identified as a key source of inefficiency in the U.S. healthcare system. Variation in the use of diagnostic tests and treatments for patients with similar symptoms or conditions has been attributed to clinical uncertainty, since the published scientific evidence base does not provide adequate information to determine which treatments are most effective for patients with specific clinical needs. The federal government has made a dramatic investment in comparative effectiveness research (CER), with the expectation that CER will influence clinical practice and improve the efficiency of healthcare delivery. To do this, CER must provide information that supports fundamental changes in healthcare delivery and informs the choice of diagnostic and treatment strategies. This article summarizes findings from a qualitative analysis of the factors that impede the translation of CER into clinical practice and those that facilitate it. A case-study methodology is used to explore the extent to which these factors led to changes in clinical practice following five recent key CER studies. The enabling factors and barriers to translation for each study are discussed, the root causes for the failure of translation common to the studies are synthesized, and policy options that may optimize the impact of future CER—particularly CER funded through the American Recovery and Reinvestment Act of 2009—are proposed. PMID:28083277

Looking at CER from the managed care organization perspective.

PubMed

Cannon, H Eric

2012-05-01

The amount of available comparative effectiveness research (CER) is increasing, giving managed care organizations (MCOs) more information to use in decision making. However, MCOs may not be prepared to integrate this new and voluminous data into their current practices and policies. To describe ways that health care reform will affect MCO populations in the future, to examine examples of how MCOs have utilized CER data in the past, and to identify questions that MCOs will have to address as they integrate CER into future decision making. Unquestionably, health care reform will change the U.S. market. Millions more insured individuals will be making purchasing decisions. In addition, health care reform will mean more CER data will be available, affecting the decisions MCOs must make. In the past, MCOs may not have used CER as effectively as they could in making formulary and other policy decisions. However, there are examples that show how CER can be integrated effectively, such as Intermountain Healthcare's use of CER to create treatment guidelines, which have been shown to lower costs and improve delivery of care. In the future, MCOs will need to assess their own abilities to utilize CER, including their infrastructure of expertise, hardware, software, and protocols and processes. MCOs will also need to understand how pertinent CER is to their own needs, how it may affect benefit design, and how it will affect their customers' needs. Health care reform, and the resultant growth of CER, will have significant impact on MCOs, who will need to invest in better infrastructure and new understandings of a transforming market, changing customer bases, and evolving data.

Health technology assessment and comparative effectiveness research: a pharmaceutical industry perspective.

PubMed

Hao, Yanni; Thomas, Adrian

2013-08-01

We briefly review the characteristics of several established health technology assessment (HTA) programs in industrialized societies including Germany, the UK and France. Special attention is paid on two issues: the position of HTA in coverage decision making and the role of economic assessment in evaluation processes. Although law makers in the USA have barred the use of NICE's cost/quality-adjusted life year or similar health economics approaches by public payers for coverage decision making, there are suggestions of prioritizing relative efficacy evaluation over economic assessment under a comparative effectiveness research (CER) framework to inform payment rates of public payers (an approach similar to German and French HTA processes). However, such an approach is unlikely to prove viable. It should also be noted that, if cost considerations are made explicit in US CER policy decisions, CER may become an unsustainable approach undermined by a conflicting emphasis on both cost containment and a demand for costly comparative evidence. On the other hand, properly designed CER initiatives can serve as a facilitator of more efficient research activities and drug development models. With these points in mind, the likely pathway of US CER is explored and the plausible impact on industry innovation is discussed.

The missing link in preconceptional care: the role of comparative effectiveness research.

PubMed

Salihu, Hamisu M; Salinas, Abraham; Mogos, Mulubrhan

2013-07-01

This paper discusses an important element that is missing from the existing algorithm of preconception care, namely, comparative effectiveness research (CER). To our knowledge, there has been limited assessment of the comparative effectiveness of diverse interventions that promote preconception health, conditions under which these are most effective, for which particular populations, and their comparative costs. CER can improve the decision making process for the funding, development, implementation, and evaluation of comprehensive preconception care programs, specifically by identifying the most effective interventions with acceptable costs to society. This paper will examine the framework behind preconception care and how the inclusion of comparative effectiveness research and evaluation into the existing algorithm of preconception care could foster improvement in maternal and child health. We discuss challenges and opportunities regarding the utilization of CER in the decision making process in preconception health, and finally, we provide recommendations for future directions.

The Missing Link in Preconceptional Care: The Role of Comparative Effectiveness Research

PubMed Central

Salihu, Hamisu M.; Salinas, Abraham; Mogos, Mulubrhan

2012-01-01

This paper discusses an important element that is missing from the existing algorithm of preconception care, namely, comparative effectiveness research (CER). To our knowledge, there has been limited assessment of the comparative effectiveness of diverse interventions that promote preconception health, conditions under which these are most effective, for which particular populations, and their comparative costs. CER can improve the decision making process for the funding, development, implementation, and evaluation of comprehensive preconception care programs, specifically by identifying the most effective interventions with acceptable costs to society. This paper will examine the framework behind preconception care and how the inclusion of comparative effectiveness research and evaluation into the existing algorithm of preconception care could foster improvement in maternal and child health. We discuss challenges and opportunities regarding the utilization of CER in the decision making process in preconception health, and finally, we provide recommendations for future directions. PMID:22718466

Stakeholder assessment of comparative effectiveness research needs for Medicaid populations.

PubMed

Fischer, Michael A; Allen-Coleman, Cora; Farrell, Stephen F; Schneeweiss, Sebastian

2015-09-01

Patients, providers and policy-makers rely heavily on comparative effectiveness research (CER) when making complex, real-world medical decisions. In particular, Medicaid providers and policy-makers face unique challenges in decision-making because their program cares for traditionally underserved populations, especially children, pregnant women and people with mental illness. Because these patient populations have generally been underrepresented in research discussions, CER questions for these groups may be understudied. To address this problem, the Agency for Healthcare Research and Quality commissioned our team to work with Medicaid Medical Directors and other stakeholders to identify relevant CER questions. Through an iterative process of topic identification and refinement, we developed relevant, feasible and actionable questions based on issues affecting Medicaid programs nationwide. We describe challenges and limitations and provide recommendations for future stakeholder engagement.

Stakeholder assessment of comparative effectiveness research needs for Medicaid populations

PubMed Central

Fischer, Michael A; Allen-Coleman, Cora; Farrell, Stephen F; Schneeweiss, Sebastian

2015-01-01

Patients, providers and policy-makers rely heavily on comparative effectiveness research (CER) when making complex, real-world medical decisions. In particular, Medicaid providers and policy-makers face unique challenges in decision-making because their program cares for traditionally underserved populations, especially children, pregnant women and people with mental illness. Because these patient populations have generally been underrepresented in research discussions, CER questions for these groups may be understudied. To address this problem, the Agency for Healthcare Research and Quality commissioned our team to work with Medicaid Medical Directors and other stakeholders to identify relevant CER questions. Through an iterative process of topic identification and refinement, we developed relevant, feasible and actionable questions based on issues affecting Medicaid programs nationwide. We describe challenges and limitations and provide recommendations for future stakeholder engagement. PMID:26388438

Got CER? Educating Pharmacists for Practice in the Future: New Tools for New Challenges.

PubMed

Perfetto, Eleanor M; Anyanwu, Chinenye; Pickering, Matthew K; Zaghab, Roxanne Ward; Graff, Jennifer S; Eichelberger, Bernadette

2016-06-01

Understanding how treatments work in the real world and in real patients is an important and complex task. In recent years, comparative effectiveness research (CER) studies have become more available for health care providers to inform evidence-based decision making. There is variability in the strengths and limitations of this new evidence, and researchers and decision makers are faced with challenges when assessing the quality of these new methods and CER studies. To (a) describe an online tool developed by the CER Collaborative, composed of the Academy of Managed Care Pharmacy, the International Society for Pharmacoeconomics and Outcomes Research, and the National Pharmaceutical Council, and (b) provide an early evaluation of the training program impact on learners' self-reported abilities to evaluate and incorporate CER studies into their decision making. To encourage greater transparency, consistency, and uniformity in the development and assessment of CER studies, the CER Collaborative developed an online tool to assist researchers, new and experienced clinicians, and decision makers in producing and evaluating CER studies. A training program that supports the use of the online tool was developed to improve the ability and confidence of individuals to apply CER study findings in their daily work. Seventy-one health care professionals enrolled in 3 separate cohorts for the training program. Upon completion, learners assessed their abilities to interpret and apply findings from CER studies by completing on online evaluation questionnaire. The first 3 cohorts of learners to complete the training program consisted of 71 current and future health care practitioners and researchers. At completion, learners indicated high confidence in their CER evidence assessment abilities (mean = 4.2). Learners reported a 27.43%-59.86% improvement in capabilities to evaluate various CER studies and identify study design flaws (mean evaluation before CER Certificate Program [CCP] scores = 1.86-3.14 and post-CCP scores = 3.92-4.24). Additionally, 63% of learners indicated that they expected to increase their use of evidence from CER studies in at least 1-2 problem decisions per month. The CER Collaborative has responded to the need for increased practitioner training to improve understanding and application of new CER studies. The CER Collaborative tool and certificate training program are innovative solutions to help decision makers meet the challenges they face in honing their skills to best incorporate credible and relevant CER evidence into their decision making. The CER Collaborative, the development of the questionnaires and web-based tool, and the development of the CER Certificate Program were supported by grants and in-kind contributions from the Academy of Managed Care Pharmacy (AMCP), the International Society for Pharmacoeconomics and Outcomes Research (ISPOR), and the National Pharmaceutical Council (NPC). The University of Maryland School of Pharmacy conducted its work under a contract with the AMCP Foundation and grant funding from the NPC. Perfetto is employed by the University of Maryland and the National Health Council and serves as assistant editor for the Journal of Managed Care & Specialty Pharmacy, consults for Avelere, and serves as a member of advisory boards for the PQA and CMTP. Pickering received support from the NPC for activities related to this research. Eichelberger is employed by the Academy of Managed Care Pharmacy. Eichelberger and Graff are with the CER Collaborative. Graff is employed by the National Pharmaceutical Council. Study concept and design were primarily contributed by Perfetto, Graff, and Eichelberger, along with Anyanwu and assisted by Pickering and Ward Zaghab. Pickering and Ward Zaghab took the lead in data collection, with assistance from the other authors, and data interpretation was performed by Perfetto, Graff, Pickering, and Ward Zaghab, with assistance from the other authors. The manuscript was written by Perfetto and Anyanwu, with assistance from the other authors, and revised by Graff, Perfetto, Anyanwu, and Pickering, assisted by Eichelberger and Ward Zaghab.

Global comparative healthcare effectiveness research: evaluating sustainable programmes in low & middle resource settings.

PubMed

Balkrishnan, Rajesh; Chang, Jongwha; Patel, Isha; Yang, Fang; Merajver, Sofia D

2013-03-01

The need to focus healthcare expenditures on innovative and sustainable health systems that efficiently use existing effective therapies are the major drivers stimulating Comparative Effectiveness Research (CER) across the globe. Lack of adequate access and high cost of essential medicines and technologies in many countries increases morbidity and mortality and cost of care that forces people and families into poverty due to disability and out-of-pocket expenses. This review illustrates the potential of value-added global health care comparative effectiveness research in shaping health systems and health care delivery paradigms in the "global south". Enabling the development of effective CER systems globally paves the way for tangible local and regional definitions of equity in health care because CER fosters the sharing of critical assets, resources, skills, and capabilities and the development of collaborative of multi-sectorial frameworks to improve health outcomes and metrics globally.

Comparative effectiveness research (CER): a summary of AHRQ's CER on therapies for rheumatoid arthritis.

PubMed

Oderda, Gary M; Balfe, Lisa M

2011-01-01

In recent years, the U.S. government has designated funding of several large-scale initiatives for comparative effectiveness research (CER) in health care. The American Recovery and Reinvestment Act (ARRA) of 2009 apportioned more than $1 billion to support CER programs administered by the Department of Health and Human Services (DHHS), the National Institutes of Health (NIH), and the Agency for Healthcare Research and Quality (AHRQ). CER is generally defined as the undertaking of original research or systematic reviews of published literature in order to compare the benefits and risks of different approaches to preventing, diagnosing, or treating diseases. These approaches may include diagnostic tests, medications, medical devices, and surgeries. The overall goals of CER are to support informed health care decisions by patients, clinicians, payers, and policy makers and to apply its evidence to ultimately improve the quality, effectiveness, and efficiency of health care. To (a) provide managed care professionals with general definitions of CER, specifically as it is administered by AHRQ; (b) discuss the importance of CER to clinical and managed care pharmacists; and (c) summarize key methods and findings from AHRQ's 2007 comparative effectiveness review on therapies for rheumatoid arthritis (RA). As supported by AHRQ, CER is conducted in order to synthesize comprehensive evidence on the comparative benefits and harms of treatment interventions. The findings from comparative effectiveness reviews can thus contribute to informing therapeutic strategies and treatment decisions. In 2007, a multitude of RA treatment options and studies motivated AHRQ to commission a systematic comparative effectiveness review. Conducted by investigators at the RTI-University of North Carolina Evidence-Based Practice Center, the review included comparisons of synthetic disease-modifying antirheumatic drugs (DMARDs), biologic agents, synthetic DMARDs versus biologic agents, and various combination therapies. Head-to-head comparisons of synthetic DMARDs generally revealed no significant differences in long-term clinical and radiographic outcomes, or in functional capacity or health-related quality of life. Two nonrandomized prospective cohort studies and 1 open-label effectiveness trial reported no differences in ACR20 and ACR50 response rates in patients treated with the tissue necrosis factor (TNF)-alpha inhibitors etanercept and infliximab. Comparisons of TNF-alpha inhibitors generally indicated no significant differences in rates of adverse events, including serious infections, and no increases in rates over time. In comparisons of a biologic agent combined with methotrexate versus a biologic agent alone, combination therapies were generally associated with better clinical response rates and better outcomes of functional capacity and quality of life. The most common adverse events observed in studies on biologic agents were diarrhea, headache, nausea, rhinitis, injection site reactions, and upper respiratory tract infections.

A survey of informatics platforms that enable distributed comparative effectiveness research using multi-institutional heterogeneous clinical data

PubMed Central

Sittig, Dean F.; Hazlehurst, Brian L.; Brown, Jeffrey; Murphy, Shawn; Rosenman, Marc; Tarczy-Hornoch, Peter; Wilcox, Adam B.

2012-01-01

Comparative Effectiveness Research (CER) has the potential to transform the current healthcare delivery system by identifying the most effective medical and surgical treatments, diagnostic tests, disease prevention methods and ways to deliver care for specific clinical conditions. To be successful, such research requires the identification, capture, aggregation, integration, and analysis of disparate data sources held by different institutions with diverse representations of the relevant clinical events. In an effort to address these diverse demands, there have been multiple new designs and implementations of informatics platforms that provide access to electronic clinical data and the governance infrastructure required for inter-institutional CER. The goal of this manuscript is to help investigators understand why these informatics platforms are required and to compare and contrast six, large-scale, recently funded, CER-focused informatics platform development efforts. We utilized an 8-dimension, socio-technical model of health information technology use to help guide our work. We identified six generic steps that are necessary in any distributed, multi-institutional CER project: data identification, extraction, modeling, aggregation, analysis, and dissemination. We expect that over the next several years these projects will provide answers to many important, and heretofore unanswerable, clinical research questions. PMID:22692259

Applications of propensity score methods in observational comparative effectiveness and safety research: where have we come and where should we go?

PubMed

Borah, Bijan J; Moriarty, James P; Crown, William H; Doshi, Jalpa A

2014-01-01

Propensity score (PS) methods have proliferated in recent years in observational studies in general and in observational comparative effectiveness research (CER) in particular. PS methods are an important set of tools for estimating treatment effects in observational studies, enabling adjustment for measured confounders in an easy-to-understand and transparent way. This article demonstrates how PS methods have been used to address specific CER questions from 2001 through to 2012 by identifying six impactful studies from this period. This article also discusses areas for improvement, including data infrastructure, and a unified set of guidelines in terms of PS implementation and reporting, which will boost confidence in evidence generated through observational CER using PS methods.

Observational methods in comparative effectiveness research.

PubMed

Concato, John; Lawler, Elizabeth V; Lew, Robert A; Gaziano, J Michael; Aslan, Mihaela; Huang, Grant D

2010-12-01

Comparative effectiveness research (CER) may be defined informally as an assessment of available options for treating specific medical conditions in selected groups of patients. In this context, the most prominent features of CER are the various patient populations, medical ailments, and treatment options involved in any particular project. Yet, each research investigation also has a corresponding study design or "architecture," and in patient-oriented research a common distinction used to describe such designs are randomized controlled trials (RCTs) versus observational studies. The purposes of this overview, with regard to CER, are to (1) understand how observational studies can provide accurate results, comparable to RCTs; (2) recognize strategies used in selected newer methods for conducting observational studies; (3) review selected observational studies from the Veterans Health Administration; and (4) appreciate the importance of fundamental methodological principles when conducting or evaluating individual studies. Published by Elsevier Inc.

Young adult and parent stakeholder perspectives on participation in patient-centered comparative effectiveness research.

PubMed

Saunders, Tully; Mackie, Thomas I; Shah, Supriya; Gooding, Holly; de Ferranti, Sarah D; Leslie, Laurel K

2016-08-01

Explore perspectives of adolescent and young adult (AYA) and parent stakeholders regarding their engagement in comparative effectiveness research (CER) evaluating cholesterol screening and treatment strategies for 17-21 year olds. All nine AYAs and parent stakeholders participating in a 20-member panel of AYAs, parents and professionals (i.e., clinicians, researchers, policy makers, payers), completed a quantitative survey and a semistructured interview at the completion of the core CER study. AYAs and parents stakeholders emphasized the role of power differentials regarding shared knowledge, relationships and trust, and logistics. To mitigate power differentials, stakeholders recommended more materials, clearer definition of roles and in-person meetings. Perceived positive outcomes included diversity of perspectives provided, better understanding their own health and decision-making and improving CER.

Publication of comparative effectiveness research has not increased in high-impact medical journals, 2004-2013.

PubMed

Hester, Laura L; Poole, Charles; Suarez, Elizabeth A; Der, Jane S; Anderson, Olivia G; Almon, Kathryn G; Shirke, Avanti V; Brookhart, M Alan

2017-04-01

To explore the impact of increasing interest and investment in patient-centered research, this study sought to describe patterns of comparative effectiveness research (CER) and patient-reported outcomes (PROs) in pharmacologic intervention studies published in widely read medical journals from 2004-2013. We identified 2335 articles published in five widely read medical journals from 2004-2013 with ≥1 intervention meeting the US Food and Drug Administration's definitions for a drug, biologic, or vaccine. Six trained reviewers extracted characteristics from a 20% random sample of articles (468 studies). We calculated the proportion of studies with CER and PROs. Trends were summarized using locally-weighted means and 95% confidence intervals. Of the 468 sampled studies, 30% used CER designs and 33% assessed PROs. The proportion of studies using CER designs did not meaningfully increase over the study period. However, we observed an increase in the use of PROs. Among pharmacological intervention studies published in widely read medical journals from 2004-2013, we identified no increase in CER. Randomized, placebo-controlled trials continue to be the dominant study design for assessing pharmacologic interventions. Increasing trends in PRO use may indicate greater acceptance of these outcomes as evidence for clinical benefit. Copyright © 2017 Elsevier Inc. All rights reserved.

Prioritizing comparative effectiveness research for cancer diagnostics using a regional stakeholder approach.

PubMed

Klein, Gregory; Gold, Laura S; Sullivan, Sean D; Buist, Diana S M; Ramsey, Scott; Kreizenbeck, Karma; Snell, Kyle; Loggers, Elizabeth Trice; Gifford, Joseph; Watkins, John B; Kessler, Larry

2012-05-01

This paper describes our process to engage regional stakeholders for prioritizing comparative effectiveness research (CER) in cancer diagnostics. We also describe a novel methodology for incorporating stakeholder data and input to inform the objectives of selected CER studies. As an integrated component to establishing the infrastructure for community-based CER on diagnostic technologies, we have assembled a regional stakeholder group composed of local payers, clinicians and state healthcare representatives to not only identify and prioritize CER topics most important to the western Washington State region, but also to inform the study design of selected research areas. A landscape analysis process combining literature searches, expert consultations and stakeholder discussions was used to identify possible CER topics in cancer diagnostics. Stakeholders prioritized the top topics using a modified Delphi/group-nominal method and a standardized evaluation criteria framework to determine a final selected CER study area. Implementation of the selected study was immediate due to a unique American Recovery and Reinvestment Act funding structure involving the same researchers and stakeholders in both the prioritization and execution phases of the project. Stakeholder engagement was enhanced after study selection via a rapid analysis of a subset of payers' internal claims, coordinated by the research team, to obtain summary data of imaging patterns of use. Results of this preliminary analysis, which we termed an 'internal analysis,' were used to determine with the stakeholders the most important and feasible study objectives. Stakeholders identified PET and MRI in cancers including breast, lung, lymphoma and colorectal as top priorities. In an internal analysis of breast cancer imaging, summary data from three payers demonstrated utilization rates of advanced imaging increased between 2002 and 2009 in the study population, with a great deal of variability in use between different health plans. Assessing whether breast MRI affects treatment decisions was the top breast cancer study objective selected by the stakeholders. There were other high-priority research areas including whether MRI use improved survival that were not deemed feasible with the length of follow-up time following MRI adoption. Continuous stakeholder engagement greatly enhanced their enthusiasm for the project. We believe CER implementation will be more successful when undertaken by regional stakeholders.

Effectiveness guidance document (EGD) for Chinese medicine trials: a consensus document

PubMed Central

2014-01-01

Background There is a need for more Comparative Effectiveness Research (CER) on Chinese medicine (CM) to inform clinical and policy decision-making. This document aims to provide consensus advice for the design of CER trials on CM for researchers. It broadly aims to ensure more adequate design and optimal use of resources in generating evidence for CM to inform stakeholder decision-making. Methods The Effectiveness Guidance Document (EGD) development was based on multiple consensus procedures (survey, written Delphi rounds, interactive consensus workshop, international expert review). To balance aspects of internal and external validity, multiple stakeholders, including patients, clinicians, researchers and payers were involved in creating this document. Results Recommendations were developed for “using available data” and “future clinical studies”. The recommendations for future trials focus on randomized trials and cover the following areas: designing CER studies, treatments, expertise and setting, outcomes, study design and statistical analyses, economic evaluation, and publication. Conclusion The present EGD provides the first systematic methodological guidance for future CER trials on CM and can be applied to single or multi-component treatments. While CONSORT statements provide guidelines for reporting studies, EGDs provide recommendations for the design of future studies and can contribute to a more strategic use of limited research resources, as well as greater consistency in trial design. PMID:24885146

Doctor knows best: physician endorsements, public opinion, and the politics of comparative effectiveness research.

PubMed

Gerber, Alan S; Patashnik, Eric M; Doherty, David; Dowling, Conor M

2014-02-01

The Obama administration has made a major investment in comparative effectiveness research (CER) to learn what treatments work best for which patients. CER has the potential to reduce wasteful medical spending and improve patient outcomes, but the political sustainability of this initiative remains unclear because of concerns that it will threaten the doctor-patient relationship. An unresolved question is whether it is possible to boost public support for the use of CER as a cost-control strategy. We investigate one potential source of public support: Americans' trust in physicians as faithful agents of patient interests. We conducted two national surveys to explore the public's confidence in doctors compared to other groups. We find that doctors are viewed as harder workers, more trustworthy, and more caring than other professionals. Through survey experiments, we demonstrate that the support of doctors' groups for proposals to control costs and use CER have a greater influence on aggregate public opinion than do cues from political actors including congressional Democrats, Republicans, and a bipartisan commission. Our survey results suggest that the medical profession's stance will be an important factor in shaping the political viability of efforts to use CER as a tool for health care cost control.

Opportunities and challenges for comparative effectiveness research (CER) with Electronic Clinical Data: a perspective from the EDM forum.

PubMed

Holve, Erin; Segal, Courtney; Hamilton Lopez, Marianne

2012-07-01

The Electronic Data Methods (EDM) Forum brings together perspectives from the Prospective Outcome Systems using Patient-specific Electronic data to Compare Tests and therapies (PROSPECT) studies, the Scalable Distributed Research Networks, and the Enhanced Registries projects. This paper discusses challenges faced by the research teams as part of their efforts to develop electronic clinical data (ECD) infrastructure to support comparative effectiveness research (CER). The findings reflect a set of opportunities for transdisciplinary learning, and will ideally enhance the transparency and generalizability of CER using ECD. Findings are based on 6 exploratory site visits conducted under naturalistic inquiry in the spring of 2011. Themes, challenges, and innovations were identified in the visit summaries through coding, keyword searches, and review for complex concepts. : The identified overarching challenges and emerging opportunities include: the substantial level of effort to establish and sustain data sharing partnerships; the importance of understanding the strengths and limitations of clinical informatics tools, platforms, and models that have emerged to enable research with ECD; the need for rigorous methods to assess data validity, quality, and context for multisite studies; and, emerging opportunities to achieve meaningful patient and consumer engagement and work collaboratively with multidisciplinary teams. The new infrastructure must evolve to serve a diverse set of potential users and must scale to address a range of CER or patient-centered outcomes research (PCOR) questions. To achieve this aim-to improve the quality, transparency, and reproducibility of CER and PCOR-a high level of collaboration and support is necessary to foster partnership and best practices as part of the EDM Forum.

Comparative effectiveness research designs: an analysis of terms and coverage in Medical Subject Headings (MeSH) and Emtree*†

PubMed Central

Bekhuis, Tanja; Demner-Fushman, Dina; Crowley, Rebecca S.

2013-01-01

Objectives: We analyzed the extent to which comparative effectiveness research (CER) organizations share terms for designs, analyzed coverage of CER designs in Medical Subject Headings (MeSH) and Emtree, and explored whether scientists use CER design terms. Methods: We developed local terminologies (LTs) and a CER design terminology by extracting terms in documents from five organizations. We defined coverage as the distribution over match type in MeSH and Emtree. We created a crosswalk by recording terms to which design terms mapped in both controlled vocabularies. We analyzed the hits for queries restricted to titles and abstracts to explore scientists' language. Results: Pairwise LT overlap ranged from 22.64% (12/53) to 75.61% (31/41). The CER design terminology (n = 78 terms) consisted of terms for primary study designs and a few terms useful for evaluating evidence, such as opinion paper and systematic review. Patterns of coverage were similar in MeSH and Emtree (gamma = 0.581, P = 0.002). Conclusions: Stakeholder terminologies vary, and terms are inconsistently covered in MeSH and Emtree. The CER design terminology and crosswalk may be useful for expert searchers. For partially mapped terms, queries could consist of free text for modifiers such as nonrandomized or interrupted added to broad or related controlled terms. PMID:23646024

Enhancing Cancer Registry Data for Comparative Effectiveness Research (CER) Project: Overview and Methodology

PubMed Central

Chen, Vivien W.; Eheman, Christie R.; Johnson, Christopher J.; Hernandez, Monique N.; Rousseau, David; Styles, Timothy S.; West, Dee W.; Hsieh, Meichin; Hakenewerth, Anne M.; Celaya, Maria O.; Rycroft, Randi K.; Wike, Jennifer M.; Pearson, Melissa; Brockhouse, Judy; Mulvihill, Linda G.; Zhang, Kevin B.

2015-01-01

Following the Institute of Medicine's 2009 report on the national priorities for comparative effectiveness research (CER), funding for support of CER became available in 2009 through the American Recovery and Reinvestment Act. The Centers for Disease Control and Prevention (CDC) received funding to enhance the infrastructure of population-based cancer registries and to expand registry data collection to support CER. The CDC established 10 specialized registries within the National Program of Cancer Registries (NPCR) to enhance data collection for all cancers and to address targeted CER questions, including the clinical use and prognostic value of specific biomarkers. The project also included a special focus on detailed first course of treatment for cancers of the breast, colon, and rectum, as well as chronic myeloid leukemia (CML) diagnosed in 2011. This paper describes the methodology and the work conducted by the CDC and the NPCR specialized registries in collecting data for the 4 special focused cancers, including the selection of additional data variables, development of data collection tools and software modifications, institutional review board approvals, training, collection of detailed first course of treatment, and quality assurance. It also presents the characteristics of the study population and discusses the strengths and limitations of using population-based cancer registries to support CER as well as the potential future role of population-based cancer registries in assessing the quality of patient care and cancer control. PMID:25419602

Enhancing cancer registry data for comparative effectiveness research (CER) project: overview and methodology.

PubMed

Chen, Vivien W; Eheman, Christie R; Johnson, Christopher J; Hernandez, Monique N; Rousseau, David; Styles, Timothy S; West, Dee W; Hsieh, Meichin; Hakenewerth, Anne M; Celaya, Maria O; Rycroft, Randi K; Wike, Jennifer M; Pearson, Melissa; Brockhouse, Judy; Mulvihill, Linda G; Zhang, Kevin B

2014-01-01

Following the Institute of Medicine's 2009 report on the national priorities for comparative effectiveness research (CER), funding for support of CER became available in 2009 through the American Recovery and Re-investment Act. The Centers for Disease Control and Prevention (CDC) received funding to enhance the infrastructure of population-based cancer registries and to expand registry data collection to support CER. The CDC established 10 specialized registries within the National Program of Cancer Registries (NPCR) to enhance data collection for all cancers and to address targeted CER questions, including the clinical use and prognostic value of specific biomarkers. The project also included a special focus on detailed first course of treatment for cancers of the breast, colon, and rectum, as well as chronic myeloid leukemia (CML) diagnosed in 2011. This paper describes the methodology and the work conducted by the CDC and the NPCR specialized registries in collecting data for the 4 special focused cancers, including the selection of additional data variables, development of data collection tools and software modifications, institutional review board approvals, training, collection of detailed first course of treatment, and quality assurance. It also presents the characteristics of the study population and discusses the strengths and limitations of using population-based cancer registries to support CER as well as the potential future role of population-based cancer registries in assessing the quality of patient care and cancer control.

Comparative Effectiveness Research, Genomics-Enabled Personalized Medicine, and Rapid Learning Health Care: A Common Bond

PubMed Central

Ginsburg, Geoffrey S.; Kuderer, Nicole M.

2012-01-01

Despite stunning advances in our understanding of the genetics and the molecular basis for cancer, many patients with cancer are not yet receiving therapy tailored specifically to their tumor biology. The translation of these advances into clinical practice has been hindered, in part, by the lack of evidence for biomarkers supporting the personalized medicine approach. Most stakeholders agree that the translation of biomarkers into clinical care requires evidence of clinical utility. The highest level of evidence comes from randomized controlled clinical trials (RCTs). However, in many instances, there may be no RCTs that are feasible for assessing the clinical utility of potentially valuable genomic biomarkers. In the absence of RCTs, evidence generation will require well-designed cohort studies for comparative effectiveness research (CER) that link detailed clinical information to tumor biology and genomic data. CER also uses systematic reviews, evidence-quality appraisal, and health outcomes research to provide a methodologic framework for assessing biologic patient subgroups. Rapid learning health care (RLHC) is a model in which diverse data are made available, ideally in a robust and real-time fashion, potentially facilitating CER and personalized medicine. Nonetheless, to realize the full potential of personalized care using RLHC requires advances in CER and biostatistics methodology and the development of interoperable informatics systems, which has been recognized by the National Cancer Institute's program for CER and personalized medicine. The integration of CER methodology and genomics linked to RLHC should enhance, expedite, and expand the evidence generation required for fully realizing personalized cancer care. PMID:23071236

Privacy Technology to Support Data Sharing for Comparative Effectiveness Research: A SYSTEMATIC REVIEW

PubMed Central

Jiang, Xiaoqian; Sarwate, Anand D.; Ohno-Machado, Lucila

2013-01-01

Objective Effective data sharing is critical for comparative effectiveness research (CER), but there are significant concerns about inappropriate disclosure of patient data. These concerns have spurred the development of new technologies for privacy preserving data sharing and data mining. Our goal is to review existing and emerging techniques that may be appropriate for data sharing related to CER. Material and methods We adapted a systematic review methodology to comprehensively search the research literature. We searched 7 databases and applied three stages of filtering based on titles, abstracts, and full text to identify those works most relevant to CER. Results Based on agreement and using the arbitrage of a third party expert, we selected 97 articles for meta-analysis. Our findings are organized along major types of data sharing in CER applications (i.e., institution-to-institution, institution-hosted, and public release). We made recommendations based on specific scenarios. Limitation We limited the scope of our study to methods that demonstrated practical impact, eliminating many theoretical studies of privacy that have been surveyed elsewhere. We further limited our study to data sharing for data tables, rather than complex genomic, set-valued, time series, text, image, or network data. Conclusion State-of-the-art privacy preserving technologies can guide the development of practical tools that will scale up the CER studies of the future. However, many challenges remain in this fast moving field in terms of practical evaluations as well as applications to a wider range of data types. PMID:23774511

Identifying appropriate reference data models for comparative effectiveness research (CER) studies based on data from clinical information systems.

PubMed

Ogunyemi, Omolola I; Meeker, Daniella; Kim, Hyeon-Eui; Ashish, Naveen; Farzaneh, Seena; Boxwala, Aziz

2013-08-01

The need for a common format for electronic exchange of clinical data prompted federal endorsement of applicable standards. However, despite obvious similarities, a consensus standard has not yet been selected in the comparative effectiveness research (CER) community. Using qualitative metrics for data retrieval and information loss across a variety of CER topic areas, we compare several existing models from a representative sample of organizations associated with clinical research: the Observational Medical Outcomes Partnership (OMOP), Biomedical Research Integrated Domain Group, the Clinical Data Interchange Standards Consortium, and the US Food and Drug Administration. While the models examined captured a majority of the data elements that are useful for CER studies, data elements related to insurance benefit design and plans were most detailed in OMOP's CDM version 4.0. Standardized vocabularies that facilitate semantic interoperability were included in the OMOP and US Food and Drug Administration Mini-Sentinel data models, but are left to the discretion of the end-user in Biomedical Research Integrated Domain Group and Analysis Data Model, limiting reuse opportunities. Among the challenges we encountered was the need to model data specific to a local setting. This was handled by extending the standard data models. We found that the Common Data Model from the OMOP met the broadest complement of CER objectives. Minimal information loss occurred in mapping data from institution-specific data warehouses onto the data models from the standards we assessed. However, to support certain scenarios, we found a need to enhance existing data dictionaries with local, institution-specific information.

Bringing liraglutide to market: a CER case study.

PubMed

Oderda, Gary; Sifford-Wilson, S Monet

2012-06-01

Faced with competition from other drugs and therapies, drug manufacturers may be able to use comparative effectiveness research (CER) to help reduce barriers to a new drug's adoption and integration into formularies. But few examples exist to show how CER can be used effectively and whether the data can make a difference. To examine how CER can help strengthen a new drug's entry into the market and integration into formularies, and how ongoing CER might be valuable as a drug is implemented in the real world. A roundtable of 9 representatives from health plans, including formulary decision makers, evaluated how CER in phase 3 development of a new drug can add to the drug's strength of evidence, helping decision makers understand how and where to integrate that drug into a formulary. The round table participants viewed, as a case study, the development of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist for adults with type 2 diabetes that was approved by the FDA in January 2010. With this drug, CER was incorporated into an extensive type 2 diabetes clinical development program, comparing how the drug worked in comparison with other established therapies. Although there are many antidiabetic drugs available for use, patients with type 2 diabetes often need additional agents. The FDA approved liraglutide with the conclusion that benefits of the drug outweighed potential risks but noted the association with pancreatitis in humans and animal data that showed rare medullary thyroid cancer associated with liraglutide. Roundtable participants agreed that while pre-launch CER can be valuable, ongoing real-world research is also important for confirming expected results, identifying additional uses and indications and managing risks. The participants also suggested opportunities for additional CER studies and made recommendations for manufacturers. Roundtable thought leaders agreed that well-planned trial designs incorporating CER result in high-quality evidence that may provide sufficient data to support adoption of a new therapy onto the formulary. When more real-world data become available and confirm the phase 3 clinical trial results, decision makers may be able to use the results to change the drug's position and either lessen or extend its use.

The impact of comparative effectiveness research on interventional pain management: evolution from Medicare Modernization Act to Patient Protection and Affordable Care Act and the Patient-Centered Outcomes Research Institute.

PubMed

Manchikanti, Laxmaiah; Falco, Frank J E; Benyamin, Ramsin M; Helm, Standiford; Parr, Allan T; Hirsch, Joshua A

2011-01-01

The Patient-Centered Outcomes Research Institute (PCORI) was established by the Affordable Care Act of 2010 to promote comparative effectiveness research (CER) to assist patients, clinicians, purchasers, and policy-makers in making informed health decisions by advancing the quality and relevance of evidence concerning the manner in which diseases, disorders, and other health conditions can effectively and appropriately be prevented, diagnosed, treated, monitored, and managed through research and evidence synthesis. The development of PCORI is vested in the Medicare Modernization Act (MMA) and the American Recovery and Reinvestment Act (ARRA). The framework of CER and PCORI describes multiple elements which are vested in all 3 regulations including stakeholder involvement, public participation, and open transparent decision-making process. Overall, PCORI is much more elaborate with significant involvement of stakeholders, transparency, public participation, and open decision-making. However, there are multiple issues concerning the operation of such agencies in the United States including the predecessor of Agency for Healthcare Research and Quality (AHRQ), the Agency for Healthcare Policy and Research (AHCPR), AHRQ Effectiveness Health Care programs, and others. The CER in the United States may be described at cross-roads or at the beginnings of a scientific era of CER and evidence-based medicine (EBM). However the United States suffers as other countries, including the United Kingdom with its National Health Services (NHS) and National Institute for Health and Clinical Excellence (NICE), with major misunderstandings of methodology, an inordinate focus on methodological assessment, lack of understanding of the study design (placebo versus active control), lack of involvement of clinicians, and misinterpretation of the evidence which continues to be disseminated. Consequently, PCORI and CER have been described as government-driven solutions without following the principles of EBM with an extensive focus on costs rather than quality. It also has been stated that the central planning which has been described for PCORI and CER, a term devised to be acceptable, will be used by third party payors to override the physician's best medical judgement and patient's best interest. Further, stakeholders in PCORI are not scientists, are not balanced, and will set an agenda with an ultimate problem of comparative effectiveness and PCORI that it is not based on medical science, but rather on political science and not even under congressional authority, leading to unprecedented negative changes to health care. Thus, PCORI is operating in an ad hoc manner that is incompatible with the principles of evidence-based practice.This manuscript describes the framework of PCORI, and the role of CER and its impact on interventional pain management.

The value of including observational studies in systematic reviews was unclear: a descriptive study.

PubMed

Seida, Jennifer; Dryden, Donna M; Hartling, Lisa

2014-12-01

To evaluate (1) how often observational studies are included in comparative effectiveness reviews (CERs); (2) the rationale for including observational studies; (3) how data from observational studies are appraised, analyzed, and graded; and (4) the impact of observational studies on strength of evidence (SOE) and conclusions. Descriptive study of 23 CERs published through the Effective Health Care Program of the U.S. Agency for Healthcare Research and Quality. Authors searched for observational studies in 20 CERs, of which 18 included a median of 11 (interquartile range, 2-31) studies. Sixteen CERs incorporated the observational studies in their SOE assessments. Seventy-eight comparisons from 12 CERs included evidence from both trials and observational studies; observational studies had an impact on SOE and conclusions for 19 (24%) comparisons. There was diversity across the CERs regarding decisions to include observational studies; study designs considered; and approaches used to appraise, synthesize, and grade SOE. Reporting and methods guidance are needed to ensure clarity and consistency in how observational studies are incorporated in CERs. It was not always clear that observational studies added value in light of the additional resources needed to search for, select, appraise, and analyze such studies. Copyright © 2014 Elsevier Inc. All rights reserved.

The policy debate over public investment in comparative effectiveness research.

PubMed

Rich, Eugene C

2009-06-01

Policy makers across the political spectrum, as well as many clinicians and physician professional associations, have proposed that better information on comparative clinical effectiveness should be a key element of any solution to the US health-care cost crisis. This superficial consensus hides intense disagreements over critical issues essential to any new public effort to promote more comparative effectiveness research (CER). This article reviews the background for these disputes, summarizes the different perspectives represented by policy makers and advocates, and offers a framework to aid both practicing and academic internists in understanding the key elements of the emerging debate. Regarding the fundamental question of "what is CER," disagreements rage over whether value or cost effectiveness should be a consideration, and how specific patient perspectives should be reflected in the development and the use of such research. The question of how to pay for CER invokes controversies over the role of the market in producing such information and the private (e.g., insurers and employers) versus public responsibility for its production. The financing debate further highlights the high stakes of comparative effectiveness research, and the risks of stakeholder interests subverting any public process. Accordingly there are a range of proposals for the federal government's role in prioritization, development, and dissemination of CER. The internal medicine community, with its long history of commitment to scientific medical practice and its leadership in evidence-based medicine, should have a strong interest and play an active role in this debate.

American Recovery and Reinvestment Act-comparative effectiveness research infrastructure investments: emerging data resources, tools and publications.

PubMed

Segal, Courtney; Holve, Erin

2014-11-01

The Recovery Act provided a substantial, one-time investment in data infrastructure for comparative effectiveness research (CER). A review of the publications, data, and tools developed as a result of this support has informed understanding of the level of effort undertaken by these projects. Structured search queries, as well as outreach efforts, were conducted to identify and review resources from American Recovery and Reinvestment Act of 2009 CER projects building electronic clinical data infrastructure. The findings from this study provide a spectrum of productivity across a range of topics and settings. A total of 451 manuscripts published in 192 journals, and 141 data resources and tools were identified and address gaps in evidence on priority populations, conditions, and the infrastructure needed to support CER.

Prioritizing comparative effectiveness research for cancer diagnostics using a regional stakeholder approach

PubMed Central

Klein, Gregory; Gold, Laura S; Sullivan, Sean D; Buist, Diana SM; Ramsey, Scott; Kreizenbeck, Karma; Snell, Kyle; Loggers, Elizabeth Trice; Gifford, Joseph; Watkins, John B; Kessler, Larry

2012-01-01

Aims This paper describes our process to engage regional stakeholders for prioritizing comparative effectiveness research (CER) in cancer diagnostics. We also describe a novel methodology for incorporating stakeholder data and input to inform the objectives of selected CER studies. Materials & methods As an integrated component to establishing the infrastructure for community-based CER on diagnostic technologies, we have assembled a regional stakeholder group composed of local payers, clinicians and state healthcare representatives to not only identify and prioritize CER topics most important to the western Washington State region, but also to inform the study design of selected research areas. A landscape analysis process combining literature searches, expert consultations and stakeholder discussions was used to identify possible CER topics in cancer diagnostics. Stakeholders prioritized the top topics using a modified Delphi/group-nominal method and a standardized evaluation criteria framework to determine a final selected CER study area. Implementation of the selected study was immediate due to a unique American Recovery and Reinvestment Act funding structure involving the same researchers and stakeholders in both the prioritization and execution phases of the project. Stakeholder engagement was enhanced after study selection via a rapid analysis of a subset of payers’ internal claims, coordinated by the research team, to obtain summary data of imaging patterns of use. Results of this preliminary analysis, which we termed an ‘internal analysis,’ were used to determine with the stakeholders the most important and feasible study objectives. Results Stakeholders identified PET and MRI in cancers including breast, lung, lymphoma and colorectal as top priorities. In an internal analysis of breast cancer imaging, summary data from three payers demonstrated utilization rates of advanced imaging increased between 2002 and 2009 in the study population, with a great deal of variability in use between different health plans. Assessing whether breast MRI affects treatment decisions was the top breast cancer study objective selected by the stakeholders. There were other high-priority research areas including whether MRI use improved survival that were not deemed feasible with the length of follow-up time following MRI adoption. Conclusion Continuous stakeholder engagement greatly enhanced their enthusiasm for the project. We believe CER implementation will be more successful when undertaken by regional stakeholders. PMID:23105966

Quantitative and qualitative assessment of real world data comparative effectiveness research of systemic therapies in lung oncology: A systematic review.

PubMed

Peters, Bas J M; Janssen, Vivi E M T; Schramel, Franz M; van de Garde, Ewoudt M W

2016-10-01

The growing interest in comparative effectiveness research (CER) based on data from routine clinical practice also extends towards lung oncology. Although CER studies using real world data (RWD) have the potential to assist clinical decision-making, concerns about the quality and validity of studies with observational data subsist. The primary objective of the present study is to assess the current status of observational CER in the field of lung oncology, both quantitatively as qualitatively. We performed a systematic electronic literature database search in MEDLINE and EMBASE (up to 1 July 2015). The quality of all selected studies was assessed according to the Good ReseArch for Comparative Effectiveness (GRACE) checklist. The first selection included 657 publications. After screening the corresponding abstracts and full-text papers, 38 studies remained. A total of 36 studies included patients with advanced NSCLC. The comparison of the effectiveness of gefitinib versus erlotinib was the main objective in 22% of the studies. The median number of patients per study was 202 (range 21-10064). The number of publications increased over the years whereas the quality score remained stable over the years with several common shortcomings (checklist items M5, D1, D4, D6). The growing interest in clinical oncology CER studies using RWD is reflected in an increasing number of publications in the recent years. The studies have several common methodological shortcomings possibly limiting their applicability in clinical decision-making. To fulfil the promise of RWD CER in lung oncology effort should be continued to overcome these shortcomings. Copyright © 2016 Elsevier Ltd. All rights reserved.

Applying comparative effectiveness research methods in bipolar disorders.

PubMed

McCombs, Jeffrey S; Ganapathy, Vaidyanathan; Zolfaghari, Sara

2011-04-01

Randomized clinical trials [RCT] are the Gold Standard of medical evidence. However, observational comparative effectiveness research [CER] based on real-world data is receiving national attention. This paper demonstrates how observational CER can fill important gaps in clinical knowledge left behind by RCT approaches. An example of CER in bipolar disorders is presented. Paid claims data from a large commercial insurer were used to identify episodes of drug therapy. Episodes were defined each time a patient initiated or restarted therapy using an antipsychotic, antidepressant or mood stabilizing medication. Episode definitions were based on calculations of continuous days of drug therapy using a 15 day gap definition. 105,440 episodes of drug therapy were included in the analysis. Most episodes were initiated using a mood stabilizing drug (40%) or an antidepressant (40%). Over 59% of all episodes were for augmentation therapy, followed by switching episodes (25%) and restart episodes (16%). Patient outcomes measured by either duration of uninterrupted therapy or one-year post-treatment cost varied significantly with patient treatment history, especially episode type. The comparative effectiveness of alternative therapies was sensitive to the extent to which treatment history is taken into account. Observational research can evaluate patient outcomes across a wide range of clinical presentations with regard to the patient's treatment history. Treatment history is a major determinant of patient compliance and future treatment costs. Failure to account for treatment history can introduce bias into comparative effectiveness results. Observational CER research can also uncover important questions that require future research. Copyright © 2010 Elsevier B.V. All rights reserved.

Clinical evidence inputs to comparative effectiveness research could impact the development of novel treatments.

PubMed

Eber, Michael R; Goldman, Dana P; Lakdawalla, Darius N; Philipson, Tomas J; Pritchard, Daryl; Huesch, Marco; Summers, Nicholas; Linthicum, Mark T; Sullivan, Jeff; Dubois, Robert W

2015-05-07

This study aims to analyze the impacts of a range of clinical evidence generation scenarios associated with comparative effectiveness research (CER) on pharmaceutical innovation. We used the Global Pharmaceutical Policy Model to project the effect of changes in pharmaceutical producer costs, revenues and timings on drug innovation and health for the age 55+ populations in the USA and Europe through year 2060 using three clinical scenarios. Changes in producer incentives from widespread CER evidence generation and use had varied but often large predicted impacts on simulated outcomes in 2060. Effect on the number of new drug introductions ranged from a 81.1% reduction to a 45.5% increase, and the effect on population-level life expectancy ranged from a 15.6% reduction to a 11.4% increase compared to baseline estimates. The uncertainty surrounding the consequences of increased clinical evidence generation and use on innovation calls for a carefully measured approach to CER implementation, balancing near-term benefits to spending and health with long-term implications for innovation.

A comprehensive framework for data quality assessment in CER.

PubMed

Holve, Erin; Kahn, Michael; Nahm, Meredith; Ryan, Patrick; Weiskopf, Nicole

2013-01-01

The panel addresses the urgent need to ensure that comparative effectiveness research (CER) findings derived from diverse and distributed data sources are based on credible, high-quality data; and that the methods used to assess and report data quality are consistent, comprehensive, and available to data consumers. The panel consists of representatives from four teams leveraging electronic clinical data for CER, patient centered outcomes research (PCOR), and quality improvement (QI) and seeks to change the current paradigm where data quality assessment (DQA) is performed "behind the scenes" using one-off project specific methods. The panelists will present their process of harmonizing existing models for describing and measuring clinical data quality and will describe a comprehensive integrated framework for assessing and reporting DQA findings. The collaborative project is supported by the Electronic Data Methods (EDM) Forum, a three-year grant from the Agency for Healthcare Research and Quality (AHRQ) to facilitate learning and foster collaboration across a set of CER, PCOR, and QI projects designed to build infrastructure and methods for collecting and analyzing prospective data from electronic clinical data .

Comparative-effectiveness research to aid population decision making by relating clinical outcomes and quality-adjusted life years.

PubMed

Campbell, Jonathan D; Zerzan, Judy; Garrison, Louis P; Libby, Anne M

2013-04-01

Comparative-effectiveness research (CER) at the population level is missing standardized approaches to quantify and weigh interventions in terms of their clinical risks, benefits, and uncertainty. We proposed an adapted CER framework for population decision making, provided example displays of the outputs, and discussed the implications for population decision makers. Building on decision-analytical modeling but excluding cost, we proposed a 2-step approach to CER that explicitly compared interventions in terms of clinical risks and benefits and linked this evidence to the quality-adjusted life year (QALY). The first step was a traditional intervention-specific evidence synthesis of risks and benefits. The second step was a decision-analytical model to simulate intervention-specific progression of disease over an appropriate time. The output was the ability to compare and quantitatively link clinical outcomes with QALYs. The outputs from these CER models include clinical risks, benefits, and QALYs over flexible and relevant time horizons. This approach yields an explicit, structured, and consistent quantitative framework to weigh all relevant clinical measures. Population decision makers can use this modeling framework and QALYs to aid in their judgment of the individual and collective risks and benefits of the alternatives over time. Future research should study effective communication of these domains for stakeholders. Copyright © 2013 Elsevier HS Journals, Inc. All rights reserved.

CER, PBE, SCIRehab, NIDRR, and other important abbreviations.

PubMed

Dijkers, Marcel P; Whiteneck, Gale G; Gassaway, Julie

2013-04-01

Comparative effectiveness research (CER) has been receiving much attention (and government funding) in recent years, stemming from dissatisfaction with much medical and health care research, which does not produce actionable evidence that can be used by clinicians, patients, and policymakers. Rehabilitation research has been characterized by similar weaknesses and by often inadequate research designs. The SCIRehab study of the outcomes of inpatient spinal cord injury rehabilitation is one of a small number of rehabilitation practice-based evidence (PBE) studies in recent years that allows for the comparison of interventions by all disciplines for relevant real-life outcomes. This introduction to a series of articles resulting from the SCIRehab project discusses the need for and the nature of CER, and places the SCIRehab study and other PBE studies in the light of CER. After a description of the highlights of the analyses in this supplement, we provide a preliminary evaluation of SCIRehab, counting the articles and presentations from the study, the resources that went into this vast project, and the lessons learned that may benefit future rehabilitation PBE investigators. Copyright © 2013 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Civil Service Workforce Market Supply and the Effect on Cost Estimating Relationship (CERS) that May Effect the Productivity Factors for Future NASA Missions

NASA Technical Reports Server (NTRS)

Sterk, Steve; Chesley, Stephan

2008-01-01

The upcoming retirement of the Baby Boomers will leave a workforce age gap between the younger generation (the future NASA decision makers) and the gray beards. This paper will reflect on the average age of the workforce across NASA Centers, the Aerospace Industry and other Government Agencies, like DoD. This paper will dig into Productivity and Realization Factors and how they get applied to bi-monthly (payroll) data for true full-time equivalent (FTE) calculations that could be used at each of the NASA Centers and other business systems that are on the forefront in being implemented. This paper offers some comparative costs analysis/solutions, from simple FTE cost-estimating relationships (CERs) versus CERs for monthly time-phasing activities for small research projects that start and get completed within a government fiscal year. This paper will present the results of a parametric study investigating the cost-effectiveness of alternative performance-based CERs and how they get applied into the Center's forward pricing rate proposals (FPRP). True CERs based on the relationship of a younger aged workforce will have some effects on labor rates used in both commercial cost models and other internal home-grown cost models which may impact the productivity factors for future NASA missions.

76 FR 44929 - Agency Information Collection Activities: Proposed Collection; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-27

... proposed information collection project: ``Evaluation of ARRA Comparative Effectiveness Research... INFORMATION: Proposed Project Evaluation of ARRA Comparative Effectiveness Research Dissemination Contractor... for reviewing and disseminating Comparative Effectiveness Research (CER) and findings to clinicians...

Role of comparative effectiveness research in cancer funding decisions in Ontario, Canada.

PubMed

Hoch, Jeffrey S; Hodgson, David C; Earle, Craig C

2012-12-01

Recently, the evidence-based drug funding process in Ontario, Canada, was challenged by a young mother with a breast tumor too small, based on the evidence that existed at the time, to qualify for an expensive drug. In reality, this is only the latest in a number of challenges the publicly funded health care system has had to deal with in the face of an evolving drug policy landscape. This article defines comparative effectiveness research (CER), considering how it is viewed differently in the United States and Canada. It also reviews the role CER now plays in the Ontario drug funding process and concludes with a review of the challenges and opportunities of using observational data to conduct CER and incorporate it into policy making within a universal health care system. Many of the issues faced by Ontario are relevant beyond Canada, including in the United States during this period of health care reform.

Challenges in using electronic health record data for CER: experience of 4 learning organizations and solutions applied.

PubMed

Bayley, K Bruce; Belnap, Tom; Savitz, Lucy; Masica, Andrew L; Shah, Nilay; Fleming, Neil S

2013-08-01

To document the strengths and challenges of using electronic health records (EHRs) for comparative effectiveness research (CER). A replicated case study of comparative effectiveness in hypertension treatment was conducted across 4 health systems, with instructions to extract data and document problems encountered using a specified list of required data elements. Researchers at each health system documented successes and challenges, and suggested solutions for addressing challenges. Data challenges fell into 5 categories: missing data, erroneous data, uninterpretable data, inconsistencies among providers and over time, and data stored in noncoded text notes. Suggested strategies to address these issues include data validation steps, use of surrogate markers, natural language processing, and statistical techniques. A number of EHR issues can hamper the extraction of valid data for cross-health system comparative effectiveness studies. Our case example cautions against a blind reliance on EHR data as a single definitive data source. Nevertheless, EHR data are superior to administrative or claims data alone, and are cheaper and timelier than clinical trials or manual chart reviews. All 4 participating health systems are pursuing pathways to more effectively use EHR data for CER.A partnership between clinicians, researchers, and information technology specialists is encouraged as a way to capitalize on the wealth of information contained in the EHR. Future developments in both technology and care delivery hold promise for improvement in the ability to use EHR data for CER.

A CTSA Agenda to Advance Methods for Comparative Effectiveness Research

PubMed Central

Helfand, Mark; Tunis, Sean; Whitlock, Evelyn P.; Pauker, Stephen G.; Basu, Anirban; Chilingerian, Jon; Harrell Jr., Frank E.; Meltzer, David O.; Montori, Victor M.; Shepard, Donald S.; Kent, David M.

2011-01-01

Abstract Clinical research needs to be more useful to patients, clinicians, and other decision makers. To meet this need, more research should focus on patient‐centered outcomes, compare viable alternatives, and be responsive to individual patients’ preferences, needs, pathobiology, settings, and values. These features, which make comparative effectiveness research (CER) fundamentally patient‐centered, challenge researchers to adopt or develop methods that improve the timeliness, relevance, and practical application of clinical studies. In this paper, we describe 10 priority areas that address 3 critical needs for research on patient‐centered outcomes (PCOR): (1) developing and testing trustworthy methods to identify and prioritize important questions for research; (2) improving the design, conduct, and analysis of clinical research studies; and (3) linking the process and outcomes of actual practice to priorities for research on patient‐centered outcomes. We argue that the National Institutes of Health, through its clinical and translational research program, should accelerate the development and refinement of methods for CER by linking a program of methods research to the broader portfolio of large, prospective clinical and health system studies it supports. Insights generated by this work should be of enormous value to PCORI and to the broad range of organizations that will be funding and implementing CER. Clin Trans Sci 2011; Volume 4: 188–198 PMID:21707950

CYberinfrastructure for COmparative effectiveness REsearch (CYCORE): improving data from cancer clinical trials.

PubMed

Patrick, Kevin; Wolszon, Laura; Basen-Engquist, Karen M; Demark-Wahnefried, Wendy; Prokhorov, Alex V; Barrera, Stephanie; Baru, Chaitan; Farcas, Emilia; Krueger, Ingolf; Palmer, Doug; Raab, Fred; Rios, Phil; Ziftci, Celal; Peterson, Susan

2011-03-01

Improved approaches and methodologies are needed to conduct comparative effectiveness research (CER) in oncology. While cancer therapies continue to emerge at a rapid pace, the review, synthesis, and dissemination of evidence-based interventions across clinical trials lag in comparison. Rigorous and systematic testing of competing therapies has been clouded by age-old problems: poor patient adherence, inability to objectively measure the environmental influences on health, lack of knowledge about patients' lifestyle behaviors that may affect cancer's progression and recurrence, and limited ability to compile and interpret the wide range of variables that must be considered in the cancer treatment. This lack of data integration limits the potential for patients and clinicians to engage in fully informed decision-making regarding cancer prevention, treatment, and survivorship care, and the translation of research results into mainstream medical care. Particularly important, as noted in a 2009 report on CER to the President and Congress, the limited focus on health behavior-change interventions was a major hindrance in this research landscape (DHHS 2009). This paper describes an initiative to improve CER for cancer by addressing several of these limitations. The Cyberinfrastructure for Comparative Effectiveness Research (CYCORE) project, informed by the National Science Foundation's 2007 report "Cyberinfrastructure Vision for 21(st) Century Discovery" has, as its central aim, the creation of a prototype for a user-friendly, open-source cyberinfrastructure (CI) that supports acquisition, storage, visualization, analysis, and sharing of data important for cancer-related CER. Although still under development, the process of gathering requirements for CYCORE has revealed new ways in which CI design can significantly improve the collection and analysis of a wide variety of data types, and has resulted in new and important partnerships among cancer researchers engaged in advancing health-related CI.

Ceramide and Its Related Neurochemical Networks as Targets for Some Brain Disorder Therapies.

PubMed

Brodowicz, Justyna; Przegaliński, Edmund; Müller, Christian P; Filip, Malgorzata

2018-02-01

Correlational and causal comparative research link ceramide (Cer), the precursor of complex sphingolipids, to some psychiatric (e.g., depression, schizophrenia (SZ), alcohol use disorder, and morphine antinociceptive tolerance) and neurological (e.g., Alzheimer's disease (AD), Parkinson disease (PD)) disorders. Cer generation can occur through the de novo synthesis pathway, the sphingomyelinase pathways, and the salvage pathway. The discoveries that plasma Cer concentration increase during depressive episodes in patients and that tricyclic and tetracyclic antidepressants functionally inhibit acid sphingomyelinase (ASM), the enzyme that catalyzes the degradation of sphingomyelin to Cer, have initiated a series of studies on the role of the ASM-Cer system in depressive disorder. Disturbances in the metabolism of Cer or SM are associated with the occurrence of SZ and PD. In both PD and SZ patients, the elevated levels of Cer or SM in the brain regions were associated with the disease. AD patients showed also an abnormal metabolism of brain Cer at early stages of the disease which may suggest Cer as an AD biomarker. In plasma of AD patients and in AD transgenic mice, ASM activity was increased. In contrast, partial ASM inhibition of Aβ deposition improved memory deficits. Furthermore, in clinical and preclinical research, ethanol enhanced activation of ASM followed by Cer production. Limited data have shown that Cer plays an important role in the development of morphine antinociceptive tolerance. In summary, clinical and preclinical findings provide evidence that targeting the Cer system should be considered as an innovative translational strategy for some brain disorders.

Cerebellin in the rat adrenal gland: gene expression and effects of CER and [des-Ser1]CER on the secretion and growth of cultured adrenocortical cells.

PubMed

Rucinski, Marcin; Albertin, Giovanna; Spinazzi, Raffaella; Ziolkowska, Agnieszka; Nussdorfer, Gastone G; Malendowicz, Ludwick K

2005-03-01

Cerebellin (CER) is a regulatory peptide, originally isolated from rat cerebellum, which derives from the cleavage of precerebellin (Cbln), three types of which (Cbln1-3) have been identified in humans and rats. CER is also expressed in several extra-cerebellar tissues, including adrenal gland, and evidence has been provided that CER exerts a modulatory action on human and rat adrenal gland. Hence, we have investigated the expression of Cbln1-3 mRNAs and CER protein-immunoreactivity (IR) in the various zones of rat adrenal glands, and the effects of CER and its metabolite [des-Ser(1)]CER (des-CER) on the secretion and growth of cultured rat adrenocortical cells. Reverse transcription-polymerase chain reaction showed high and low expression of Cbln2 mRNA in zona glomerulosa (ZG) and zona fasciculata-reticularis, respectively. Cbln1 was not expressed, and Cbln3 mRNA was detected only in ZG. No Cbln expression was found in adrenal medulla. Immunocytochemistry demonstrated the presence of CER-IR exclusively in the adrenal cortex, the reaction being more intense in ZG. As expected, ACTH (10(-8) M) markedly enhanced corticosterone secretion and lowered proliferation rate of cultured adrenocortical cells. CER was ineffective, while des-CER exerted an ACTH-like effect, but only at the lowest concentration (10(-10) M). Taken together, these findings allow us to conclude that CER is expressed in rat adrenal cortex, and to suggest that CER conversion to des-CER by endopeptidases is needed for CER to exert its autocrine-paracrine regulatory functions.

Comparisons among Health Behavior Surveys: Implications for the Design of Informatics Infrastructures That Support Comparative Effectiveness Research.

PubMed

Yoon, Sunmoo; Wilcox, Adam B; Bakken, Suzanne

2013-01-01

To address the electronic health data fragmentation that is a methodological limitation of comparative effectiveness research (CER), the Washington Heights Inwood Informatics Infrastructure for Comparative Effectiveness Research (WICER) project is creating a patient-centered research data warehouse (RDW) by linking electronic clinical data (ECD) from New York Presbyterian Hospital's clinical data warehouse with ECD from ambulatory care, long-term care, and home health settings and the WICER community health survey (CHS). The purposes of the research were to identify areas of overlap between the WICER CHS and two other surveys that include health behavior data (the Behavioral Risk Factor Surveillance System (BRFSS) Survey and the New York City Community Health Survey (NYC CHS)) and to identify gaps in the current WICER RDW that have the potential to affect patient-centered CER. We compared items across the three surveys at the item and conceptual levels. We also compared WICER RDW (ECD and WICER CHS), BRFSS, and NYC CHS to the County Health Ranking framework. We found that 22 percent of WICER items were exact matches with BRFSS and that there were no exact matches between WICER CHS and NYC CHS items not also contained in BRFSS. The results suggest that BRFSS and, to a lesser extent, NYC CHS have the potential to serve as population comparisons for WICER CHS for some health behavior-related data and thus may be particularly useful for considering the generalizability of CER study findings. Except for one measure related to health behavior (motor vehicle crash deaths), the WICER RDW's comprehensive coverage supports the mortality, morbidity, and clinical care measures specified in the County Health Ranking framework but is deficient in terms of some socioeconomic factors and descriptions of the physical environment as captured in BRFSS. Linkage of these data in the WICER RDW through geocoding can potentially facilitate patient-centered CER that integrates important socioeconomic and physical environment influences on health outcomes. The research methods and findings may be relevant to others interested in either integrating health behavior data into RDWs to support patient-centered CER or conducting population-level comparisons.

Civil Service Workforce Market Supply and the Effect on the Cost Estimating Relationships (CERs) that may effect the Productivity Factors for Future NASA Missions

NASA Technical Reports Server (NTRS)

Sterk, Steve; Chesley, Stephen

2008-01-01

The upcoming retirement of the Baby Boomers on the horizon will leave a performance gap between younger generation (the future NASA decision makers) and the gray beards. This paper will reflect on the average age of workforce across NASA Centers, the Aerospace Industry and other Government Agencies, like DoD. This papers will dig into Productivity and Realization Factors and how they get applied to bimonthly (payroll data) for true FTE calculations that could be used at each of the NASA Centers and other business systems that are on the forefront in being implemented. This paper offers some comparative costs solutions, from simple - full time equivalent (FTE) cost estimating relationships CERs, to complex - CERs for monthly time-phasing activities for small research projects that start and get completed within a government fiscal year. This paper will present the results of a parametric study investigating the cost-effectiveness of different alternatives performance based cost estimating relationships (CERs) and how they get applied into the Center s forward pricing rate proposals (FPRP). True CERs based on the relationship of a younger aged workforce will have some effects on labor rates used in both commercial cost models and internal home-grown cost models which may impact the productivity factors for future NASA missions.

A framework for assessing the value of diagnostic imaging in the era of comparative effectiveness research.

PubMed

Gazelle, G Scott; Kessler, Larry; Lee, David W; McGinn, Thomas; Menzin, Joseph; Neumann, Peter J; van Amerongen, Derek; White, Leigh Ann

2011-12-01

In June 2009, the Federal Coordinating Council for Comparative Effectiveness Research submitted a report to the President and Congress in which the Council described the purpose of comparative effectiveness research (CER) as developing evidence-based information for interventions and determining under what circumstances an intervention is effective (1). With the enactment of the Patient Protection and Affordable Care Act, a Patient-centered Outcomes Research Institute (PCORI) was established to assist decision makers in making evidence-based health decisions through synthesis and dissemination of clinical CER of health interventions (2). Its founding has underscored a heightened need for health policy makers to consider the impact of health care technologies on final outcomes of interest--for example, functional status, quality of life, disability, major clinical events, and mortality (3-5). © RSNA, 2011.

Optimizing health information technology's role in enabling comparative effectiveness research.

PubMed

Navathe, Amol S; Conway, Patrick H

2010-12-01

Health information technology (IT) is a key enabler of comparative effectiveness research (CER). Health IT standards for data sharing are essential to advancing the research data infrastructure, and health IT is critical to the next step of incorporating clinical data into data sources. Four key principles for advancement of CER are (1) utilization of data as a strategic asset, (2) leveraging public-private partnerships, (3) building robust, scalable technology platforms, and (4) coordination of activities across government agencies. To maximize the value of the resources, payers and providers must contribute data to initiatives, engage with government agencies on lessons learned, continue to develop new technologies that address key challenges, and utilize the data to improve patient outcomes and conduct research.

Caveats for the Use of Operational Electronic Health Record Data in Comparative Effectiveness Research

PubMed Central

Hersh, William R.; Weiner, Mark G.; Embi, Peter J.; Logan, Judith R.; Payne, Philip R.O.; Bernstam, Elmer V.; Lehmann, Harold P.; Hripcsak, George; Hartzog, Timothy H.; Cimino, James J.; Saltz, Joel H.

2013-01-01

The growing amount of data in operational electronic health record (EHR) systems provides unprecedented opportunity for its re-use for many tasks, including comparative effectiveness research (CER). However, there are many caveats to the use of such data. EHR data from clinical settings may be inaccurate, incomplete, transformed in ways that undermine their meaning, unrecoverable for research, of unknown provenance, of insufficient granularity, and incompatible with research protocols. However, the quantity and real-world nature of these data provide impetus for their use, and we develop a list of caveats to inform would-be users of such data as well as provide an informatics roadmap that aims to insure this opportunity to augment CER can be best leveraged. PMID:23774517

77 FR 8871 - Agency Information Collection Activities: Proposed Collection; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-15

... Agency for Healthcare Research and Quality's (AHRQ's) Effective Healthcare (EHC) Program and Comparative... Agency for Healthcare Research and Quality's (AHRQ's) Effective Healthcare (EHC) Program and Comparative... and use of comparative effectiveness research (CER). Although stakeholder engagement has been central...

Recovery Effects of Oral Administration of Glucosylceramide and Beet Extract on Skin Barrier Destruction by UVB in Hairless Mice.

PubMed

Tokudome, Yoshihiro; Masutani, Noriomi; Uchino, Shohei; Fukai, Hisano

2017-10-27

Purified glucosylceramide from beet extract (beet GlcCer) and beet extract containing an equal amount of GlcCer were administered orally to ultra violet B (UVB)-irradiated mice, and differences in the protective effects against skin barrier dysfunction caused by UVB irradiation were compared. In the beet GlcCer group, epidermal thickening and the decrease in stratum corneum (SC) ceramide content caused by UVB irradiation were reduced. In the group that was orally administered beet extract containing glucosylceramide, effects similar to those in the beet GlcCer group were observed. Oral administration of beet GlcCer had no obvious effects against an increase in TEWL or decrease in SC water content after UVB irradiation, but there was improvement in the beet extract group. Oral administration of beet GlcCer is effective in improving skin barrier function in UVB-irradiated mice. Beet extract contains constituents other than GlcCer that are also effective in improving skin barrier function.

Complexation of C6-Ceramide with Cholesteryl Phosphocholine – A Potent Solvent-Free Ceramide Delivery Formulation for Cells in Culture

PubMed Central

Långvik, Otto; Pulli, Ilari; Törnquist, Kid; Slotte, J. Peter

2013-01-01

Ceramides are potent bioactive molecules in cells. However, they are very hydrophobic molecules, and difficult to deliver efficiently to cells. We have made fluid bilayers from a short-chain D-erythro-ceramide (C6-Cer) and cholesteryl phosphocholine (CholPC), and have used this as a formulation to deliver ceramide to cells. C6-Cer complexed with CholPC led to much larger biological effects in cultured cells (rat thyroid FRTL-5 and human HeLa cells in culture) compared to C6-Cer dissolved in dimethyl sulfoxide (DMSO). Inhibition of cell proliferation and induction of apoptosis was significantly more efficient by C6-Cer/CholPC compared to C6-Cer dissolved in DMSO. C6-Cer/CholPC also permeated cell membranes and caused mitochondrial Ca2+ influx more efficiently than C6-Cer in DMSO. Even though CholPC was taken up by cells to some extent (from C6-Cer/CholPC bilayers), and was partially hydrolyzed to free cholesterol (about 9%), none of the antiproliferative effects were due to CholPC or excess cholesterol. The ceramide effect was not limited to D-erythro-C6-Cer, since L-erythro-C6-Cer and D-erythro-C6-dihydroCer also inhibited cell priolifereation and affected Ca2+ homeostasis. We conclude that C6-Cer complexed to CholPC increased the bioavailability of the short-chain ceramide for cells, and potentiated its effects in comparison to solvent-dissolved C6-Cer. This new ceramide formulation appears to be superior to previous solvent delivery approaches, and may even be useful with longer-chain ceramides. PMID:23620740

Making genomic medicine evidence-based and patient-centered: a structured review and landscape analysis of comparative effectiveness research.

PubMed

Phillips, Kathryn A; Deverka, Patricia A; Sox, Harold C; Khoury, Muin J; Sandy, Lewis G; Ginsburg, Geoffrey S; Tunis, Sean R; Orlando, Lori A; Douglas, Michael P

2017-10-01

Comparative effectiveness research (CER) in genomic medicine (GM) measures the clinical utility of using genomic information to guide clinical care in comparison to appropriate alternatives. We summarized findings of high-quality systematic reviews that compared the analytic and clinical validity and clinical utility of GM tests. We focused on clinical utility findings to summarize CER-derived evidence about GM and identify evidence gaps and future research needs. We abstracted key elements of study design, GM interventions, results, and study quality ratings from 21 systematic reviews published in 2010 through 2015. More than half (N = 13) of the reviews were of cancer-related tests. All reviews identified potentially important clinical applications of the GM interventions, but most had significant methodological weaknesses that largely precluded any conclusions about clinical utility. Twelve reviews discussed the importance of patient-centered outcomes, although few described evidence about the impact of genomic medicine on these outcomes. In summary, we found a very limited body of evidence about the effect of using genomic tests on health outcomes and many evidence gaps for CER to address.Genet Med advance online publication 13 April 2017.

Making genomic medicine evidence-based and patient-centered: a structured review and landscape analysis of comparative effectiveness research

PubMed Central

Phillips, Kathryn A.; Deverka, Patricia A.; Sox, Harold C.; Khoury, Muin J.; Sandy, Lewis G.; Ginsburg, Geoffrey S.; Tunis, Sean R.; Orlando, Lori A.; Douglas, Michael P.

2017-01-01

Comparative effectiveness research (CER) in genomic medicine (GM) measures the clinical utility of using genomic information to guide clinical care in comparison to appropriate alternatives. We summarized findings of high-quality systematic reviews that compared the analytic and clinical validity and clinical utility of GM tests. We focused on clinical utility findings to summarize CER-derived evidence about GM and identify evidence gaps and future research needs. We abstracted key elements of study design, GM interventions, results, and study quality ratings from 21 systematic reviews published in 2010 through 2015. More than half (N = 13) of the reviews were of cancer-related tests. All reviews identified potentially important clinical applications of the GM interventions, but most had significant methodological weaknesses that largely precluded any conclusions about clinical utility. Twelve reviews discussed the importance of patient-centered outcomes, although few described evidence about the impact of genomic medicine on these outcomes. In summary, we found a very limited body of evidence about the effect of using genomic tests on health outcomes and many evidence gaps for CER to address. Genet Med advance online publication 13 April 2017 PMID:28406488

Potential Applications of Phyto-Derived Ceramides in Improving Epidermal Barrier Function.

PubMed

Tessema, Efrem N; Gebre-Mariam, Tsige; Neubert, Reinhard H H; Wohlrab, Johannes

2017-01-01

The outer most layer of the skin, the stratum corneum, consists of corneocytes which are coated by a cornified envelope and embedded in a lipid matrix of ordered lamellar structure. It is responsible for the skin barrier function. Ceramides (CERs) are the backbone of the intercellular lipid membranes. Skin diseases such as atopic dermatitis and psoriasis and aged skin are characterized by dysfunctional skin barrier and dryness which are associated with reduced levels of CERs. Previously, the effectiveness of supplementation of synthetic and animal-based CERs in replenishing the depleted natural skin CERs and restoring the skin barrier function have been investigated. Recently, however, the barrier function improving effect of plant-derived CERs has attracted much attention. Phyto-derived CERs (phytoCERs) are preferable due to their assumed higher safety as they are mostly isolated from dietary sources. The beneficial effects of phytoCER-based oral dietary supplements for skin hydration and skin barrier reinforcement have been indicated in several studies involving animal models as well as human subjects. Ingestible dietary supplements containing phytoCERs are also widely available on the market. Nonetheless, little effort has been made to investigate the potential cosmetic applications of topically administered phytoCERs. Therefore, summarizing the foregoing investigations and identifying the gap in the scientific data on plant-derived CERs intended for skin-health benefits are of paramount importance. In this review, an attempt is made to synthesize the information available in the literature regarding the effects of phytoCER-based oral dietary supplements on skin hydration and barrier function with the underlying mechanisms. © 2017 S. Karger AG, Basel.

Different Effects of Long- and Short-Chain Ceramides on the Gel-Fluid and Lamellar-Hexagonal Transitions of Phospholipids: A Calorimetric, NMR, and X-Ray Diffraction Study

PubMed Central

Sot, Jesús; Aranda, Francisco J.; Collado, M.-Isabel; Goñi, Félix M.; Alonso, Alicia

2005-01-01

The effects on dielaidoylphosphatidylethanolamine (DEPE) bilayers of ceramides containing different N-acyl chains have been studied by differential scanning calorimetry small angle x-ray diffraction and 31P-NMR spectroscopy. N-palmitoyl (Cer16), N-hexanoyl (Cer6), and N-acetyl (Cer2) sphingosines have been used. Both the gel-fluid and the lamellar-inverted hexagonal transitions of DEPE have been examined in the presence of the various ceramides in the 0-25 mol % concentration range. Pure hydrated ceramides exhibit cooperative endothermic order-disorder transitions at 93°C (Cer16), 60°C (Cer6), and 54°C (Cer2). In DEPE bilayers, Cer16 does not mix with the phospholipid in the gel phase, giving rise to high-melting ceramide-rich domains. Cer16 favors the lamellar-hexagonal transition of DEPE, decreasing the transition temperature. Cer2, on the other hand, is soluble in the gel phase of DEPE, decreasing the gel-fluid and increasing the lamellar-hexagonal transition temperatures, thus effectively stabilizing the lamellar fluid phase. In addition, Cer2 was peculiar in that no equilibrium could be reached for the Cer2-DEPE mixture above 60°C, the lamellar-hexagonal transition shifting with time to temperatures beyond the instrumental range. The properties of Cer6 are intermediate between those of the other two, this ceramide decreasing both the gel-fluid and lamellar-hexagonal transition temperatures. Temperature-composition diagrams have been constructed for the mixtures of DEPE with each of the three ceramides. The different behavior of the long- and short-chain ceramides can be rationalized in terms of their different molecular geometries, Cer16 favoring negative curvature in the monolayers, thus inverted phases, and the opposite being true of the micelle-forming Cer2. These differences may be at the origin of the different physiological effects that are sometimes observed for the long- and short-chain ceramides. PMID:15695626

Using the LOINC Semantic Structure to Integrate Community-based Survey Items into a Concept-based Enterprise Data Dictionary to Support Comparative Effectiveness Research.

PubMed

Co, Manuel C; Boden-Albala, Bernadette; Quarles, Leigh; Wilcox, Adam; Bakken, Suzanne

2012-01-01

In designing informatics infrastructure to support comparative effectiveness research (CER), it is necessary to implement approaches for integrating heterogeneous data sources such as clinical data typically stored in clinical data warehouses and those that are normally stored in separate research databases. One strategy to support this integration is the use of a concept-oriented data dictionary with a set of semantic terminology models. The aim of this paper is to illustrate the use of the semantic structure of Clinical LOINC (Logical Observation Identifiers, Names, and Codes) in integrating community-based survey items into the Medical Entities Dictionary (MED) to support the integration of survey data with clinical data for CER studies.

Commentary: Will academia embrace comparative effectiveness research?

PubMed

Lauer, Michael S

2011-06-01

In recent medical history, a number of therapies that were widely adopted based on observational data or pathophysiological constructs turned out to be useless or even harmful when tested in randomized comparative effectiveness trials. These therapies not only harmed patients but also did a disservice to the practical education of medical students, residents, and fellows. These trainees effectively learned that it is acceptable to implement practices even in the absence of high-quality evidence, and so they may not have learned how to analyze the quality of evidence. In this issue of Academic Medicine, seven groups address critical aspects of the intersection between comparative effectiveness research (CER) and academic medicine. Their topics include the need at academic health centers for cultural shifts, for addressing conflicts of interest, for exploiting academic talent and electronic information resources, for interacting well with policy makers, for incorporating economic evaluations, for incorporating tests of educational methods, for developing multidisciplinary models, and for integrating CER into "predictive health." This commentary argues that academia must embrace CER by insisting on the highest levels of evidence, by viewing all clinical interactions as opportunities for scientific advancement, by setting an example for policy makers and colleagues working in nonacademic settings, and by engaging all physicians in the clinical research enterprise.

Some methodological points to consider when performing systematic reviews in comparative effectiveness research.

PubMed

Berlin, Jesse A; Cepeda, M Soledad

2012-02-01

The purpose of comparative effectiveness research (CER) is to assist consumers, clinicians, purchasers, and policy makers to make informed decisions that will improve health care at both the individual and population levels. There is an ongoing discussion as to what types of evidence are appropriate to inform CER and how best to interpret various forms of evidence. The purpose of this article is primarily to highlight several interesting methodological issues in the conduct of CER reviews. We describe several key challenges related to randomized trials, with a particular focus on noninferiority studies, which include active comparators used to assess 'assay sensitivity' (defined below), and on the use of randomized studies to perform indirect comparisons between therapies. We touch briefly on the use of observational studies in CER, particularly because of the importance of observational studies in assessing infrequently occurring harms. We argue that studies that may be perceived as unsuitable to address some CER questions may well be appropriate to address others. As an example, noninferiority studies (assuming they include an appropriate comparator at an appropriate dose), are sometimes discounted or excluded from consideration because of concerns that the sponsor's incentive is to conduct a study that is biased toward showing no difference between the treatment groups. If the purpose of a systematic review of CER is to show superiority with respect to a purported benefit, including studies that may be biased toward equality of treatments would tend to underestimate the proposed benefit, that is, the bias works against the sponsor. This is not a comprehensive review of all methodological issues related to CER, and we recognize that there may be dissenting opinions regarding some of the points we raise. In considering the use of systematic reviews, we believe it is sound advice to perform the head-to-head comparison when possible, in the relevant populations, using endpoints relevant to patients, caregivers, physicians, or payers. These endpoints should include patient-reported outcomes (e.g., symptoms), when relevant. Indirect comparisons and mixed treatment meta-analyses may be useful for simultaneously comparing multiple treatments, provided the assumptions underlying such analyses are plausible.

Effects of alpha-galactosylceramides on bone marrow cells in vitro and hematopoiesis in vivo.

PubMed

Motoki, K; Morita, M; Kobayashi, E; Uchida, T; Fukushima, H; Koezuka, Y

1996-07-01

We found that AGL-517, an alpha-galactosylceramide (alpha-GalCer), possesses potent radioprotective activities against mice irradiated with 9 Gy of X-ray in contrast to its having no effect on mice irradiated with 10 Gy of X-ray. The result suggested the possibility that alpha-GalCers protect mice from bone marrow death. To examine this possibility, we examined the effects of two kinds of alpha- and beta-GalCers on counts of platelets (PLT) and white blood cells (WBC) in the peripheral blood of normal mice and mice irradiated in a whole body with 5 Gy of X-ray. alpha-GalCers significantly increased the PLT and WBC counts of both mice in comparison with the vehicle-treated group, and their potencies were stronger than those of their beta-types. Furthermore, we evaluated the in vitro bone marrow cell-proliferation stimulatory activities of four kinds of GalCers, and found that alpha-GalCers show stronger stimulatory effects than beta-types. These results demonstrate that the alpha-configuration of GalCers plays an important role in the manifestation of the above-mentioned activities of GalCers. The results also suggest that alpha-GalCers may be useful as hematopoietic stimulators as well as radioprotective agents.

Characteristics of community health organizations and decision-makers considering the adoption of motivational interviewing.

PubMed

Williams, Jessica Roberts; Dusablon, Tracy; Williams, Weston O; Blais, Marissa Puckett; Hennessy, Kevin D

2014-07-01

Research related to the adoption of comparative effectiveness research (CER) in mental health practice is limited. This study explores the factors that influence decisions to adopt motivational interviewing (MI)-an evidence-based practice (EBP) grounded in CER-among decision-makers (n = 311) in community health organizations (n = 92). Descriptive analyses focus on organization and decision-maker characteristics and processes that may influence the decision to adopt an EBP, including demographics, structure and operations, readiness, attitudes, barriers, and facilitators. Within-group agreement is examined to determine the degree to which participants within each organization gave similar responses. Results show characteristics differed according to type of organization (community health versus community behavioral health) and position (directors versus staff). Within-group agreement was also influenced by position. These findings indicate different strategies may be needed to best disseminate CER to the two groups.

ECONOMICS OF INDIVIDUALIZATION IN COMPARATIVE EFFECTIVENESS RESEARCH AND A BASIS FOR A PATIENT-CENTERED HEALTH CARE

PubMed Central

Basu, Anirban

2011-01-01

The United States aspires to use information from comparative effectiveness research (CER) to reduce waste and contain costs without instituting a formal rationing mechanism or compromising patient or physician autonomy with regard to treatment choices. With such ambitious goals, traditional combinations of research designs and analytical methods used in CER may lead to disappointing results. In this paper, I study how alternate regimes of comparative effectiveness information help shape the marginal benefits (demand) curve in the population and how such perceived demand curves impact decision-making at the individual patient level and welfare at the societal level. I highlight the need to individualize comparative effectiveness research in order to generate the true (normative) demand curve for treatments. I discuss methodological principles that guide research designs for such studies. Using an example of the comparative effect of substance abuse treatments on crime, I use novel econometric methods to salvage individualized information from an existing dataset. PMID:21601299

Economics of individualization in comparative effectiveness research and a basis for a patient-centered health care.

PubMed

Basu, Anirban

2011-05-01

The United States aspires to use information from comparative effectiveness research (CER) to reduce waste and contain costs without instituting a formal rationing mechanism or compromising patient or physician autonomy with regard to treatment choices. With such ambitious goals, traditional combinations of research designs and analytical methods used in CER may lead to disappointing results. In this paper, I study how alternate regimes of comparative effectiveness information help shape the marginal benefits (demand) curve in the population and how such perceived demand curves impact decision-making at the individual patient level and welfare at the societal level. I highlight the need to individualize comparative effectiveness research in order to generate the true (normative) demand curve for treatments. I discuss methodological principles that guide research designs for such studies. Using an example of the comparative effect of substance abuse treatments on crime, I use novel econometric methods to salvage individualized information from an existing dataset. Copyright © 2011 Elsevier B.V. All rights reserved.

Building sustainable multi-functional prospective electronic clinical data systems.

PubMed

Randhawa, Gurvaneet S; Slutsky, Jean R

2012-07-01

A better alignment in the goals of the biomedical research enterprise and the health care delivery system can help fill the large gaps in our knowledge of the impact of clinical interventions on patient outcomes in the real world. There are several initiatives underway to align the research priorities of patients, providers, researchers, and policy makers. These include Agency for Healthcare Research and Quality (AHRQ)-supported projects to build flexible prospective clinical electronic data infrastructure that meet the needs of these diverse users. AHRQ has previously supported the creation of 2 distributed research networks as a new approach to conduct comparative effectiveness research (CER) while protecting a patient's confidential information and the proprietary needs of a clinical organization. It has applied its experience in building these networks in directing the American Recovery and Reinvestment Act funds for CER to support new clinical electronic infrastructure projects that can be used for several purposes including CER, quality improvement, clinical decision support, and disease surveillance. In addition, AHRQ has funded a new Electronic Data Methods forum to advance the methods in clinical informatics, research analytics, and governance by actively engaging investigators from the American Recovery and Reinvestment Act-funded projects and external stakeholders.

Managing Commercial Educational Research.

ERIC Educational Resources Information Center

Hall, William C.

This manual discusses major differences between academic and commercial educational research (CER) and provides suggestions to help researchers who want to conduct CER. The paper is based on the experiences of the TAFE National Center for Research and Development Ltd in Leabrook (Australia). Focus is on describing how to apply for grants and how…

Facts, fallacies, and politics of comparative effectiveness research: Part 2 - implications for interventional pain management.

PubMed

Manchikanti, Laxmaiah; Falco, Frank J E; Boswell, Mark V; Hirsch, Joshua A

2010-01-01

The United States leads the world in many measures of health care innovation. However, it has been criticized to lag behind many developed nations in important health outcomes including mortality rates and higher health care costs. The surveys have shown the United States to outspend all other Organisation for Economic Co-operation and Development (OECD) countries with spending on health goods and services per person of $7,290 - almost 2(1/2) times the average of all OECD countries in 2007. Rising health care costs in the United States have been estimated to increase to 19.1% of gross domestic product (GDP) or $4.4 trillion by 2018. CER is defined as the generation and synthesis of evidence that compares the benefits and harms of alternate methods to prevent, diagnose, treat, and monitor a clinical condition or to improve the delivery of care. The, comparative effectiveness research (CER) has been touted by supporters with high expectations to resolve most ill effects of health care in the United States providing high quality, less expensive, universal health care. The efforts of CER in the United States date back to the late 1970s and it was officially inaugurated with the enactment of the Medicare Modernization Act (MMA). It has been rejuvenated with the American Recovery and Reinvestment Act (ARRA) of 2009 with an allocation of $1.1 billion. CER has been the basis of decision for health care in many other countries. Of all the available agencies, the National Institute for Health and Clinical Excellence (NICE) of the United Kingdom is the most advanced, stable, and has provided significant evidence, though based on rigid and proscriptive economic and clinical formulas. While CER is taking a rapid surge in the United States, supporters and opponents are emerging expressing their views. Since interventional pain management is a new and evolving specialty, with ownership claimed by numerous organizations, at times it is felt as if it has many fathers and other times it becomes an orphan. Part 2 of this comprehensive review will provide facts, fallacies, and politics of CER along with discussion of potential outcomes, impact of CER on health care delivery, and implications for interventional pain management in the United States.

Using the CER Hub to ensure data quality in a multi-institution smoking cessation study.

PubMed

Walker, Kari L; Kirillova, Olga; Gillespie, Suzanne E; Hsiao, David; Pishchalenko, Valentyna; Pai, Akshatha Kalsanka; Puro, Jon E; Plumley, Robert; Kudyakov, Rustam; Hu, Weiming; Allisany, Art; McBurnie, MaryAnn; Kurtz, Stephen E; Hazlehurst, Brian L

2014-01-01

Comparative effectiveness research (CER) studies involving multiple institutions with diverse electronic health records (EHRs) depend on high quality data. To ensure uniformity of data derived from different EHR systems and implementations, the CER Hub informatics platform developed a quality assurance (QA) process using tools and data formats available through the CER Hub. The QA process, implemented here in a study of smoking cessation services in primary care, used the 'emrAdapter' tool programmed with a set of quality checks to query large samples of primary care encounter records extracted in accord with the CER Hub common data framework. The tool, deployed to each study site, generated error reports indicating data problems to be fixed locally and aggregate data sharable with the central site for quality review. Across the CER Hub network of six health systems, data completeness and correctness issues were prevalent in the first iteration and were considerably improved after three iterations of the QA process. A common issue encountered was incomplete mapping of local EHR data values to those defined by the common data framework. A highly automated and distributed QA process helped to ensure the correctness and completeness of patient care data extracted from EHRs for a multi-institution CER study in smoking cessation. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Analysis of aerosol-cloud-precipitation interactions based on MODIS data

NASA Astrophysics Data System (ADS)

Cheng, Feng; Zhang, Jiahua; He, Junliang; Zha, Yong; Li, Qiannan; Li, Yunmei

2017-01-01

Aerosols exert an indirect impact on climate change via its impact on clouds by altering its radiative and optical properties which, in turn, changes the process of precipitation. Over recent years how to study the indirect climate effect of aerosols has become an important research topic. In this study we attempted to understand the complex mutual interactions among aerosols, clouds and precipitation through analysis of the spatial correlation between aerosol optical depth (AOD), cloud effective radius (CER) and precipitation during 2000-2012 in central-eastern China that has one of the highest concentrations of aerosols globally. With the assistance of moderate resolution imaging spectroradiometer (MODIS)-derived aerosol and cloud product data, this analysis focuses on regional differentiation and seasonal variation of the correlation in which in situ observed precipitation was incorporated. On the basis of the achieved results, we proposed four patterns depicting the mutual interactions between aerosols, clouds and precipitation. They characterize the indirect effects of aerosols on the regional scale. These effects can be summarized as complex seasonal variations and north-south regional differentiation over the study area. The relationship between AOD and CER is predominated mostly by the first indirect effect (the negative correlation between AOD and CER) in the north of the study area in the winter and spring seasons, and over the entire study area in the summer season. The relationship between CER and precipitation is dominated chiefly by the second indirect effect (the positive correlation between CER and precipitation) in the northern area in summer and over the entire study area in autumn. It must be noted that aerosols are not the factor affecting clouds and rainfall singularly. It is the joint effect of aerosols with other factors such as atmospheric dynamics that governs the variation in clouds and rainfall.

Stakeholder Priorities for Comparative Effectiveness Research in Chronic Obstructive Pulmonary Disease

PubMed Central

Lindenauer, Peter K.; Au, David H.; Carson, Shannon S.; Lee, Todd A.; McBurnie, Mary Ann; Naureckas, Edward T.; Vollmer, William M.; Mularski, Richard A.

2013-01-01

Comparative effectiveness research (CER) is intended to address the expressed needs of patients, clinicians, and other stakeholders. Representatives of 54 stakeholder groups with an interest in chronic obstructive pulmonary disease (COPD) participated in workshops convened by the COPD Outcomes-based Network for Clinical Effectiveness and Research Translation (CONCERT) over a 2-year period. Year 1 focused on chronic care and care coordination. Year 2 focused on acute care and transitions in care between healthcare settings. Discussions and provisional voting were conducted via teleconferences and e-mail exchanges before the workshop. Final prioritization votes occurred after in-person discussions at the workshop. We used a modified Delphi approach to facilitate discussions and consensus building. To more easily quantify preferences and to evaluate the internal consistency of rankings, the Analytic Hierarchy Process was incorporated in Year 2. Results of preworkshop and final workshop voting often differed, suggesting that prioritization efforts relying solely on requests for topics from stakeholder groups without in-person discussion may provide different research priorities. Research priorities varied across stakeholder groups, but generally focused on studies to evaluate different approaches to healthcare delivery (e.g., spirometry for diagnosis and treatment, integrated healthcare strategies during transitions in care) rather than head-to-head comparisons of medications. This research agenda may help to inform groups intending to respond to CER funding opportunities in COPD. The methodologies used, detailed in the online supplement, may also help to inform prioritization efforts for CER in other health conditions. PMID:23155144

Stakeholder priorities for comparative effectiveness research in chronic obstructive pulmonary disease: a workshop report.

PubMed

Krishnan, Jerry A; Lindenauer, Peter K; Au, David H; Carson, Shannon S; Lee, Todd A; McBurnie, Mary Ann; Naureckas, Edward T; Vollmer, William M; Mularski, Richard A

2013-02-01

Comparative effectiveness research (CER) is intended to address the expressed needs of patients, clinicians, and other stakeholders. Representatives of 54 stakeholder groups with an interest in chronic obstructive pulmonary disease (COPD) participated in workshops convened by the COPD Outcomes-based Network for Clinical Effectiveness and Research Translation (CONCERT) over a 2-year period. Year 1 focused on chronic care and care coordination. Year 2 focused on acute care and transitions in care between healthcare settings. Discussions and provisional voting were conducted via teleconferences and e-mail exchanges before the workshop. Final prioritization votes occurred after in-person discussions at the workshop. We used a modified Delphi approach to facilitate discussions and consensus building. To more easily quantify preferences and to evaluate the internal consistency of rankings, the Analytic Hierarchy Process was incorporated in Year 2. Results of preworkshop and final workshop voting often differed, suggesting that prioritization efforts relying solely on requests for topics from stakeholder groups without in-person discussion may provide different research priorities. Research priorities varied across stakeholder groups, but generally focused on studies to evaluate different approaches to healthcare delivery (e.g., spirometry for diagnosis and treatment, integrated healthcare strategies during transitions in care) rather than head-to-head comparisons of medications. This research agenda may help to inform groups intending to respond to CER funding opportunities in COPD. The methodologies used, detailed in the online supplement, may also help to inform prioritization efforts for CER in other health conditions.

Using the LOINC Semantic Structure to Integrate Community-based Survey Items into a Concept-based Enterprise Data Dictionary to Support Comparative Effectiveness Research

PubMed Central

Co, Manuel C.; Boden-Albala, Bernadette; Quarles, Leigh; Wilcox, Adam; Bakken, Suzanne

2012-01-01

In designing informatics infrastructure to support comparative effectiveness research (CER), it is necessary to implement approaches for integrating heterogeneous data sources such as clinical data typically stored in clinical data warehouses and those that are normally stored in separate research databases. One strategy to support this integration is the use of a concept-oriented data dictionary with a set of semantic terminology models. The aim of this paper is to illustrate the use of the semantic structure of Clinical LOINC (Logical Observation Identifiers, Names, and Codes) in integrating community-based survey items into the Medical Entities Dictionary (MED) to support the integration of survey data with clinical data for CER studies. PMID:24199059

Docosahexaenoic acid antagonizes the boosting effect of palmitic acid on LPS inflammatory signaling by inhibiting gene transcription and ceramide synthesis

PubMed Central

Jin, Junfei; Lu, Zhongyang; Li, Yanchun; Cowart, L. Ashley; Lopes-Virella, Maria F.

2018-01-01

It is well known that saturated fatty acids (SFAs) and unsaturated fatty acid, in particular omega-3 polyunsaturated fatty acids (n-3 PUFAs), have different effects on inflammatory signaling: SFAs are pro-inflammatory but n-3 PUFAs have strong anti-inflammatory properties. We have reported that palmitic acid (PA), a saturated fatty acid, robustly amplifies lipopolysaccharide (LPS) signaling to upregulate proinflammatory gene expression in macrophages. We also reported that the increased production of ceramide (CER) via sphingomyelin (SM) hydrolysis and CER de novo synthesis plays a key role in the synergistic effect of LPS and PA on proinflammatory gene expression. However, it remains unclear if n-3 PUFAs are capable of antagonizing the synergistic effect of LPS and PA on gene expression and CER production. In this study, we employed the above macrophage culture system and lipidomical analysis to assess the effect of n-3 PUFAs on proinflammatory gene expression and CER production stimulated by LPS and PA. Results showed that DHA strongly inhibited the synergistic effect of LPS and PA on proinflammatory gene expression by targeting nuclear factor kappa B (NFκB)-dependent gene transcription. Results also showed that DHA inhibited the cooperative effect of LPS and PA on CER production by targeting CER de novo synthesis, but not SM hydrolysis. Furthermore, results showed that myriocin, a specific inhibitor of serine palmitoyltransferase, strongly inhibited both LPS-PA-stimulated CER synthesis and proinflammatory gene expression, indicating that CER synthesis is associated with proinflammatory gene expression and that inhibition of CER synthesis contributes to DHA-inhibited proinflammatory gene expression. Taken together, this study demonstrates that DHA antagonizes the boosting effect of PA on LPS signaling on proinflammatory gene expression by targeting both NFκB-dependent transcription and CER de novo synthesis in macrophages. PMID:29474492

Docosahexaenoic acid antagonizes the boosting effect of palmitic acid on LPS inflammatory signaling by inhibiting gene transcription and ceramide synthesis.

PubMed

Jin, Junfei; Lu, Zhongyang; Li, Yanchun; Cowart, L Ashley; Lopes-Virella, Maria F; Huang, Yan

2018-01-01

It is well known that saturated fatty acids (SFAs) and unsaturated fatty acid, in particular omega-3 polyunsaturated fatty acids (n-3 PUFAs), have different effects on inflammatory signaling: SFAs are pro-inflammatory but n-3 PUFAs have strong anti-inflammatory properties. We have reported that palmitic acid (PA), a saturated fatty acid, robustly amplifies lipopolysaccharide (LPS) signaling to upregulate proinflammatory gene expression in macrophages. We also reported that the increased production of ceramide (CER) via sphingomyelin (SM) hydrolysis and CER de novo synthesis plays a key role in the synergistic effect of LPS and PA on proinflammatory gene expression. However, it remains unclear if n-3 PUFAs are capable of antagonizing the synergistic effect of LPS and PA on gene expression and CER production. In this study, we employed the above macrophage culture system and lipidomical analysis to assess the effect of n-3 PUFAs on proinflammatory gene expression and CER production stimulated by LPS and PA. Results showed that DHA strongly inhibited the synergistic effect of LPS and PA on proinflammatory gene expression by targeting nuclear factor kappa B (NFκB)-dependent gene transcription. Results also showed that DHA inhibited the cooperative effect of LPS and PA on CER production by targeting CER de novo synthesis, but not SM hydrolysis. Furthermore, results showed that myriocin, a specific inhibitor of serine palmitoyltransferase, strongly inhibited both LPS-PA-stimulated CER synthesis and proinflammatory gene expression, indicating that CER synthesis is associated with proinflammatory gene expression and that inhibition of CER synthesis contributes to DHA-inhibited proinflammatory gene expression. Taken together, this study demonstrates that DHA antagonizes the boosting effect of PA on LPS signaling on proinflammatory gene expression by targeting both NFκB-dependent transcription and CER de novo synthesis in macrophages.

Hydration effects on the barrier function of stratum corneum lipids: Raman analysis of ceramides 2, III and 5.

PubMed

Tfayli, Ali; Jamal, Dima; Vyumvuhore, Raoul; Manfait, Michel; Baillet-Guffroy, Arlette

2013-11-07

The stratum corneum is the outermost layer of the skin; its barrier function is highly dependent on the composition and the structure as well as the organization of lipids in its extracellular matrix. Ceramides, free fatty acids and cholesterol represent the major lipid classes present in this matrix. They play an important role in maintaining the normal hydration levels required for the normal physiological function. Despite the advancement in the understanding of the structure, composition and the function of the stratum corneum (SC), the concern of "dry skin" remains important in dermatology and care research. Most studies focus on the quantification of water in the skin using different techniques including Raman spectroscopy, while the studies that investigate the effect of hydration on the quality of the barrier function of the skin are limited. Raman spectroscopy provides structural, conformational and organizational information that could help elucidate the effect of hydration on the barrier function of the skin. In order to assess the effect of relative humidity on the lipid barrier function; we used Raman spectroscopy to follow-up the evolution of the conformation and the organization of three synthetic ceramides (CER) differing from each other by the nature of their polar heads (sphingosine, phytosphingosine and α hydroxyl sphingosine), CER 2, III and 5 respectively. CER III and 5 showed a more compact and ordered organization with stronger polar interactions at intermediate relative humidity values, while CER 2 showed opposite tendencies to those observed with CER III and 5.

Closing the information gap: informing better medical decisionmaking through the use of post-market safety and comparative effectiveness information.

PubMed

Fox, Bethany

2012-01-01

While FDA gathers vast amounts of data about prescription drugs prior to their marketing approval, important information about the relative effectiveness and long term safety of products is not required for approval, and often is never collected. Increased postmarket research on the safety and comparative effectiveness of products would improve medical decisionmaking and lead to better clinical outcomes. Fortunately, Congress has recognized the value of this information for healthcare professionals. In response to a congressional mandate in the FDA Amendments Act (FDAAA), FDA is developing the Sentinel Initiative, an active surveillance system for monitoring postmarket drug safety issues. FDAAA also authorized FDA to require a drug sponsor to conduct postmarket safety studies or clinical trials to address a specific safety concern. To increase the repository of comparative effectiveness information, Congress established the Patient-Centered Outcomes Research Institute (PCORI) in the Patient Protection and Affordable Care Act (PPACA), directing it to manage comparative effectiveness research (CER). This article discusses the need for better safety and comparative effectiveness information and outlines methods to efficiently conduct the research and communicate it effectively to healthcare professionals. Coordination between FDA and the PCORI in gathering and communicating postmarket information is recommended. Medical source data collected by the Sentinel Initiative should be used for CER in addition to postmarket safety surveillance, and FDA and the PCORI should adopt identical standards for the distribution and communication of CER. Coordination between the two entities is recommended to save costs, reduce duplication of efforts, and to generate and communicate more information on prescription drugs for medical decisionmakers.

Using Medicare Data for Comparative Effectiveness Research – Opportunities and Challenges

PubMed Central

Fung, Vicki; Brand, Richard; Newhouse, Joseph; Hsu, John

2013-01-01

Background With the introduction of Part D drug benefits, Medicare collects information on diagnoses, treatments, and clinical events for millions of beneficiaries. These data are a promising resource for comparative effectiveness research (CER) on treatments, benefit designs, and delivery systems. Objectives We explore the data available for researchers and approaches that could be used to enhance the value of Medicare data for CER. Challenges and Opportunities Using currently available Medicare data for CER is challenging; as with all administrative data, it is not possible to capture every factor that contributes to prescribing decisions and patients are not randomly assigned to treatments. In addition, Part D plan selection and switching may influence treatment decisions and contribute to selection bias. Exploiting certain program aspects can help address these limitations. For example, ongoing changes in Medicare or plan policies, and the random assignment of beneficiaries who receive Part D low income subsidies into plans with different formularies could yield natural experiments. Policy implications Refining policies around time to data release, provision of additional data elements, and linkage with greater beneficiary-level information would improve the value and usability of these data. Improving the transparency and reproduceability of findings, and potential open access to qualified stakeholders are also important policy considerations. Work is needed to reconcile data needs with current policies and goals. Conclusions Medicare data provides a rich resource for CER. Leveraging existing program elements combined with some administrative changes in data availability could create large datasets for evaluating treatment patterns, spending, and coverage decisions. PMID:21819169

Metabolic Conversion of Ceramides in HeLa Cells - A Cholesteryl Phosphocholine Delivery Approach

PubMed Central

Kjellberg, Matti A.; Lönnfors, Max; Slotte, J. Peter; Mattjus, Peter

2015-01-01

Ceramides can be delivered to cultured cells without solvents in the form of complexes with cholesteryl phosphocholine. We have analysed the delivery of three different radiolabeled D-erythro-ceramides (C6-Cer, C10-Cer and C16-Cer) to HeLa cells, and followed their metabolism as well as the cell viability. We found that all three ceramides were successfully taken up by HeLa cells when complexed to CholPC in an equimolar ratio, and show that the ceramides show different rates of cellular uptake and metabolic fate. The C6-Cer had the highest incorporation rate, followed by C10-Cer and C16-Cer, respectively. The subsequent effect on cell viability strongly correlated with the rate of incorporation, where C6-Cer had the strongest apoptotic effects. Low-dose (1 μM) treatment with C6-Cer favoured conversion of the precursor to sphingomyelin, whereas higher concentrations (25–100 μM) yielded increased conversion to C6-glucosylceramide. Similar results were obtained for C10-Cer. In the lower-dose C16-Cer experiments, most of the precursor was degraded, whereas at high-dose concentrations the precursor remained un-metabolized. Using this method, we demonstrate that ceramides with different chain lengths clearly exhibit varying rates of cellular uptake. The cellular fate of the externally delivered ceramides are clearly connected to their rate of incorporation and their subsequent effects on cell viability may be in part determined by their chain length. PMID:26599810

Consumer involvement in systematic reviews of comparative effectiveness research.

PubMed

Kreis, Julia; Puhan, Milo A; Schünemann, Holger J; Dickersin, Kay

2013-12-01

The Institute of Medicine recently recommended that comparative effectiveness research (CER) should involve input from consumers. While systematic reviews are a major component of CER, little is known about consumer involvement. To explore current approaches to involving consumers in US-based and key international organizations and groups conducting or commissioning systematic reviews ('organizations'). In-depth, semi-structured interviews with key informants and review of organizations' websites. Seventeen highly regarded US-based and international (Cochrane Collaboration, Campbell Collaboration) organizations. Organizations that usually involve consumers (seven of 17 in our sample) involve them at a programmatic level in the organization or in individual reviews through one-time consultation or on-going collaboration. For example, consumers may suggest topics, provide input on the key questions of the review, provide comments on draft protocols and reports, serve as co-authors or on an advisory group. Organizations involve different types of consumers (individual patients, consumer advocates, families and caregivers), recruiting them mainly through patient organizations and consumer networks. Some offer training in research methods, and one developed training for researchers on how to involve consumers. Little formal evaluation of the effects of consumer involvement is being carried out. Consumers are currently involved in systematic reviews in a variety of ways and for various reasons. Assessing which approaches are most effective in achieving different aims of consumer involvement is now required to inform future recommendations on consumer involvement in CER. © 2012 John Wiley & Sons Ltd.

Consumer involvement in systematic reviews of comparative effectiveness research

PubMed Central

Kreis, Julia; Puhan, Milo A.; Schünemann, Holger J.; Dickersin, Kay

2012-01-01

Abstract Background  The Institute of Medicine recently recommended that comparative effectiveness research (CER) should involve input from consumers. While systematic reviews are a major component of CER, little is known about consumer involvement. Objective  To explore current approaches to involving consumers in US‐based and key international organizations and groups conducting or commissioning systematic reviews (‘organizations’). Design  In‐depth, semi‐structured interviews with key informants and review of organizations’ websites. Setting and participants  Seventeen highly regarded US‐based and international (Cochrane Collaboration, Campbell Collaboration) organizations. Results  Organizations that usually involve consumers (seven of 17 in our sample) involve them at a programmatic level in the organization or in individual reviews through one‐time consultation or on‐going collaboration. For example, consumers may suggest topics, provide input on the key questions of the review, provide comments on draft protocols and reports, serve as co‐authors or on an advisory group. Organizations involve different types of consumers (individual patients, consumer advocates, families and caregivers), recruiting them mainly through patient organizations and consumer networks. Some offer training in research methods, and one developed training for researchers on how to involve consumers. Little formal evaluation of the effects of consumer involvement is being carried out. Conclusions  Consumers are currently involved in systematic reviews in a variety of ways and for various reasons. Assessing which approaches are most effective in achieving different aims of consumer involvement is now required to inform future recommendations on consumer involvement in CER. PMID:22390732

By activating Fas/ceramide synthase 6/p38 kinase in lipid rafts, Stichoposide D inhibits growth of leukemia xenografts

PubMed Central

Yun, Seong-Hoon; Park, Eun-Seon; Shin, Sung-Won; Ju, Mi-Ha; Han, Jin-Yeong; Jeong, Jin-Sook; Kim, Sung-Hyun; Stonik, Valentin A.; Kwak, Jong-Young; Park, Joo-In

2015-01-01

Stichoposide D (STD) is a marine triterpene glycoside isolated from sea cucumbers. We examined the molecular mechanisms underlying the antitumor activity of STD in human leukemia cells. The role of Fas (CD95), ceramide synthase 6 (CerS6) and p38 kinase during STD-induced apoptosis was examined in human leukemia cells. In addition, the antitumor effects of STD in K562 and HL-60 leukemia xenograft models were investigated. We found that STD induces Fas translocation to lipid rafts, and thus mediates cell apoptosis. We also observed the activation of CerS6 and p38 kinase during STD-induced apoptosis. The use of methyl-β-cyclodextrin and nystatin to disrupt lipid rafts prevents the clustering of Fas and the activation of CerS6 and p38 kinase, and also inhibits STD-induced apoptosis. Specific inhibition by Fas, CerS6, and p38 kinase siRNA transfection partially blocked STD-induced apoptosis. In addition, STD has antitumor activity through the activation of CerS6 and p38 kinase without displaying any toxicity in HL-60 and K562 xenograft models. We observed that the anti-tumor effect of STD is partially prevented in CerS6 shRNA-silenced xenograft models. We first report that Fas/CerS6/p38 kinase activation in lipid rafts by STD is involved in its anti-leukemic activity. We also established that STD is able to enhance the chemosensitivity of K562 cells to etoposide or Ara-C. These data suggest that STD may be used alone or in combination with other chemotherapeutic agents to treat leukemia. PMID:26318294

75 FR 13293 - Meeting of the National Advisory Council for Healthcare Research and Quality

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-19

..., and initiatives. The agenda will include a progress report on Comparative Effectiveness Research (CER... DEPARTMENT OF HEALTH AND HUMAN SERVICES Agency for Healthcare Research and Quality Meeting of the National Advisory Council for Healthcare Research and Quality AGENCY: Agency for Healthcare Research and...

HDL mimetic peptide CER-522 treatment regresses left ventricular diastolic dysfunction in cholesterol-fed rabbits.

PubMed

Merlet, Nolwenn; Busseuil, David; Mihalache-Avram, Teodora; Mecteau, Melanie; Shi, Yanfen; Nachar, Walid; Brand, Genevieve; Brodeur, Mathieu R; Charpentier, Daniel; Rhainds, David; Sy, Gavin; Schwendeman, Anna; Lalwani, Narendra; Dasseux, Jean-Louis; Rhéaume, Eric; Tardif, Jean-Claude

2016-07-15

High-density lipoprotein (HDL) infusions induce rapid improvement of experimental atherosclerosis in rabbits but their effect on ventricular function remains unknown. We aimed to evaluate the effects of the HDL mimetic peptide CER-522 on left ventricular diastolic dysfunction (LVDD). Rabbits were fed with a cholesterol- and vitamin D2-enriched diet until mild aortic valve stenosis and hypercholesterolemia-induced LV hypertrophy and LVDD developed. Animals then received saline or 10 or 30mg/kg CER-522 infusions 6 times over 2weeks. We performed serial echocardiograms and LV histology to evaluate the effects of CER-522 therapy on LVDD. LVDD was reduced by CER-522 as shown by multiple parameters including early filling mitral deceleration time, deceleration rate, Em/Am ratio, E/Em ratio, pulmonary venous velocities, and LVDD score. These findings were associated with reduced macrophages (RAM-11 positive cells) in the pericoronary area and LV, and decreased levels of apoptotic cardiomyocytes in CER-522-treated rabbits. CER-522 treatment also resulted in decreased atheromatous plaques and internal elastic lamina area in coronary arteries. CER-522 improves LVDD in rabbits, with reductions of LV macrophage accumulation, cardiomyocyte apoptosis, coronary atherosclerosis and remodelling. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Regression of coronary atherosclerosis with infusions of the high-density lipoprotein mimetic CER-001 in patients with more extensive plaque burden.

PubMed

Kataoka, Yu; Andrews, Jordan; Duong, MyNgan; Nguyen, Tracy; Schwarz, Nisha; Fendler, Jessica; Puri, Rishi; Butters, Julie; Keyserling, Constance; Paolini, John F; Dasseux, Jean-Louis; Nicholls, Stephen J

2017-06-01

CER-001 is an engineered pre-beta high-density lipoprotein (HDL) mimetic, which rapidly mobilizes cholesterol. Infusion of CER-001 3 mg/kg exhibited a potentially favorable effect on plaque burden in the CHI-SQUARE (Can HDL Infusions Significantly Quicken Atherosclerosis Regression) study. Since baseline atheroma burden has been shown as a determinant for the efficacy of HDL infusions, the degree of baseline atheroma burden might influence the effect of CER-001. CHI-SQUARE compared the effect of 6 weekly infusions of CER-001 (3, 6 and 12 mg/kg) vs. placebo on coronary atherosclerosis in 369 patients with acute coronary syndrome (ACS) using serial intravascular ultrasound (IVUS). Baseline percent atheroma volume (B-PAV) cutoff associated with atheroma regression following CER-001 infusions was determined by receiver-operating characteristics curve analysis. 369 subjects were stratified according to the cutoff. The effect of CER-001 at different doses was compared to placebo in each group. A B-PAV ≥30% was the optimal cutoff associated with PAV regression following CER-001 infusions. CER-001 induced PAV regression in patients with B-PAV ≥30% but not in those with B-PAV <30% (-0.45%±2.65% vs. +0.34%±1.69%, P=0.01). Compared to placebo, the greatest PAV regression was observed with CER-001 3mg/kg in patients with B-PAV ≥30% (-0.96%±0.34% vs. -0.25%±0.31%, P=0.01), whereas there were no differences between placebo (+0.09%±0.36%) versus CER-001 in patients with B-PAV <30% (3 mg/kg; +0.41%±0.32%, P=0.39; 6 mg/kg; +0.27%±0.36%, P=0.76; 12 mg/kg; +0.32%±0.37%, P=0.97). Infusions of CER-001 3 mg/kg induced the greatest atheroma regression in ACS patients with higher B-PAV. These findings identify ACS patients with more extensive disease as most likely to benefit from HDL mimetic therapy.

Regression of coronary atherosclerosis with infusions of the high-density lipoprotein mimetic CER-001 in patients with more extensive plaque burden

PubMed Central

Kataoka, Yu; Andrews, Jordan; Duong, MyNgan; Nguyen, Tracy; Schwarz, Nisha; Fendler, Jessica; Puri, Rishi; Butters, Julie; Keyserling, Constance; Paolini, John F.; Dasseux, Jean-Louis

2017-01-01

Background CER-001 is an engineered pre-beta high-density lipoprotein (HDL) mimetic, which rapidly mobilizes cholesterol. Infusion of CER-001 3 mg/kg exhibited a potentially favorable effect on plaque burden in the CHI-SQUARE (Can HDL Infusions Significantly Quicken Atherosclerosis Regression) study. Since baseline atheroma burden has been shown as a determinant for the efficacy of HDL infusions, the degree of baseline atheroma burden might influence the effect of CER-001. Methods CHI-SQUARE compared the effect of 6 weekly infusions of CER-001 (3, 6 and 12 mg/kg) vs. placebo on coronary atherosclerosis in 369 patients with acute coronary syndrome (ACS) using serial intravascular ultrasound (IVUS). Baseline percent atheroma volume (B-PAV) cutoff associated with atheroma regression following CER-001 infusions was determined by receiver-operating characteristics curve analysis. 369 subjects were stratified according to the cutoff. The effect of CER-001 at different doses was compared to placebo in each group. Results A B-PAV ≥30% was the optimal cutoff associated with PAV regression following CER-001 infusions. CER-001 induced PAV regression in patients with B-PAV ≥30% but not in those with B-PAV <30% (−0.45%±2.65% vs. +0.34%±1.69%, P=0.01). Compared to placebo, the greatest PAV regression was observed with CER-001 3mg/kg in patients with B-PAV ≥30% (−0.96%±0.34% vs. −0.25%±0.31%, P=0.01), whereas there were no differences between placebo (+0.09%±0.36%) versus CER-001 in patients with B-PAV <30% (3 mg/kg; +0.41%±0.32%, P=0.39; 6 mg/kg; +0.27%±0.36%, P=0.76; 12 mg/kg; +0.32%±0.37%, P=0.97). Conclusions Infusions of CER-001 3 mg/kg induced the greatest atheroma regression in ACS patients with higher B-PAV. These findings identify ACS patients with more extensive disease as most likely to benefit from HDL mimetic therapy. PMID:28567351

Do Bayesian adaptive trials offer advantages for comparative effectiveness research? Protocol for the RE-ADAPT study

PubMed Central

Luce, Bryan R; Broglio, Kristine R; Ishak, K Jack; Mullins, C Daniel; Vanness, David J; Fleurence, Rachael; Saunders, Elijah; Davis, Barry R

2013-01-01

Background Randomized clinical trials, particularly for comparative effectiveness research (CER), are frequently criticized for being overly restrictive or untimely for health-care decision making. Purpose Our prospectively designed REsearch in ADAptive methods for Pragmatic Trials (RE-ADAPT) study is a ‘proof of concept’ to stimulate investment in Bayesian adaptive designs for future CER trials. Methods We will assess whether Bayesian adaptive designs offer potential efficiencies in CER by simulating a re-execution of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study using actual data from ALLHAT. Results We prospectively define seven alternate designs consisting of various combinations of arm dropping, adaptive randomization, and early stopping and describe how these designs will be compared to the original ALLHAT design. We identify the one particular design that would have been executed, which incorporates early stopping and information-based adaptive randomization. Limitations While the simulation realistically emulates patient enrollment, interim analyses, and adaptive changes to design, it cannot incorporate key features like the involvement of data monitoring committee in making decisions about adaptive changes. Conclusion This article describes our analytic approach for RE-ADAPT. The next stage of the project is to conduct the re-execution analyses using the seven prespecified designs and the original ALLHAT data. PMID:23983160

The Electronic Data Methods (EDM) forum for comparative effectiveness research (CER).

PubMed

Holve, Erin; Segal, Courtney; Lopez, Marianne Hamilton; Rein, Alison; Johnson, Beth H

2012-07-01

AcademyHealth convened the Electronic Data Methods (EDM) Forum to collect, synthesize, and share lessons from eleven projects that are building infrastructure and using electronic clinical data for comparative effectiveness research (CER) and patient-centered outcomes research (PCOR). This paper provides a brief review of participating projects and provides a framework of common challenges. EDM Forum staff conducted a text review of relevant grant programs' funding opportunity announcements; projects' research plans; and available information on projects' websites. Additional information was obtained from presentations provided by each project; phone calls with project principal investigators, affiliated partners, and staff from the Agency for Healthcare Research and Quality (AHRQ); and six site visits. Projects participating in the EDM Forum are building infrastructure and developing innovative strategies to address a set of methodological, and data and informatics challenges, here identified in a common framework. The eleven networks represent more than 20 states and include a range of partnership models. Projects vary substantially in size, from 11,000 to more than 7.5 million individuals. Nearly all of the AHRQ priority populations and conditions are addressed. In partnership with the projects, the EDM Forum is focused on identifying and sharing lessons learned to advance the national dialogue on the use of electronic clinical data to conduct CER and PCOR. These efforts have the shared goal of addressing challenges in traditional research studies and data sources, and aim to build infrastructure and generate evidence to support a learning health care system that can improve patient outcomes.

Effectiveness guidance document (EGD) for acupuncture research - a consensus document for conducting trials

PubMed Central

2012-01-01

Background There is a need for more Comparative Effectiveness Research (CER) to strengthen the evidence base for clinical and policy decision-making. Effectiveness Guidance Documents (EGD) are targeted to clinical researchers. The aim of this EGD is to provide specific recommendations for the design of prospective acupuncture studies to support optimal use of resources for generating evidence that will inform stakeholder decision-making. Methods Document development based on multiple systematic consensus procedures (written Delphi rounds, interactive consensus workshop, international expert review). To balance aspects of internal and external validity, multiple stakeholders including patients, clinicians and payers were involved. Results Recommendations focused mainly on randomized studies and were developed for the following areas: overall research strategy, treatment protocol, expertise and setting, outcomes, study design and statistical analyses, economic evaluation, and publication. Conclusion The present EGD, based on an international consensus developed with multiple stakeholder involvement, provides the first systematic methodological guidance for future CER on acupuncture. PMID:22953730

Development of a privacy and security policy framework for a multistate comparative effectiveness research network.

PubMed

Kim, Katherine K; McGraw, Deven; Mamo, Laura; Ohno-Machado, Lucila

2013-08-01

Comparative effectiveness research (CER) conducted in distributed research networks (DRNs) is subject to different state laws and regulations as well as institution-specific policies intended to protect privacy and security of health information. The goal of the Scalable National Network for Effectiveness Research (SCANNER) project is to develop and demonstrate a scalable, flexible technical infrastructure for DRNs that enables near real-time CER consistent with privacy and security laws and best practices. This investigation began with an analysis of privacy and security laws and state health information exchange (HIE) guidelines applicable to SCANNER participants from California, Illinois, Massachusetts, and the Federal Veteran's Administration. A 7-member expert panel of policy and technical experts reviewed the analysis and gave input into the framework during 5 meetings held in 2011-2012. The state/federal guidelines were applied to 3 CER use cases: safety of new oral hematologic medications; medication therapy management for patients with diabetes and hypertension; and informational interventions for providers in the treatment of acute respiratory infections. The policy framework provides flexibility, beginning with a use-case approach rather than a one-size-fits-all approach. The policies may vary depending on the type of patient data shared (aggregate counts, deidentified, limited, and fully identified datasets) and the flow of data. The types of agreements necessary for a DRN may include a network-level and data use agreements. The need for flexibility in the development and implementation of policies must be balanced with responsibilities of data stewardship.

Multiple Chronic Conditions and Disabilities: Implications for Health Services Research and Data Demands

PubMed Central

Iezzoni, Lisa I

2010-01-01

Increasing numbers of Americans are living with multiple chronic conditions (MCCs) and disabilities. Addressing health care needs of persons with MCCs or disabilities presents challenges on many levels. For health services researchers, priorities include (1) considering MCCs and disabilities in comparative effectiveness research (CER) and assessing quality of care; and (2) identifying and evaluating the data needed to conduct CER, performance measure development, and other research to inform health policy and public health decisions concerning persons with MCCs or disabilities. Little information is available to guide CER or treatment choices for persons with MCCs or disabilities, however, because they are typically excluded from clinical trials that produce the scientific evidence base. Furthermore, most research funding flows through public and private agencies oriented around single organ systems or diseases. Likely changes in the data landscape—notably wider dissemination of electronic health records (EHRs) and moving toward updated coding nomenclatures—may increase the information available to monitor health care service delivery and quality for persons with MCCs and disabilities. Generating this information will require new methods to extract and code information about MCCs and functional status from EHRs, especially narrative texts, and incorporating coding nomenclatures that capture critical dimensions of functional status and disability. PMID:21054370

Multilevel corporate environmental responsibility.

PubMed

Karassin, Orr; Bar-Haim, Aviad

2016-12-01

The multilevel empirical study of the antecedents of corporate social responsibility (CSR) has been identified as "the first knowledge gap" in CSR research. Based on an extensive literature review, the present study outlines a conceptual multilevel model of CSR, then designs and empirically validates an operational multilevel model of the principal driving factors affecting corporate environmental responsibility (CER), as a measure of CSR. Both conceptual and operational models incorporate three levels of analysis: institutional, organizational, and individual. The multilevel nature of the design allows for the assessment of the relative importance of the levels and of their components in the achievement of CER. Unweighted least squares (ULS) regression analysis reveals that the institutional-level variables have medium relationships with CER, some variables having a negative effect. The organizational level is revealed as having strong and positive significant relationships with CER, with organizational culture and managers' attitudes and behaviors as significant driving forces. The study demonstrates the importance of multilevel analysis in improving the understanding of CSR drivers, relative to single level models, even if the significance of specific drivers and levels may vary by context. Copyright © 2016 Elsevier Ltd. All rights reserved.

Differential effects of MPEP and diazepam in tests of conditioned emotional response and Pavlovian-to-instrumental transfer suggests 'anxiolytic' effects are mediated by different mechanisms.

PubMed

George, S A; Hutson, P H; Stephens, D N

2009-06-01

The selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) is reported to be anxiolytic in several animal models of anxiety, including the conditioned emotional response (CER) paradigm. Suppression of responding during conditioned stimulus (CS) presentation in CER may reflect behavioural competition between lever pressing and adopting a shock-avoidance posture, or it may alternatively reflect altered value of the food reward following its association with a footshock, thus reducing its ability to motivate responding. If this is the case, then drugs that reduce the CER may interfere with the mechanism by which CSs are able to motivate responding, rather than by reducing anxiety. The standard test of the ability of Pavlovian cues to motivate responding is the Pavlovian-to-instrumental transfer (PIT) paradigm and it has recently been suggested that CER may be 'negative PIT'. We compared the effect of MPEP (0, 3, 10 and 30 mg/kg) and diazepam (0, 1, 3 and 10 mg/kg) in CER and PIT. Both MPEP and diazepam significantly reduced conditioned suppression in the CER paradigm. MPEP, but not diazepam, significantly reduced PIT. The findings support the hypothesis that MPEP may reduce expression of anxiety in the CER paradigm by interfering with the way in which emotionally salient cues are able to affect behaviour, but do not support such an analysis of the effect of diazepam. Diazepam and MPEP may therefore achieve their effects in CER by influencing different psychological processes.

Conducting quantitative synthesis when comparing medical interventions: AHRQ and the Effective Health Care Program.

PubMed

Fu, Rongwei; Gartlehner, Gerald; Grant, Mark; Shamliyan, Tatyana; Sedrakyan, Art; Wilt, Timothy J; Griffith, Lauren; Oremus, Mark; Raina, Parminder; Ismaila, Afisi; Santaguida, Pasqualina; Lau, Joseph; Trikalinos, Thomas A

2011-11-01

This article is to establish recommendations for conducting quantitative synthesis, or meta-analysis, using study-level data in comparative effectiveness reviews (CERs) for the Evidence-based Practice Center (EPC) program of the Agency for Healthcare Research and Quality. We focused on recurrent issues in the EPC program and the recommendations were developed using group discussion and consensus based on current knowledge in the literature. We first discussed considerations for deciding whether to combine studies, followed by discussions on indirect comparison and incorporation of indirect evidence. Then, we described our recommendations on choosing effect measures and statistical models, giving special attention to combining studies with rare events; and on testing and exploring heterogeneity. Finally, we briefly presented recommendations on combining studies of mixed design and on sensitivity analysis. Quantitative synthesis should be conducted in a transparent and consistent way. Inclusion of multiple alternative interventions in CERs increases the complexity of quantitative synthesis, whereas the basic issues in quantitative synthesis remain crucial considerations in quantitative synthesis for a CER. We will cover more issues in future versions and update and improve recommendations with the accumulation of new research to advance the goal for transparency and consistency. Copyright © 2011 Elsevier Inc. All rights reserved.

Addressing Informatics Barriers to Conducting Observational Comparative Effectiveness Research: A Comparative Case Analysis

ERIC Educational Resources Information Center

Boone, Christopher P. D.

2013-01-01

Background: The U.S. health care system has been under immense scrutiny for ever-increasing costs and poor health outcomes for its patients. Comparative Effectiveness Research (CER) has emerged as a generally accepted practice by providers, policy makers, and scientists as an approach to identify the most clinical- and cost-effective interventions…

What do providers, payers and patients need from comparative effectiveness research on diagnostics? The case of HER2/Neu testing in breast cancer.

PubMed

Trosman, Julia R; Weldon, Christine B; Schink, Julian C; Gradishar, William J; Benson, Al B

2013-07-01

Comparing effectiveness of diagnostic tests is one of the highest priorities for comparative effectiveness research (CER) set by the Institute of Medicine. Our study aims to identify what information providers, payers and patients need from CER on diagnostics, and what challenges they encounter implementing comparative information on diagnostic alternatives in practice and policy. Using qualitative research methods and the example of two alternative protocols for HER2 testing in breast cancer, we conducted interviews with 45 stakeholders: providers (n = 25) from four academic and eight nonacademic institutions, executives (n = 13) from five major US private payers and representatives (n = 7) from two breast cancer patient advocacies. The need for additional scientific evidence to determine the preferred HER2 protocol was more common for advocates than payers (100 vs 54%; p = 0.0515) and significantly more common for advocates than providers (100 vs 40%; p = 0.0077). The availability of information allowing assessment of the implementation impact from alternative diagnostic protocols on provider institutions may mitigate the need for additional scientific evidence for some providers and payers (24 and 46%, respectively). The cost-effectiveness of alternative protocols from the societal perspective is important to payers and advocates (69 and 71%, respectively) but not to providers (0%; p = 0.0001 and p = 0.0001). The lack of reporting laboratory practices is a more common implementation challenge for payers and advocates (77 and 86%, respectively) than for providers (32%). The absence of any mechanism for patient involvement was recognized as a challenge by payers and advocates (69 and 100%, respectively) but not by providers (0%; p = 0.0001 and p = 0.0001). Comparative implementation research is needed to inform the stakeholders considering diagnostic alternatives. Transparency of laboratory practices is an important factor in enabling implementation of CER on diagnostics in practice and policy. The incongruent views of providers versus patient advocates and payers on involving patients in diagnostic decisions is a concerning challenge to utilizing the results of CER.

Observational Study Designs for Comparative Effectiveness Research: An Alternative Approach to Close Evidence Gaps in Head-and-Neck Cancer

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

Goulart, Bernardo H.L., E-mail: bhg@uw.edu; University of Washington, Seattle, Washington; Ramsey, Scott D.

Comparative effectiveness research (CER) has emerged as an approach to improve quality of care and patient outcomes while reducing healthcare costs by providing evidence to guide healthcare decisions. Randomized controlled trials (RCTs) have represented the ideal study design to support treatment decisions in head-and-neck (H and N) cancers. In RCTs, formal chance (randomization) determines treatment allocation, which prevents selection bias from distorting the measure of treatment effects. Despite this advantage, only a minority of patients qualify for inclusion in H and N RCTs, which limits the validity of their results to the broader H and N cancer patient population seenmore » in clinical practice. Randomized controlled trials often do not address other knowledge gaps in the management of H and N cancer, including treatment comparisons for rare types of H and N cancers, monitoring of rare or late toxicity events (eg, osteoradionecrosis), or in some instances an RCT is simply not feasible. Observational studies, or studies in which treatment allocation occurs independently of investigators' choice or randomization, may address several of these gaps in knowledge, thereby complementing the role of RCTs. This critical review discusses how observational CER studies complement RCTs in generating the evidence to inform healthcare decisions and improve the quality of care and outcomes of H and N cancer patients. Review topics include a balanced discussion about the strengths and limitations of both RCT and observational CER study designs; a brief description of design and analytic techniques to handle selection bias in observational studies; examples of observational studies that inform current clinical practices and management of H and N cancers; and suggestions for relevant CER questions that could be addressed by an observational study design.« less

Observational study designs for comparative effectiveness research: an alternative approach to close evidence gaps in head-and-neck cancer.

PubMed

Goulart, Bernardo H L; Ramsey, Scott D; Parvathaneni, Upendra

2014-01-01

Comparative effectiveness research (CER) has emerged as an approach to improve quality of care and patient outcomes while reducing healthcare costs by providing evidence to guide healthcare decisions. Randomized controlled trials (RCTs) have represented the ideal study design to support treatment decisions in head-and-neck (H&N) cancers. In RCTs, formal chance (randomization) determines treatment allocation, which prevents selection bias from distorting the measure of treatment effects. Despite this advantage, only a minority of patients qualify for inclusion in H&N RCTs, which limits the validity of their results to the broader H&N cancer patient population seen in clinical practice. Randomized controlled trials often do not address other knowledge gaps in the management of H&N cancer, including treatment comparisons for rare types of H&N cancers, monitoring of rare or late toxicity events (eg, osteoradionecrosis), or in some instances an RCT is simply not feasible. Observational studies, or studies in which treatment allocation occurs independently of investigators' choice or randomization, may address several of these gaps in knowledge, thereby complementing the role of RCTs. This critical review discusses how observational CER studies complement RCTs in generating the evidence to inform healthcare decisions and improve the quality of care and outcomes of H&N cancer patients. Review topics include a balanced discussion about the strengths and limitations of both RCT and observational CER study designs; a brief description of design and analytic techniques to handle selection bias in observational studies; examples of observational studies that inform current clinical practices and management of H&N cancers; and suggestions for relevant CER questions that could be addressed by an observational study design. Copyright © 2014 Elsevier Inc. All rights reserved.

Protection of a Ceramide Synthase 2 Null Mouse from Drug-induced Liver Injury

PubMed Central

Park, Woo-Jae; Park, Joo-Won; Erez-Roman, Racheli; Kogot-Levin, Aviram; Bame, Jessica R.; Tirosh, Boaz; Saada, Ann; Merrill, Alfred H.; Pewzner-Jung, Yael; Futerman, Anthony H.

2013-01-01

Very long chain (C22-C24) ceramides are synthesized by ceramide synthase 2 (CerS2). A CerS2 null mouse displays hepatopathy because of depletion of C22-C24 ceramides, elevation of C16-ceramide, and/or elevation of sphinganine. Unexpectedly, CerS2 null mice were resistant to acetaminophen-induced hepatotoxicity. Although there were a number of biochemical changes in the liver, such as increased levels of glutathione and multiple drug-resistant protein 4, these effects are unlikely to account for the lack of acetaminophen toxicity. A number of other hepatotoxic agents, such as d-galactosamine, CCl4, and thioacetamide, were also ineffective in inducing liver damage. All of these drugs and chemicals require connexin (Cx) 32, a key gap junction protein, to induce hepatotoxicity. Cx32 was mislocalized to an intracellular location in hepatocytes from CerS2 null mice, which resulted in accelerated rates of its lysosomal degradation. This mislocalization resulted from the altered membrane properties of the CerS2 null mice, which was exemplified by the disruption of detergent-resistant membranes. The lack of acetaminophen toxicity and Cx32 mislocalization were reversed upon infection with recombinant adeno-associated virus expressing CerS2. We establish that Gap junction function is compromised upon altering the sphingolipid acyl chain length composition, which is of relevance for understanding the regulation of drug-induced liver injury. PMID:24019516

76 FR 33761 - Agency Information Collection Request. 30-Day Public Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-09

... behavior change, interaction design, and service innovation to increase the understanding and adoption of Comparative Effectiveness Research (CER) information by physicians and patients. By truly understanding the...

Recommendations for incorporating patient-reported outcomes into clinical comparative effectiveness research in adult oncology.

PubMed

Basch, Ethan; Abernethy, Amy P; Mullins, C Daniel; Reeve, Bryce B; Smith, Mary Lou; Coons, Stephen Joel; Sloan, Jeff; Wenzel, Keith; Chauhan, Cynthia; Eppard, Wayland; Frank, Elizabeth S; Lipscomb, Joseph; Raymond, Stephen A; Spencer, Merianne; Tunis, Sean

2012-12-01

Examining the patient's subjective experience in prospective clinical comparative effectiveness research (CER) of oncology treatments or process interventions is essential for informing decision making. Patient-reported outcome (PRO) measures are the standard tools for directly eliciting the patient experience. There are currently no widely accepted standards for developing or implementing PRO measures in CER. Recommendations for the design and implementation of PRO measures in CER were developed via a standardized process including multistakeholder interviews, a technical working group, and public comments. Key recommendations are to include assessment of patient-reported symptoms as well as health-related quality of life in all prospective clinical CER studies in adult oncology; to identify symptoms relevant to a particular study population and context based on literature review and/or qualitative and quantitative methods; to assure that PRO measures used are valid, reliable, and sensitive in a comparable population (measures particularly recommended include EORTC QLQ-C30, FACT, MDASI, PRO-CTCAE, and PROMIS); to collect PRO data electronically whenever possible; to employ methods that minimize missing patient reports and include a plan for analyzing and reporting missing PRO data; to report the proportion of responders and cumulative distribution of responses in addition to mean changes in scores; and to publish results of PRO analyses simultaneously with other clinical outcomes. Twelve core symptoms are recommended for consideration in studies in advanced or metastatic cancers. Adherence to methodologic standards for the selection, implementation, and analysis/reporting of PRO measures will lead to an understanding of the patient experience that informs better decisions by patients, providers, regulators, and payers.

AHRQ series paper 2: principles for developing guidance: AHRQ and the effective health-care program.

PubMed

Helfand, Mark; Balshem, Howard

2010-05-01

This article describes some of the fundamental principles that have been developed to guide the work of producing comparative effectiveness reviews (CERs). We briefly describe the role stakeholders play in providing important insights that inform the evidence-gathering process, and discuss the critical role of analytic frameworks in illuminating the relationship between surrogate measures and health outcomes, providing an understanding of the context in which clinical decisions are made and the uncertainties that underlie clinical controversies. We describe the Effective Health Care program conceptual model for considering different types of evidence that emphasizes minimizing the risk of bias, but places high-quality, highly applicable evidence about effectiveness at the top of the hierarchy. Finally, we briefly describe areas of future methodological research. CERs have become a foundation for decision-making in clinical practice and health policy. To be useful, CERs must approach the evidence from a patient-centered perspective; explore the clinical logic underlying the rationale for a service; cast a broad net with respect to types of evidence, placing a high value on effectiveness and applicability, in addition to internal validity; and, present benefits and harms for treatments and tests in a consistent way.

Pathological levels of glucosylceramide change the biophysical properties of artificial and cell membranes.

PubMed

Varela, Ana R P; Ventura, Ana E; Carreira, Ana C; Fedorov, Aleksander; Futerman, Anthony H; Prieto, Manuel; Silva, Liana C

2016-12-21

Glucosylceramide (GlcCer) plays an active role in the regulation of various cellular events. Moreover, GlcCer is also a key modulator of membrane biophysical properties, which might be linked to the mechanism of its biological action. In order to understand the biophysical implications of GlcCer on membranes of living cells, we first studied the effect of GlcCer on artificial membranes containing 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), sphingomyelin (SM) and cholesterol (Chol). Using an array of biophysical methods, we demonstrate that at lower GlcCer/Chol ratios, GlcCer stabilizes SM/Chol-enriched liquid-ordered domains. However, upon decreasing the Chol content, GlcCer significantly increased membrane order through the formation of gel domains. Changes in pH disturbed the packing properties of GlcCer-containing membranes, leading to an increase in membrane fluidity and reduced membrane electronegativity. To address the biophysical impact of GlcCer in biological membranes, studies were performed in wild type and in fibroblasts treated with conduritol-B-epoxide (CBE), which causes intracellular GlcCer accumulation, and in fibroblasts from patients with type I Gaucher disease (GD). Decreased membrane fluidity was observed in cells containing higher levels of GlcCer, such as in CBE-treated and GD cells. Together, we demonstrate that elevated GlcCer levels change the biophysical properties of cellular membranes, which might compromise membrane-associated cellular events and be of relevance for understanding the pathology of diseases, such as GD, in which GlcCer accumulates at high levels.

EBM, HTA, and CER: clearing the confusion.

PubMed

Luce, Bryan R; Drummond, Michael; Jönsson, Bengt; Neumann, Peter J; Schwartz, J Sanford; Siebert, Uwe; Sullivan, Sean D

2010-06-01

The terms evidence-based medicine (EBM), health technology assessment (HTA), comparative effectiveness research (CER), and other related terms lack clarity and so could lead to miscommunication, confusion, and poor decision making. The objective of this article is to clarify their definitions and the relationships among key terms and concepts. This article used the relevant methods and policy literature as well as the websites of organizations engaged in evidence-based activities to develop a framework to explain the relationships among the terms EBM, HTA, and CER. This article proposes an organizing framework and presents a graphic demonstrating the differences and relationships among these terms and concepts. More specific terminology and concepts are necessary for an informed and clear public policy debate. They are even more important to inform decision making at all levels and to engender more accountability by the organizations and individuals responsible for these decisions.

[Patient-reported and patient-weighted outcomes in ophthalmology].

PubMed

Scheibler, F; Finger, R P; Grosselfinger, R; Dintsios, C-M

2010-03-01

Considering patients' values and preferences in comparative effectiveness research (CER) is one of the main challenges in ophthalmology (value-based medicine). This article defines core terms in CER. The concept of patient-relevant (or patient-important) outcomes is distinguished from patient-reported outcomes (PRO) by means of examples in the field of ophthalmology. In order to be able to give a consistant recommendation if an intervention leads to conflicting results for different outcomes (trade-off), a ranking of outcomes will be necessary. Examples of studies in glaucoma patients are provided that demonstrate the possibilities of ranking of outcomes based on patient preferences.

Rationale and design of the STAR randomized controlled trial to accelerate adoption of childhood obesity comparative effectiveness research.

PubMed

Taveras, Elsie M; Marshall, Richard; Horan, Christine M; Gillman, Matthew W; Hacker, Karen; Kleinman, Ken P; Koziol, Renata; Price, Sarah; Simon, Steven R

2013-01-01

Comparative effectiveness research (CER) evidence on childhood obesity provides the basis for effective screening and management strategies in pediatric primary care. The uses of health information technology including decision support tools in the electronic health records (EHRs), as well as remote and mobile support to families, offer the potential to accelerate the adoption of childhood obesity CER evidence. The Study of Technology to Accelerate Research (STAR) is a three-arm, cluster-randomized controlled trial being conducted in 14 pediatric offices in Massachusetts designed to enroll 800, 6 to 12 year old children with a body mass index (BMI)≥ 95th percentile seen in primary care at those practices. We will examine the extent to which computerized decision support tools in the EHR delivered to primary care providers at the point of care, with or without direct-to-parent support and coaching, will increase adoption of CER evidence for management of obese children. Direct-to-parent intervention components include telephone coaching and twice-weekly text messages. Point-of-care outcomes include obesity diagnosis, nutrition and physical activity counseling, and referral to weight management. One-year child-level outcomes include changes in BMI and improvements in diet, physical activity, screen time, and sleep behaviors, as well as cost and cost-effectiveness. STAR will determine the extent to which decision support tools in EHRs with or without direct-to-parent support will increase adoption of evidence-based obesity management strategies in pediatric practice and improve childhood obesity-related outcomes. Copyright © 2012 Elsevier Inc. All rights reserved.

Measurement in Comparative Effectiveness Research

PubMed Central

Chubak, Jessica; Rutter, Carolyn M.; Kamineni, Aruna; Johnson, Eric A.; Stout, Natasha K.; Weiss, Noel S.; Doria-Rose, V. Paul; Doubeni, Chyke A.; Buist, Diana S.M.

2013-01-01

Comparative effectiveness research (CER) on preventive services can shape policy and help patients, their providers, and public health practitioners select regimens and programs for disease prevention. Patients and providers need information about the relative effectiveness of various regimens they may choose. Decision makers need information about the relative effectiveness of various programs to offer or recommend. The goal of this paper is to define and differentiate measures of relative effectiveness of regimens and programs for disease prevention. Cancer screening is used to demonstrate how these measures differ in an example of two hypothetic screening regimens and programs. Conceptually and algebraically defined measures of relative regimen and program effectiveness are also presented. The measures evaluate preventive services that range from individual tests through organized, population-wide prevention programs. Examples illustrate how effective screening regimens may not result in effective screening programs and how measures can vary across subgroups and settings. Both regimen and program relative effectiveness measures assess benefits of prevention services in real-world settings, but each addresses different scientific and policy questions. As the body of CER grows, a common lexicon for various measures of relative effectiveness becomes increasingly important to facilitate communication and shared understanding among researchers, healthcare providers, patients, and policymakers. PMID:23597816

Assessing the comparative effectiveness of newly marketed medications: methodological challenges and implications for drug development.

PubMed

Schneeweiss, S; Gagne, J J; Glynn, R J; Ruhl, M; Rassen, J A

2011-12-01

Comparative-effectiveness research (CER) aims to produce actionable evidence regarding the effectiveness and safety of medical products and interventions as they are used outside of controlled research settings. Although CER evidence regarding medications is particularly needed shortly after market approval, key methodological challenges include (i) potential bias due to channeling of patients to the newly marketed medication because of various patient-, physician-, and system-related factors; (ii) rapid changes in the characteristics of the user population during the early phase of marketing; and (iii) lack of timely data and the often small number of users in the first few months of marketing. We propose a mix of approaches to generate comparative-effectiveness data in the early marketing period, including sequential cohort monitoring with secondary health-care data and propensity score (PS) balancing, as well as extended follow-up of phase III and phase IV trials, indirect comparisons of placebo-controlled trials, and modeling and simulation of virtual trials.

Interrupted time series design: a useful approach for studying interventions targeting participation.

PubMed

Anaby, Dana; Lal, Shalini; Huszczynski, Justine; Maich, Jana; Rogers, Jade; Law, Mary

2014-11-01

Comparative effectiveness research (CER) strives for evidence to inform clinical decisions for specific clients in typical health care settings. While the randomized controlled trial (RCT) is well-aligned with the objectives of CER, this design may not be feasible or applicable to all research questions, particularly those pertaining to clinical decision making and individually based change. It is important, therefore, to consider alternative approaches, especially when studying complex and subjective outcomes such as children's participation. We propose the use of interrupted time series (ITS) quasi-experimental design for its potential application in determining the effectiveness of participation-focused interventions. In this perspective, ITS design is described, ascertaining its advantages and limitations, and suggestions are provided to overcome challenges to implementation. Results of a case study using the ITS approach to evaluate changes in participation of an adolescent with physical disabilities are described. Finally, strategies to implement this design in practice are suggested.

Epidermal Hydration Is Improved by Enhanced Ceramide Metabolism in Aged C57BL/6J Mice After Dietary Supplementation of Royal Jelly.

PubMed

Jeon, Sanghun; Cho, Yunhi

2015-09-01

Epidermal hydration is maintained by the epidermal lipid barrier, of which ceramide (Cer) is the major constituent. We examined the dietary effect of royal jelly (RJ) on epidermal hydration in aged mice. Altered Cer metabolism was further determined by measuring epidermal levels of individual Cer, glucosylceramide (GC), and sphingomyelin (SM) species, and of Cer-metabolizing enzymes. Aged C57BL/6J mice were fed a control diet (group AGED) or diets with 1% RJ harvested from two different areas (groups AGED+RJ1:AGED + RJ2) for 16 weeks. Aged C57BL/6J mice with no dietary intervention (the control group: group C) represented the onset of aging. In group AGED, epidermal levels of hydration, Cer1/2/5/6/7, GC-A/B/C/D, SM1/2/3, and β-glucocerebrosidase (GCase) protein, an enzyme of GC hydrolysis for Cer generation, were lower than in group C; these levels, as well as those of Cer3/4 and acidic sphingomyelinase (aSMase) protein, an enzyme of SM hydrolysis for Cer generation, were higher in group AGED + RJ1 than in group AGED. Despite increases in GC-B, SM1/2/3, and serine palmitoyltransferase2 protein, an enzyme of de novo Cer synthesis, in group AGED + RJ2 to levels higher than in group AGED, epidermal levels of hydration, Cer1-7, GC-A/C/D, GCase, and aSMase proteins were similar in these two groups. Expression of GCase and aSMase mRNAs, and of Cer synthase3 and ceramidase proteins, enzymes of de novo Cer synthesis and degradation, did not differ among groups. Dietary RJ1 improved epidermal hydration by enhancing Cer metabolism with increased levels of all Cer, GC, and SM species, and of GCase and aSMase proteins.

Patient-centered outcomes research in radiology: trends in funding and methodology.

PubMed

Lee, Christoph I; Jarvik, Jeffrey G

2014-09-01

The creation of the Patient-Centered Outcomes Research Trust Fund and the Patient-Centered Outcomes Research Institute (PCORI) through the Patient Protection and Affordable Care Act of 2010 presents new opportunities for funding patient-centered comparative effectiveness research (CER) in radiology. We provide an overview of the evolution of federal funding and priorities for CER with a focus on radiology-related priority topics over the last two decades, and discuss the funding processes and methodological standards outlined by PCORI. We introduce key paradigm shifts in research methodology that will be required on the part of radiology health services researchers to obtain competitive federal grant funding in patient-centered outcomes research. These paradigm shifts include direct engagement of patients and other stakeholders at every stage of the research process, from initial conception to dissemination of results. We will also discuss the increasing use of mixed methods and novel trial designs. One of these trial designs, the pragmatic trial, has the potential to be readily applied to evaluating the effectiveness of diagnostic imaging procedures and imaging-based interventions among diverse patient populations in real-world settings. Copyright © 2014 AUR. Published by Elsevier Inc. All rights reserved.

The Acyl Desaturase CER17 Is Involved in Producing Wax Unsaturated Primary Alcohols and Cutin Monomers1[OPEN

PubMed Central

Yang, Xianpeng; Zhao, Huayan; Kosma, Dylan K.; Dyer, John M.; Li, Rongjun; Liu, Xiulin; Wang, Zhouya; Jenks, Matthew A.

2017-01-01

We report n-6 monounsaturated primary alcohols (C26:1, C28:1, and C30:1 homologs) in the cuticular waxes of Arabidopsis (Arabidopsis thaliana) inflorescence stem, a class of wax not previously reported in Arabidopsis. The Arabidopsis cer17 mutant was completely deficient in these monounsaturated alcohols, and CER17 was found to encode a predicted ACYL-COENZYME A DESATURASE LIKE4 (ADS4). Studies of the Arabidopsis cer4 mutant and yeast variously expressing CER4 (a predicted fatty acyl-CoA reductase) with CER17/ADS4, demonstrated CER4’s principal role in synthesis of these monounsaturated alcohols. Besides unsaturated alcohol deficiency, cer17 mutants exhibited a thickened and irregular cuticle ultrastructure and increased amounts of cutin monomers. Although unsaturated alcohols were absent throughout the cer17 stem, the mutation’s effects on cutin monomers and cuticle ultrastructure were much more severe in distal than basal stems, consistent with observations that the CER17/ADS4 transcript was much more abundant in distal than basal stems. Furthermore, distal but not basal stems of a double mutant deficient for both CER17/ADS4 and LONG-CHAIN ACYL-COA SYNTHETASE1 produced even more cutin monomers and a thicker and more disorganized cuticle ultrastructure and higher cuticle permeability than observed for wild type or either mutant parent, indicating a dramatic genetic interaction on conversion of very long chain acyl-CoA precursors. These results provide evidence that CER17/ADS4 performs n-6 desaturation of very long chain acyl-CoAs in both distal and basal stems and has a major function associated with governing cutin monomer amounts primarily in the distal segments of the inflorescence stem. PMID:28069670

The Acyl Desaturase CER17 Is Involved in Producing Wax Unsaturated Primary Alcohols and Cutin Monomers.

PubMed

Yang, Xianpeng; Zhao, Huayan; Kosma, Dylan K; Tomasi, Pernell; Dyer, John M; Li, Rongjun; Liu, Xiulin; Wang, Zhouya; Parsons, Eugene P; Jenks, Matthew A; Lü, Shiyou

2017-02-01

We report n-6 monounsaturated primary alcohols (C 26:1 , C 28:1 , and C 30:1 homologs) in the cuticular waxes of Arabidopsis (Arabidopsis thaliana) inflorescence stem, a class of wax not previously reported in Arabidopsis. The Arabidopsis cer17 mutant was completely deficient in these monounsaturated alcohols, and CER17 was found to encode a predicted ACYL-COENZYME A DESATURASE LIKE4 (ADS4). Studies of the Arabidopsis cer4 mutant and yeast variously expressing CER4 (a predicted fatty acyl-CoA reductase) with CER17/ADS4, demonstrated CER4's principal role in synthesis of these monounsaturated alcohols. Besides unsaturated alcohol deficiency, cer17 mutants exhibited a thickened and irregular cuticle ultrastructure and increased amounts of cutin monomers. Although unsaturated alcohols were absent throughout the cer17 stem, the mutation's effects on cutin monomers and cuticle ultrastructure were much more severe in distal than basal stems, consistent with observations that the CER17/ADS4 transcript was much more abundant in distal than basal stems. Furthermore, distal but not basal stems of a double mutant deficient for both CER17/ADS4 and LONG-CHAIN ACYL-COA SYNTHETASE1 produced even more cutin monomers and a thicker and more disorganized cuticle ultrastructure and higher cuticle permeability than observed for wild type or either mutant parent, indicating a dramatic genetic interaction on conversion of very long chain acyl-CoA precursors. These results provide evidence that CER17/ADS4 performs n-6 desaturation of very long chain acyl-CoAs in both distal and basal stems and has a major function associated with governing cutin monomer amounts primarily in the distal segments of the inflorescence stem. © 2017 American Society of Plant Biologists. All Rights Reserved.

Ablation of ceramide synthase 2 exacerbates dextran sodium sulphate-induced colitis in mice due to increased intestinal permeability.

PubMed

Kim, Ye-Ryung; Volpert, Giora; Shin, Kyong-Oh; Kim, So-Yeon; Shin, Sun-Hye; Lee, Younghay; Sung, Sun Hee; Lee, Yong-Moon; Ahn, Jung-Hyuck; Pewzner-Jung, Yael; Park, Woo-Jae; Futerman, Anthony H; Park, Joo-Won

2017-12-01

Ceramides mediate crucial cellular processes including cell death and inflammation and have recently been implicated in inflammatory bowel disease. Ceramides consist of a sphingoid long-chain base to which fatty acids of various length can be attached. We now investigate the effect of alerting the ceramide acyl chain length on a mouse model of colitis. Ceramide synthase (CerS) 2 null mice, which lack very-long acyl chain ceramides with concomitant increase of long chain bases and C16-ceramides, were more susceptible to dextran sodium sulphate-induced colitis, and their survival rate was markedly decreased compared with that of wild-type littermates. Using mixed bone-marrow chimeric mice, we showed that the host environment is primarily responsible for intestinal barrier dysfunction and increased intestinal permeability. In the colon of CerS2 null mice, the expression of junctional adhesion molecule-A was markedly decreased and the phosphorylation of myosin light chain 2 was increased. In vitro experiments using Caco-2 cells also confirmed an important role of CerS2 in maintaining epithelial barrier function; CerS2-knockdown via CRISPR-Cas9 technology impaired barrier function. In vivo myriocin administration, which normalized long-chain bases and C16-ceramides of the colon of CerS2 null mice, increased intestinal permeability as measured by serum FITC-dextran levels, indicating that altered SLs including deficiency of very-long-chain ceramides are critical for epithelial barrier function. In conclusion, deficiency of CerS2 influences intestinal barrier function and the severity of experimental colitis and may represent a potential mechanism for inflammatory bowel disease pathogenesis. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Energy restriction and the prevention of breast cancer.

PubMed

Harvie, Michelle; Howell, Anthony

2012-05-01

Energy restriction (ER) to control weight is a potential strategy for breast cancer prevention. The protective effects of habitual continuous energy restriction (CER) and weight loss on breast tumour formation have been conclusively demonstrated in animal studies over the past 100 years, and more recently in women using data from observational studies and bariatric surgery. Intermittent energy restriction (IER) and intermittent fasting (IF) are possible alternative preventative approaches which may be easier for individuals to undertake and possibly more effective than standard CER. Here, we summarise the available data on CER, IER and IF with special emphasis on their potential for breast cancer prevention. In animals, IER is superior or equivalent to CER with the exception of carcinogen-induced tumour models when initiated soon after carcinogen exposure. There are no human data on IER and breast cancer risk, but three studies demonstrated IER and CER to be equivalent for weight loss. IF regimens also reduce mammary tumour formation in animal models and also led to weight loss in human subjects, but have not been directly compared with CER. Animal and some human data suggest that both IER and IF may differ mechanistically compared with CER and may bring about greater reduction in hepatic and visceral fat stores, insulin-like growth factor 1 (IGF-1) levels and cell proliferation, and increased insulin sensitivity and adiponectin levels. Although IER and IF were first studied 65 years ago, we conclude that further studies are required to assess their values compared with CER.

Complex Effects of 24:1 Sphingolipids in Membranes Containing Dioleoylphosphatidylcholine and Cholesterol.

PubMed

García-Arribas, Aritz B; González-Ramírez, Emilio J; Sot, Jesús; Areso, Itziar; Alonso, Alicia; Goñi, Félix M

2017-06-06

The effects of C24:1 sphingolipids have been tested in phospholipid bilayers containing cholesterol. Confocal microscopy, differential scanning calorimetry, and atomic force microscopy imaging and force curves have been used. More precisely, the effects of C24:1 ceramide (nervonoyl ceramide, nCer) were evaluated and compared to those of C16:0 ceramide (palmitoyl ceramide, pCer) in bilayers composed basically of dioleoylphosphatidylcholine, sphingomyelin (either C24:1, nSM or C16:0, pSM) and cholesterol. Combination of equimolecular amounts of C24:1 and C16:0 sphingolipids were also studied under the same conditions. Results show that both pCer and nCer are capable of forming segregated gel domains. Force spectroscopy data point to nCer having a lower stiffening effect than pCer, while the presence of nSM reduces the stiffness. DSC reveals T m reduction by nSM in every case. Furthermore, pSM seems to better accommodate both ceramides in a single phase of intermediate properties, while nSM partial accommodation of ceramides generates different gel phases with higher stiffnesses caused by interceramide cooperation. If both pSM and nSM are present, a clear preference of both ceramides toward pSM is observed. These findings show the sharp increase in complexity when membranes exhibit different sphingolipids of varying N-acyl chains, which should be a common issue in an actual cell membrane environment.

The effects of surface structure mutations in Arabidopsis thaliana on the polarization of reflections from virus-infected leaves.

PubMed

Maxwell, D J; Partridge, J C; Roberts, N W; Boonham, N; Foster, G D

2017-01-01

The way in which light is polarized when reflected from leaves can be affected by infection with plant viruses. This has the potential to influence viral transmission by insect vectors due to altered visual attractiveness of infected plants. The optical and topological properties of cuticular waxes and trichomes are important determinants of how light is polarized upon reflection. Changes in expression of genes involved in the formation of surface structures have also been reported following viral infection. This paper investigates the role of altered surface structures in virus-induced changes to polarization reflection from leaves. The percentage polarization of reflections from Arabidopsis thaliana cer5, cer6 and cer8 wax synthesis mutants, and the gl1 leaf hair mutant, was compared to those from wild-type (WT) leaves. The cer5 mutant leaves were less polarizing than WT on the adaxial and abaxial surfaces; gl1 leaves were more polarizing than WT on the adaxial surfaces. The cer6 and cer8 mutations did not significantly affect polarization reflection. The impacts of Turnip vein clearing virus (TVCV) infection on the polarization of reflected light were significantly affected by cer5 mutation, with the reflections from cer5 mutants being higher than those from WT leaves, suggesting that changes in CER5 expression following infection could influence the polarization of the reflections. There was, however, no significant effect of the gl1 mutation on polarization following TVCV infection. The cer5 and gl1 mutations did not affect the changes in polarization following Cucumber mosaic virus (CMV) infection. The accumulation of TVCV and CMV did not differ significantly between mutant and WT leaves, suggesting that altered expression of surface structure genes does not significantly affect viral titres, raising the possibility that if such regulatory changes have any adaptive value it may possibly be through impacts on viral transmission.

Observational studies in systematic [corrected] reviews of comparative effectiveness: AHRQ and the Effective Health Care Program.

PubMed

Norris, Susan L; Atkins, David; Bruening, Wendy; Fox, Steven; Johnson, Eric; Kane, Robert; Morton, Sally C; Oremus, Mark; Ospina, Maria; Randhawa, Gurvaneet; Schoelles, Karen; Shekelle, Paul; Viswanathan, Meera

2011-11-01

Systematic reviewers disagree about the ability of observational studies to answer questions about the benefits or intended effects of pharmacotherapeutic, device, or procedural interventions. This study provides a framework for decision making on the inclusion of observational studies to assess benefits and intended effects in comparative effectiveness reviews (CERs). The conceptual model and recommendations were developed using a consensus process by members of the methods workgroup of the Effective Health Care Program of the Agency for Healthcare Research and Quality. In considering whether to use observational studies in CERs for addressing beneficial effects, reviewers should answer two questions: (1) Are there gaps in the evidence from randomized controlled trials (RCTs)? (2) Will observational studies provide valid and useful information? The latter question involves the following: (a) refocusing the study questions on gaps in the evidence from RCTs, (b) assessing the risk of bias of the body of evidence of observational studies, and (c) assessing whether available observational studies address the gap review questions. Because it is unusual to find sufficient evidence from RCTs to answer all key questions concerning benefit or the balance of benefits and harms, comparative effectiveness reviewers should routinely assess the appropriateness of inclusion of observational studies for questions of benefit. Furthermore, reviewers should explicitly state the rationale for inclusion or exclusion of observational studies when conducting CERs. Copyright © 2011 Elsevier Inc. All rights reserved.

Evaluating Comparative Effectiveness Research Priorities for Care Coordination in Chronic Obstructive Pulmonary Disease: A Community-Based eDelphi Study

PubMed Central

Alber, Julia; Paige, Samantha; Castro, Daniela; Singh, Briana

2015-01-01

Background Despite research supporting the use of care coordination in chronic obstructive pulmonary disease (COPD), there is relatively little known about the comparative effectiveness of different strategies used to organize care for patients. To investigate the most important COPD care coordination strategies, community-based stakeholder input is needed, especially from medically underserved populations. Web-based platforms are electronic tools now being used to bring together individuals from underrepresented populations to share input and obtain clarification on comparative effectiveness research (CER) ideas, questions, and hypotheses. Objective Use low computer-literate, collaborative survey technology to evaluate stakeholder priorities for CER in COPD care coordination. Methods A mixed-method, concurrent triangulation design was used to collect survey data from a virtual advisory board of community-based stakeholders including medically underserved patients with COPD, informal caregivers, clinicians, and research scientists. The eDelphi method was used to conduct 3 iterative rounds of Web-based surveys. In the first 2 survey rounds, panelists viewed a series of “mini research prospectus” YouTube video presentations and rated their level of agreement with the importance of 10 COPD care coordination topics using 7-point Likert scales. In the final third-round survey, panelists ranked (1=most important, 8=least important) and commented on 8 remaining topics that panelists favored most throughout the first 2 survey rounds. Following the third-round survey, panelists were asked to provide feedback on the potential impact of a Web-based stakeholder engagement network dedicated to improving CER in COPD. Results Thirty-seven panelists rated the following care coordination topics as most important (lower means indicate greater importance): (1) measurement of quality of care (mean 2.73, SD 1.95); (2) management of COPD with other chronic health issues (mean 2.92, SD 1.67); (3) pulmonary rehabilitation as a model for care (mean 3.72; SD 1.93); (4) quality of care coordination (mean 4.12, SD 2.41); and (5) comprehensive COPD patient education (mean 4.27, SD 2.38). Stakeholder comments on the relative importance of these care coordination topics primarily addressed the importance of comparing strategies for COPD symptom management and evaluating new methods for patient-provider communication. Approximately one half of the virtual panel assembled indicated that a Web-based stakeholder engagement network could enable more online community meetings (n=19/37, 51%) and facilitate more opportunities to suggest, comment on, and vote for new CER ideas in COPD (n=18/37, 49%). Conclusions Members of this unique virtual advisory board engaged in a structured Web-based communication process that identified the most important community-specific COPD care coordination research topics and questions. Findings from this study support the need for more CER that evaluates quality of care measures used to assess the delivery of treatments and interventions among medically underserved patients with COPD. PMID:26268741

Development of CER-001: Preclinical Dose Selection Through to Phase I Clinical Findings.

PubMed

Keyserling, Constance H; Barbaras, Ronald; Benghozi, Renee; Dasseux, Jean-Louis

2017-05-01

CER-001 comprises recombinant human apolipoprotein A-I complexed with phospholipids that mimics natural, nascent, pre-β high-density lipoprotein (HDL). We present animal model data showing dose-dependent increases in cholesterol efflux with CER-001 and its subsequent elimination by reverse lipid transport, together with inhibition of atherosclerotic plaque progression. We report the first phase I study results with CER-001 in humans, starting at 0.25 mg/kg, which is 1/80th of the safe dose (20 mg/kg) established in 4-week multiple-dose animal studies dosed every second day. Healthy volunteers, 18-55 years old with a low-density lipoprotein-cholesterol:HDL-cholesterol ratio greater than 3.0, received single intravenous escalating doses of CER-001 (0.25-45.0 mg/kg) and placebo in a double-blind randomised cross-over fashion. Subjects were followed up for 3 weeks post-dose. Assessments included adverse event monitoring, blood sampling, and clinical laboratory measurements. Thirty-two subjects were enrolled. All CER-001 doses (0.25-45 mg/kg) were safe and well tolerated, with an adverse event profile similar to placebo. Effects on clinical chemistry, haematology and coagulation parameters were comparable to placebo. No adverse effects of CER-001 on electrocardiograms were observed. No antibodies to apolipoprotein A-I were detected following single-dose administration of CER-001. Plasma apolipoprotein A-I levels increased in a dose-related manner and returned to baseline by 24 h post-dose for doses up to 10 mg/kg but remained in circulation for >72 h post-dose for doses >10 mg/kg. CER-001 caused elevations in plasma cholesterol and total and unesterified cholesterol in the HDL fraction. Mobilisation of unesterified cholesterol in the HDL fraction was seen with CER-001 at doses as low as 2 mg/kg. CER-001 is well tolerated when administered to humans as single doses up to 45 mg/kg and mobilises and eliminates cholesterol via reverse lipid transport.

Measurement in comparative effectiveness research.

PubMed

Chubak, Jessica; Rutter, Carolyn M; Kamineni, Aruna; Johnson, Eric A; Stout, Natasha K; Weiss, Noel S; Doria-Rose, V Paul; Doubeni, Chyke A; Buist, Diana S M

2013-05-01

Comparative effectiveness research (CER) on preventive services can shape policy and help patients, their providers, and public health practitioners select regimens and programs for disease prevention. Patients and providers need information about the relative effectiveness of various regimens they may choose. Decision makers need information about the relative effectiveness of various programs to offer or recommend. The goal of this paper is to define and differentiate measures of relative effectiveness of regimens and programs for disease prevention. Cancer screening is used to demonstrate how these measures differ in an example of two hypothetical screening regimens and programs. Conceptually and algebraically defined measures of relative regimen and program effectiveness also are presented. The measures evaluate preventive services that range from individual tests through organized, population-wide prevention programs. Examples illustrate how effective screening regimens may not result in effective screening programs and how measures can vary across subgroups and settings. Both regimen and program relative effectiveness measures assess benefits of prevention services in real-world settings, but each addresses different scientific and policy questions. As the body of CER grows, a common lexicon for various measures of relative effectiveness becomes increasingly important to facilitate communication and shared understanding among researchers, healthcare providers, patients, and policymakers. Copyright © 2013 American Journal of Preventive Medicine. All rights reserved.

Data quality assessment for comparative effectiveness research in distributed data networks

PubMed Central

Brown, Jeffrey; Kahn, Michael; Toh, Sengwee

2015-01-01

Background Electronic health information routinely collected during healthcare delivery and reimbursement can help address the need for evidence about the real-world effectiveness, safety, and quality of medical care. Often, distributed networks that combine information from multiple sources are needed to generate this real-world evidence. Objective We provide a set of field-tested best practices and a set of recommendations for data quality checking for comparative effectiveness research (CER) in distributed data networks. Methods Explore the requirements for data quality checking and describe data quality approaches undertaken by several existing multi-site networks. Results There are no established standards regarding how to evaluate the quality of electronic health data for CER within distributed networks. Data checks of increasing complexity are often employed, ranging from consistency with syntactic rules to evaluation of semantics and consistency within and across sites. Temporal trends within and across sites are widely used, as are checks of each data refresh or update. Rates of specific events and exposures by age group, sex, and month are also common. Discussion Secondary use of electronic health data for CER holds promise but is complex, especially in distributed data networks that incorporate periodic data refreshes. The viability of a learning health system is dependent on a robust understanding of the quality, validity, and optimal secondary uses of routinely collected electronic health data within distributed health data networks. Robust data quality checking can strengthen confidence in findings based on distributed data network. PMID:23793049

Impact of Postapproval Evidence Generation on the Biopharmaceutical Industry.

PubMed

Milne, Christopher-Paul; Cohen, Joshua P; Felix, Abigail; Chakravarthy, Ranjana

2015-08-01

Meeting marketplace demands for proving the value of new products requires more data than the industry has routinely produced. These data include evidence from comparative effectiveness research (CER), including randomized, controlled trials; pragmatic clinical trials; observational studies; and meta-analyses. We designed and conducted a survey to examine the industry's perceptions on new data requirements regarding CER evidence, the acceptability of postapproval study types, payer-specific issues related to CER, communication of data being generated postapproval, and methods used for facilitating postapproval evidence generation. CER is being used by payers for most types of postapproval decisions. Randomized, controlled trials were indicated as the most acceptable form of evidence. At the same time, there was support for the utility of other types of studies, such as pragmatic clinical trials and observational studies. Respondents indicated the use of multiple formats for communicating postapproval data with many different stakeholders including regulators, payers, providers, and patients. Risk-sharing agreements with payers were unanimously supported by respondents with regard to certain products with unclear clinical and economic outcomes at launch. In these instances, conditional reimbursement through coverage with evidence development was considered a constructive option. The Food and Drug Administration's initiative called Regulatory Science was considered by the respondents as having the most impact on streamlining the generation of postapproval research-related evidence. The biopharmaceutical industry is faced with a broad and complex set of challenges related to evidence generation for postapproval decisions by a variety of health care system stakeholders. Uncertainty remains as to how the industry and payers use postapproval studies to guide decision making with regard to pricing and reimbursement status. Correspondingly, there is uncertainty regarding whether the industry's investment in CER will have a positive return on investment in terms of reimbursement and market access. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

Arabidopsis ECERIFERUM9 involvement in cuticle formation and maintenance of plant water status.

PubMed

Lü, Shiyou; Zhao, Huayan; Des Marais, David L; Parsons, Eugene P; Wen, Xiaoxue; Xu, Xiaojing; Bangarusamy, Dhinoth K; Wang, Guangchao; Rowland, Owen; Juenger, Thomas; Bressan, Ray A; Jenks, Matthew A

2012-07-01

Mutation of the ECERIFERUM9 (CER9) gene in Arabidopsis (Arabidopsis thaliana) causes elevated amounts of 18-carbon-length cutin monomers and a dramatic shift in the cuticular wax profile (especially on leaves) toward the very-long-chain free fatty acids tetracosanoic acid (C₂₄) and hexacosanoic acid (C₂₆). Relative to the wild type, cer9 mutants exhibit elevated cuticle membrane thickness over epidermal cells and cuticular ledges with increased occlusion of the stomatal pore. The cuticular phenotypes of cer9 are associated with delayed onset of wilting in plants experiencing water deficit, lower transpiration rates, and improved water use efficiency measured as carbon isotope discrimination. The CER9 protein thus encodes a novel determinant of plant drought tolerance-associated traits, one whose deficiency elevates cutin synthesis, redistributes wax composition, and suppresses transpiration. Map-based cloning identified CER9, and sequence analysis predicted that it encodes an E3 ubiquitin ligase homologous to yeast Doa10 (previously shown to target endoplasmic reticulum proteins for proteasomal degradation). To further elucidate CER9 function, the impact of CER9 deficiency on interactions with other genes was examined using double mutant and transcriptome analyses. For both wax and cutin, cer9 showed mostly additive effects with cer6, long-chain acyl-CoA synthetase1 (lacs1), and lacs2 and revealed its role in early steps of both wax and cutin synthetic pathways. Transcriptome analysis revealed that the cer9 mutation affected diverse cellular processes, with primary impact on genes associated with diverse stress responses. The discovery of CER9 lays new groundwork for developing novel cuticle-based strategies for improving the drought tolerance and water use efficiency of crop plants.

Impact of the long chain omega-acylceramides on the stratum corneum lipid nanostructure. Part 1: Thermotropic phase behaviour of CER[EOS] and CER[EOP] studied using X-ray powder diffraction and FT-Raman spectroscopy.

PubMed

Kessner, Doreen; Brezesinski, Gerald; Funari, Sergio S; Dobner, Bodo; Neubert, Reinhard H H

2010-01-01

The stratum corneum (SC), the outermost layer of the mammalian skin, is the main skin barrier. Ceramides (CERs) as the major constituent of the SC lipid matrix are of particular interest. At the moment, 11 classes of CERs are identified, but the effect of each single ceramide species is still not known. Therefore in this article, the thermotropic behaviour of the long chain omega-acylceramides CER[EOS] and CER[EOP] was studied using X-ray powder diffraction and FT-Raman spectroscopy. It was found that the omega-acylceramides CER[EOS] and CER[EOP] do not show a pronounced polymorphism which is observed for shorter chain ceramides as a significant feature. The phase behaviour of both ceramides is strongly influenced by the extremely long acyl-chain residue. The latter has a much stronger influence compared with the structure of the polar head group, which is discussed as extremely important for the appearance of a rich polymorphism. Despite the strong influence of the long chain, the additional OH-group of the phyto-sphingosine type CER[EOP] influences the lamellar repeat distance and the chain packing. The less polar sphingosine type CER[EOS] is stronger influenced by the long acyl-chain residue. Hydration is necessary for the formation of an extended hydrogen-bonding network between the polar head groups leading to the appearance of a long-periodicity phase (LPP). In contrast, the more polar CER[EOP] forms the LPP with densely packed alkyl chains already in the dry state.

Cytokine-induced release of ceramide-enriched exosomes as a mediator of cell death signaling in an oligodendroglioma cell line[S

PubMed Central

Podbielska, Maria; Szulc, Zdzisław M.; Kurowska, Ewa; Hogan, Edward L.; Bielawski, Jacek; Bielawska, Alicja; Bhat, Narayan R.

2016-01-01

Th1 pro-inflammatory cytokines, i.e., TNF-α and IFN-γ, in combination are known to induce cell death in several cell types, including oligodendrocytes, but the mechanism of their synergistic cytotoxicity is unclear. Although ceramide (Cer) has been implicated in cytokine- and stress-induced cell death, its intracellular levels alone cannot explain cytokine synergy. We considered the possibility that Cer released as part of extracellular vesicles may contribute to cytokine-induced synergistic cell death. Using a human oligodendroglioma (HOG) cell line as a model, here we show that exosomes derived from TNF-α-treated “donor” cells, while being mildly toxic to fresh cultures (similar to individual cytokines), induce enhanced cell death when added to IFN-γ-primed target cultures in a fashion resembling the effect of cytokine combination. Further, the sphingolipid profiles of secreted exosomes, as determined by HPLC-MS/MS, revealed that the treatment with the cytokines time-dependently induced the formation and exosomal release, in particular of C16-, C24-, and C24:1-Cer species; C16-, C24-, and C24:1-dihydroCer species; and C16-, C24-, and C24:1-SM species. Finally, exogenous C6-Cer or C16-Cer mimicked and enhanced the cytotoxic effects of the cytokines upon HOG cells, thereby supporting the cell death-signaling role of extracellular Cer. PMID:27623848

78 FR 63551 - Self-Regulatory Organizations; NYSE MKT LLC; Notice of Filing and Immediate Effectiveness of...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-24

... Panel, which would be renamed the CER Panel to distinguish it from the Obvious Error Panel (``OE Panel... to the Panel, which will be renamed the CER Panel to distinguish it from the Obvious Error Panel... respect to a transaction, the party can appeal that determination to the CER Panel within 30 minutes of...

78 FR 63555 - Self-Regulatory Organizations; NYSE Arca, Inc.; Notice of Filing and Immediate Effectiveness of...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-24

... Catastrophic Error has occurred, subject to an appeal to the Panel, which would be renamed the CER Panel to... Panel, which will be renamed the CER Panel to distinguish it from the Obvious Error Panel (``OE Panel... transaction, the party can appeal that determination to the CER Panel within 30 minutes of receiving...

Conditioned Emotional Response: Performance Decrement in Humans as a Function of Task Complexity. Final Report.

ERIC Educational Resources Information Center

Sachs, David A.; May, Jack G., Jr.

This study was designed to investigate the effects of increasing levels of task complexity on the conditioned emotional response (CER) with human subjects (Ss). Three hypotheses were proposed: (1) the CER would increase as task complexity increased, (2) there would be sex differences between Ss with respect to the interaction between the CER and…

The Multi-Frequency Correlation Between Eua and sCER Futures Prices: Evidence from the Emd Approach

NASA Astrophysics Data System (ADS)

Zhang, Yue-Jun; Huang, Yi-Song

2015-05-01

Currently European Union Allowances (EUA) and secondary Certified Emission Reduction (sCER) have become two dominant carbon trading assets for investors and their linkage attracts much attention from academia and practitioners in recent years. Under this circumstance, we use the empirical mode decomposition (EMD) approach to decompose the two carbon futures contract prices and discuss their correlation from the multi-frequency perspective. The empirical results indicate that, first, the EUA and sCER futures price movements can be divided into those triggered by the long-term, medium-term and short-term market impacts. Second, the price movements in the EUA and sCER futures markets are primarily caused by the long-term impact, while the short-term impact can only explain a small fraction. Finally, the long-term (short-term) effect on EUA prices is statistically uncorrelated with the short-term (long-term) effect of sCER prices, and there is a medium or strong lead-and-lag correlation between the EUA and sCER price components with the same time scales. These results may provide some important insights of price forecast and arbitraging activities for carbon futures market investors, analysts and regulators.

Beatty Wind Monitoring Project

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

Hurt, Rick

2009-06-01

The UNLV Center for Energy Research (CER) and Valley Electric Association (VEA) worked with Kitty Shubert of the Beatty Economic Redevelopment Corporation (BERC) to install two wind monitoring stations outside the town of Beatty, Nevada. The following is a description of the two sites. The information for a proposed third site is also shown. The sites were selected from previous work by the BERC and Idaho National Laboratory. The equipment was provided by the BERC and installed by researchers from the UNLV CER.

Effects of temperature and light on photosynthesis of dominant species of a northern hardwood forest. [Populus grandidentata, Quercus rubra, Betula papyrifera

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

Jurik, T.W.; Weber, J.A.; Gates, D.M.

1988-06-01

The response of CO{sub 2} exchange rate (CER) to temperature and light was determined for 14 dominant plant species of a northern deciduous hardwood forest in northern lower Michigan. Leaves at the top of the canopy had temperature optima near 25 C for CER, whereas leaves in the understory had optima near 20 C. There was no change in optimum temperature over the growing season, and overall shapes of response curves were similar among species. The lack of change in temperature optima may be a result of little change in growing conditions rather than a lack of ability to acclimatize.more » Nine of 11 species in the understory had no significant differences in light-saturated, maximum CERs, whereas at the top of the canopy Populus grandidentata had a higher maximum CER than Quercus rubra and Betula papyrifera. The species in the understory also differed little in light-saturation points for CER. Species at the top of the canopy had higher values for maximum CER, light-saturation point for CER, and maximum conductance than did species in the understory.« less

Effect of open-label infusion of an apoA-I-containing particle (CER-001) on RCT and artery wall thickness in patients with FHA[S

PubMed Central

Kootte, Ruud S.; Smits, Loek P.; van der Valk, Fleur M.; Dasseux, Jean-Louis; Keyserling, Constance H.; Barbaras, Ronald; Paolini, John F.; Santos, Raul D.; van Dijk, Theo H.; Dallinga-van Thie, Geesje M.; Nederveen, Aart J.; Mulder, Willem J. M.; Hovingh, G. Kees; Kastelein, John J. P.; Groen, Albert K.; Stroes, Erik S.

2015-01-01

Reverse cholesterol transport (RCT) contributes to the anti-atherogenic effects of HDL. Patients with the orphan disease, familial hypoalphalipoproteinemia (FHA), are characterized by decreased tissue cholesterol removal and an increased atherogenic burden. We performed an open-label uncontrolled proof-of-concept study to evaluate the effect of infusions with a human apoA-I-containing HDL-mimetic particle (CER-001) on RCT and the arterial vessel wall in FHA. Subjects received 20 infusions of CER-001 (8 mg/kg) during 6 months. Efficacy was assessed by measuring (apo)lipoproteins, plasma-mediated cellular cholesterol efflux, fecal sterol excretion (FSE), and carotid artery wall dimension by MRI and artery wall inflammation by 18F-fluorodeoxyglucose-positron emission tomography/computed tomography scans. We included seven FHA patients: HDL-cholesterol (HDL-c), 13.8 [1.8–29.1] mg/dl; apoA-I, 28.7 [7.9–59.1] mg/dl. Following nine infusions in 1 month, apoA-I and HDL-c increased directly after infusion by 27.0 and 16.1 mg/dl (P = 0.018). CER-001 induced a 44% relative increase (P = 0.018) in in vitro cellular cholesterol efflux with a trend toward increased FSE (P = 0.068). After nine infusions of CER-001, carotid mean vessel wall area decreased compared with baseline from 25.0 to 22.8 mm2 (P = 0.043) and target-to-background ratio from 2.04 to 1.81 (P = 0.046). In FHA-subjects, CER-001 stimulates cholesterol mobilization and reduces artery wall dimension and inflammation, supporting further evaluation of CER-001 in FHA patients. PMID:25561459

Effect of open-label infusion of an apoA-I-containing particle (CER-001) on RCT and artery wall thickness in patients with FHA.

PubMed

Kootte, Ruud S; Smits, Loek P; van der Valk, Fleur M; Dasseux, Jean-Louis; Keyserling, Constance H; Barbaras, Ronald; Paolini, John F; Santos, Raul D; van Dijk, Theo H; Dallinga-van Thie, Geesje M; Nederveen, Aart J; Mulder, Willem J M; Hovingh, G Kees; Kastelein, John J P; Groen, Albert K; Stroes, Erik S

2015-03-01

Reverse cholesterol transport (RCT) contributes to the anti-atherogenic effects of HDL. Patients with the orphan disease, familial hypoalphalipoproteinemia (FHA), are characterized by decreased tissue cholesterol removal and an increased atherogenic burden. We performed an open-label uncontrolled proof-of-concept study to evaluate the effect of infusions with a human apoA-I-containing HDL-mimetic particle (CER-001) on RCT and the arterial vessel wall in FHA. Subjects received 20 infusions of CER-001 (8 mg/kg) during 6 months. Efficacy was assessed by measuring (apo)lipoproteins, plasma-mediated cellular cholesterol efflux, fecal sterol excretion (FSE), and carotid artery wall dimension by MRI and artery wall inflammation by (18)F-fluorodeoxyglucose-positron emission tomography/computed tomography scans. We included seven FHA patients: HDL-cholesterol (HDL-c), 13.8 [1.8-29.1] mg/dl; apoA-I, 28.7 [7.9-59.1] mg/dl. Following nine infusions in 1 month, apoA-I and HDL-c increased directly after infusion by 27.0 and 16.1 mg/dl (P = 0.018). CER-001 induced a 44% relative increase (P = 0.018) in in vitro cellular cholesterol efflux with a trend toward increased FSE (P = 0.068). After nine infusions of CER-001, carotid mean vessel wall area decreased compared with baseline from 25.0 to 22.8 mm(2) (P = 0.043) and target-to-background ratio from 2.04 to 1.81 (P = 0.046). In FHA-subjects, CER-001 stimulates cholesterol mobilization and reduces artery wall dimension and inflammation, supporting further evaluation of CER-001 in FHA patients. Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.

Membrane Restructuring Events during the Enzymatic Generation of Ceramides with Very Long-Chain Polyunsaturated Fatty Acids.

PubMed

Peñalva, Daniel A; Antollini, Silvia S; Ambroggio, Ernesto E; Aveldaño, Marta I; Fanani, María L

2018-04-10

In rat sperm heads, sphingomyelin (SM) species that contain very long-chain polyunsaturated fatty acid (V-SM) become ceramides (V-Cer) after inducing in vitro the acrosomal reaction. The reason for such a specific location of this conversion, catalyzed by a sphingomyelinase (SMase), has received little investigation so far. Here, the effects of SMase were compared in unilamellar vesicles (large unilamellar vesicles (LUVs), giant unilamellar vesicles (GUVs)) containing phosphatidylcholine, and either V-SM or a palmitate-rich SM (P-SM). In uniformly sized LUVs at 37 °C, more V-Cer was generated and more rapidly than P-Cer. Nephelometry and dynamic light scattering showed that LUVs tended to form large lipid particles more intensely, and Förster resonance energy transfer (FRET) increases suggested that lateral lipid mixing was more marked when V-Cer rather than P-Cer was produced. As reported by 6-dodecanoyl-2-dimethyl-aminopnaphthalene (Laurdan) and 1,6-diphenyl-1,3,5,-hexatriene (DPH), the production of V-Cer resulted in higher and faster restriction in lipid mobility than that of P-Cer, implying a stronger increase in membrane dehydration and microviscosity. Moreover, DPH anisotropy suggested a higher solubility of V-Cer than that of P-Cer in the liquid-disordered phase. At room temperature, liquid-condensed lateral domains appeared in P-SM- but not in V-SM-containing GUVs. The former maintained their size while losing their contents gradually during SMase action, whereas the latter became permeable earlier and reduced their size in few minutes until suddenly collapsing. The fast and potent generation of V-Cer may contribute to the membrane restructuring events that occur on the acrosome-reacted sperm head.

Gromwell (Lithospermum erythrorhizon) supplementation enhances epidermal levels of ceramides, glucosylceramides, β-glucocerebrosidase, and acidic sphingomyelinase in NC/Nga mice.

PubMed

Kim, Jungmin; Cho, Yunhi

2013-10-01

We have previously reported that dietary gromwell (Lithospermum erythrorhizon; LE) prevents the development of atopic dermatitis (AD) with increased epidermal levels of total ceramide (Cer), the major lipid maintaining epidermal barrier. In this study, we investigated whether the increased level of total Cer induced by dietary LE would be related to the altered metabolism of glucosylceramide (GlcCer) and sphingomyelin (SM), two major precursor lipids in Cer generation. NC/Nga mice, an animal model of AD, were fed a control diet (group CA: atopic control) or a diet with 70% ethanol LE extracts (1% in diet; group LE) for 10 weeks. Individual species of Cer, GlcCer, and SM were analyzed by high-performance thin layer chromatography. In the epidermis of group CA, total Cer (including Cer2 and Cer5-7) and total GlcCer (including GlcCer-B/C/D) were significantly reduced; these levels in group LE were increased to levels similar to the normal control group of BALB/c mice (group C). In addition, protein expressions and activities of β-glucocerebrosidase (β-GlcCer'ase) and acidic sphingomyelinase (aSMase), enzymes for GlcCer or SM hydrolysis, respectively, were increased in group LE. However, alterations of Cer1, Cer3/4, GlcCer-A, and all SM species (including SM1-3) were not significant among groups C, CA, and LE. Dietary gromwell increases GlcCer-B/C/D, and further enhances the generation of Cer2 and Cer5-7 with high protein expressions and activities of β-GlcCer'ase and aSMase.

Monomer-dimer control of the ColE1 P(cer) promoter.

PubMed

Chatwin, H M; Summers, D K

2001-11-01

XerCD-mediated recombination at cer converts multimers of plasmid ColE1 to monomers, maximizing the number of independently segregating molecules and minimizing the frequency of plasmid loss. In addition to XerCD, recombination requires the accessory factors ArgR and PepA. The promoter P(cer), located centrally within cer, is also required for stable plasmid maintenance. P(cer) is active in plasmid multimers and directs transcription of a short RNA, Rcd, which appears to inhibit cell division. It has been proposed that Rcd is part of a checkpoint which ensures that multimer resolution is complete before the cell divides. This study has shown that ArgR does not act as a transcriptional repressor of P(cer) in plasmid monomers. P(cer) is unusual in that the -35 and -10 hexamers are separated by only 15 bp and this study has demonstrated that increasing this to a more conventional spacing results in elevated activity. An increase to 17 bp resulted in a 10- to 20-fold increase in activity, while smaller effects were seen when the spacer was increased to 16 bp or 18 bp. These observations are consistent with the hypothesis that P(cer) activation involves realignment of the -35 and -10 sequences within a recombinational synaptic complex. This predicts that a 17 bp spacer promoter derivative should be down-regulated by plasmid multimerization, and this is confirmed experimentally.

Association between plasma ceramides and inducible myocardial ischemia in patients with established or suspected coronary artery disease undergoing myocardial perfusion scintigraphy.

PubMed

Mantovani, Alessandro; Bonapace, Stefano; Lunardi, Gianluigi; Salgarello, Matteo; Dugo, Clementina; Canali, Guido; Byrne, Christopher D; Gori, Stefania; Barbieri, Enrico; Targher, Giovanni

2018-05-16

Recent studies have suggested that specific plasma ceramides are independently associated with major adverse cardiovascular events in patients with coronary artery disease (CAD), but it is currently unknown whether plasma ceramide levels are associated with stress-induced reversible myocardial ischemia. We measured six previously identified high-risk plasma ceramide molecules [Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0), and Cer(d18:1/24:1)] in 167 consecutive patients with established or suspected CAD who underwent either exercise or dypiridamole myocardial perfusion scintigraphy (MPS) for various clinical indications. Plasma ceramide levels were measured by a targeted liquid chromatography-tandem mass spectrometry assay both at baseline and after MPS. Seventy-eight patients had inducible myocardial ischemia on stress MPS. Women had significantly higher circulating levels of basal and post-stress Cer(d18:1/16:0) and Cer(d18:1/18:0) compared to men, whereas all other plasma ceramides did not differ between the sexes. Of the six measured plasma ceramides, basal Cer(d18:1/24:1) showed the strongest association with the presence of stress-induced myocardial perfusion defects in univariate analysis (unadjusted-odds ratio 1.48 per 1-SD increment, 95% confidence interval 1.08-2.04). Notably, after adjustment for age, sex, smoking, dyslipidemia, hypertension, diabetes, prior history of CAD, left ventricular ejection fraction, and type of stress testing (exercise vs. dypiridamole), all measured ceramides, except for plasma Cer(d18:1/24:0), were independently associated with the presence of inducible myocardial ischemia. Distinct plasma ceramides are positive and independent predictors of stress-induced myocardial perfusion defects in patients with established or suspected CAD referred for clinically indicated MPS. Further research is needed to examine whether distinct plasma ceramides could be a useful therapeutic target for treatment and management of CAD. Copyright © 2018. Published by Elsevier Inc.

75 FR 51260 - Combined Notice of Filings #1

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-19

...: CER Generation II, LLC. Description: CER Generation II, LLC submits tariff filing per 35.12: CER.... Applicants: CER Generation, LLC. Description: CER Generation, LLC submits tariff filing per 35.12: CER...

Cost-estimating relationships for space programs

NASA Technical Reports Server (NTRS)

Mandell, Humboldt C., Jr.

1992-01-01

Cost-estimating relationships (CERs) are defined and discussed as they relate to the estimation of theoretical costs for space programs. The paper primarily addresses CERs based on analogous relationships between physical and performance parameters to estimate future costs. Analytical estimation principles are reviewed examining the sources of errors in cost models, and the use of CERs is shown to be affected by organizational culture. Two paradigms for cost estimation are set forth: (1) the Rand paradigm for single-culture single-system methods; and (2) the Price paradigms that incorporate a set of cultural variables. For space programs that are potentially subject to even small cultural changes, the Price paradigms are argued to be more effective. The derivation and use of accurate CERs is important for developing effective cost models to analyze the potential of a given space program.

Gromwell (Lithospermum erythrorhizon) Supplementation Enhances Epidermal Levels of Ceramides, Glucosylceramides, β-Glucocerebrosidase, and Acidic Sphingomyelinase in NC/Nga Mice

PubMed Central

Kim, Jungmin; Cho, Yunhi

2013-01-01

Abstract We have previously reported that dietary gromwell (Lithospermum erythrorhizon; LE) prevents the development of atopic dermatitis (AD) with increased epidermal levels of total ceramide (Cer), the major lipid maintaining epidermal barrier. In this study, we investigated whether the increased level of total Cer induced by dietary LE would be related to the altered metabolism of glucosylceramide (GlcCer) and sphingomyelin (SM), two major precursor lipids in Cer generation. NC/Nga mice, an animal model of AD, were fed a control diet (group CA: atopic control) or a diet with 70% ethanol LE extracts (1% in diet; group LE) for 10 weeks. Individual species of Cer, GlcCer, and SM were analyzed by high-performance thin layer chromatography. In the epidermis of group CA, total Cer (including Cer2 and Cer5–7) and total GlcCer (including GlcCer-B/C/D) were significantly reduced; these levels in group LE were increased to levels similar to the normal control group of BALB/c mice (group C). In addition, protein expressions and activities of β-glucocerebrosidase (β-GlcCer'ase) and acidic sphingomyelinase (aSMase), enzymes for GlcCer or SM hydrolysis, respectively, were increased in group LE. However, alterations of Cer1, Cer3/4, GlcCer-A, and all SM species (including SM1–3) were not significant among groups C, CA, and LE. Dietary gromwell increases GlcCer-B/C/D, and further enhances the generation of Cer2 and Cer5–7 with high protein expressions and activities of β-GlcCer'ase and aSMase. PMID:24074295

Wolbachia Transfer from Rhagoletis cerasi to Drosophila simulans: Investigating the Outcomes of Host-Symbiont Coevolution

PubMed Central

Riegler, Markus; Charlat, Sylvain; Stauffer, Christian; Merçot, Hervé

2004-01-01

Wolbachia is an endosymbiont of diverse arthropod lineages that can induce various alterations of host reproduction for its own benefice. Cytoplasmic incompatibility (CI) is the most common phenomenon, which results in embryonic lethality when males that bear Wolbachia are mated with females that do not. In the cherry fruit fly, Rhagoletis cerasi, Wolbachia seems to be responsible for previously reported patterns of incompatibility between populations. Here we report on the artificial transfer of two Wolbachia variants (wCer1 and wCer2) from R. cerasi into Drosophila simulans, which was performed with two major goals in mind: first, to isolate wCer1 from wCer2 in order to individually test their respective abilities to induce CI in the new host; and, second, to test the theoretical prediction that recent Wolbachia-host associations should be characterized by high levels of CI, fitness costs to the new host, and inefficient transmission from mothers to offspring. wCer1 was unable to develop in the new host, resulting in its rapid loss after successful injection, while wCer2 was established in the new host. Transmission rates of wCer2 were low, and the infection showed negative fitness effects, consistent with our prediction, but CI levels were unexpectedly lower in the new host. Based on these parameter estimates, neither wCer1 nor wCer2 could be naturally maintained in D. simulans. The experiment thus suggests that natural Wolbachia transfer between species might be restricted by many factors, should the ecological barriers be bypassed. PMID:14711652

Wolbachia transfer from Rhagoletis cerasi to Drosophila simulans: investigating the outcomes of host-symbiont coevolution.

PubMed

Riegler, Markus; Charlat, Sylvain; Stauffer, Christian; Merçot, Hervé

2004-01-01

Wolbachia is an endosymbiont of diverse arthropod lineages that can induce various alterations of host reproduction for its own benefice. Cytoplasmic incompatibility (CI) is the most common phenomenon, which results in embryonic lethality when males that bear Wolbachia are mated with females that do not. In the cherry fruit fly, Rhagoletis cerasi, Wolbachia seems to be responsible for previously reported patterns of incompatibility between populations. Here we report on the artificial transfer of two Wolbachia variants (wCer1 and wCer2) from R. cerasi into Drosophila simulans, which was performed with two major goals in mind: first, to isolate wCer1 from wCer2 in order to individually test their respective abilities to induce CI in the new host; and, second, to test the theoretical prediction that recent Wolbachia-host associations should be characterized by high levels of CI, fitness costs to the new host, and inefficient transmission from mothers to offspring. wCer1 was unable to develop in the new host, resulting in its rapid loss after successful injection, while wCer2 was established in the new host. Transmission rates of wCer2 were low, and the infection showed negative fitness effects, consistent with our prediction, but CI levels were unexpectedly lower in the new host. Based on these parameter estimates, neither wCer1 nor wCer2 could be naturally maintained in D. simulans. The experiment thus suggests that natural Wolbachia transfer between species might be restricted by many factors, should the ecological barriers be bypassed.

Social welfare and the Affordable Care Act: is it ever optimal to set aside comparative cost?

PubMed

Mortimer, Duncan; Peacock, Stuart

2012-10-01

The creation of the Patient-Centered Outcomes Research Institute (PCORI) under the Affordable Care Act has set comparative effectiveness research (CER) at centre stage of US health care reform. Comparative cost analysis has remained marginalised and it now appears unlikely that the PCORI will require comparative cost data to be collected as an essential component of CER. In this paper, we review the literature to identify ethical and distributional objectives that might motivate calls to set priorities without regard to comparative cost. We then present argument and evidence to consider whether there is any plausible set of objectives and constraints against which priorities can be set without reference to comparative cost. We conclude that - to set aside comparative cost even after accounting for ethical and distributional constraints - would be truly to act as if money is no object. Copyright © 2012 Elsevier Ltd. All rights reserved.

Patients' views of consent in clinical trials for acute myocardial infarction: impact of trial design.

PubMed

Dickert, Neal W; Hendershot, Kristopher A; Speight, Candace D; Fehr, Alexandra E

2017-08-01

Seeking prospective informed consent is difficult in clinical trials for emergent conditions such as acute myocardial infarction (AMI). Prior data suggest that enrolment decisions of patients are often poorly informed in AMI trials but that patients prefer to be asked permission before enrolment. It is unknown whether this is true across trial designs or in comparative effectiveness research (CER) with approved treatments. Structured interviews were conducted with 30 patients with AMI. Participants considered three scenarios: (1) a CER trial of approved antiplatelet drugs; (2) a placebo-controlled trial of a novel drug to reduce myocardial injury and (3) a CER trial of an intra-aortic balloon pump versus medication. Participants were asked their desired involvement in enrolment decisions and willingness to participate. Descriptive analysis was performed of Likert scale data, and qualitative descriptive analysis was performed of textual data. Across scenarios, most participants (73%-80%) preferred to be asked permission prior to trial enrolment. Reasons for involvement included wanting to be the decision maker and a desire for transparency. Willingness to enrol was affected by trial type. Fewer participants stated they would likely enrol in a CER procedural trial than in a CER trial of approved medications (p=0.012). These findings suggest that patients prefer prospective involvement in enrolment decisions to enrolment without consent across trial types. However, their desire to participate was affected by trial type. There is a need to develop and evaluate context-sensitive approaches to consent in AMI trials that account for both the acuity of the situation and trial characteristics. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

International comparison of comparative effectiveness research in five jurisdictions: insights for the US.

PubMed

Levy, Adrian R; Mitton, Craig; Johnston, Karissa M; Harrigan, Brian; Briggs, Andrew H

2010-01-01

Spurred by a desire to improve quality of care and to understand the relative value of medical treatments, there has been a recent surge of interest in publicly funded comparative effectiveness research (CER) in the US. As health technology assessment (HTA) shares some of the same goals as CER, and publicly funded HTA has been a feature within other industrialized countries for many years, a review of HTA activities in some of these countries can be a helpful source of information for the US debate. Informed by a literature review, and in two cases augmented by informant interviews, we reviewed the organization of HTA activities in five jurisdictions: Canada, Sweden, Scotland, the Netherlands and Australia. We provide a summary description of the healthcare system in each country as well as a description of the key features of their HTA bodies, with a particular focus on the processes of HTA for listing medications on public formularies. Four of the committees evaluating medications for formulary inclusion are funded by, but remain at arm's length from, the government (Canada, Australia, Sweden and Scotland), while the process is fully embedded within the government in the Netherlands. Each of these jurisdictions has a stated preference for comparative outcomes evidence from randomized controlled trials, but will, under certain circumstances, accept randomized evidence using surrogate markers, other comparators that are not directly relevant or non-randomized evidence. Health technology evaluation committees largely comprise health professionals, with public representatives included in the Canadian, Australian and Scottish committees. Scotland is the only one of the five jurisdictions reviewed to have industry representation on the evaluation committee. We identified seven characteristics that are shared across the jurisdictions reviewed and that potentially serve as insights for development of CER in the US: (i) the process must be responsive to stakeholders' interests, in that the turn-around time for assessments must be minimized, transparency must be maximized, the process must be considered fair using universally agreed standards and the process must be modifiable based on stakeholders' requirements; (ii) the assessment of medical technologies other than drugs may present different challenges and is managed separately in other HTA organizations; (iii) because of the link between HTA and reimbursement decisions, completion of the HTA process following regulatory approval can delay market access to new technologies, thus closer integration between regulatory approval and HTA processes is being explored internationally; (iv) there is a direct or indirect link to reimbursement in the jurisdictions explored - without this link the role of CER in the US will remain advisory; (v) each jurisdiction reviewed benefits from a single payer that is informed by the process - given the diverse multipayer environment in the US, CER in the US may usefully focus on generating comparative effectiveness evidence; (vi) a common metric for assessing intended and unintended effects of treatment allows comparison across different technologies; and (vii) one stated focus of CER is on therapeutic benefit among 'high-priority populations', including specific demographic groups (the elderly and children, racial and ethnic minorities) and individuals with disabilities, multiple chronic conditions and specific genomic factors. This will be difficult to achieve because epidemiological evidence of differences in therapeutic benefit among subgroups is detected through effect modification, or more specifically, statistical evidence of effect measure modification, typically on relative measures of effect. Few randomized trials have enough power to detect effect modification and these have been uncommon in the scientific literature. As consideration is given to the development of a publicly funded CER body in the US, much can be learned from the international experience. Nevertheless, there are some distinctive features of the US healthcare system that must be taken into account when assessing the transferability of these insights.

Nutrition Frontiers - Summer 2017 | Division of Cancer Prevention

Cancer.gov

Volume 8, Issue 3 Dear Colleague, The summer issue of Nutrition Frontiers showcases insulin-like growth factor and vitamin D in prostate cancer risk, bile acid and FXR inactivation and gender dissimilarity, and CerS6, a novel transcriptional target of p53 protein. Meet our spotlight investigator, Dr. Wendy Russell, and her research on the functional role of the gut microbiota.

Nanoporous Polymer Films of Cyanate Ester Resins Designed by Using Ionic Liquids as Porogens.

PubMed

Fainleib, Alexander; Vashchuk, Alina; Starostenko, Olga; Grigoryeva, Olga; Rogalsky, Sergiy; Nguyen, Thi-Thanh-Tam; Grande, Daniel

2017-12-01

Novel nanoporous film materials of thermostable cyanate ester resins (CERs) were generated by polycyclotrimerization of dicyanate ester of bisphenol E in the presence of varying amounts (from 20 to 40 wt%) of an ionic liquid (IL), i.e., 1-heptylpyridinium tetrafluoroborate, followed by its quantitative extraction after complete CER network formation. The completion of CER formation and IL extraction was assessed using gel fraction content determination, FTIR, 1 H NMR, and energy-dispersive X-ray spectroscopy (EDX). SEM and DSC-based thermoporometry analyses demonstrated the formation of nanoporous structures after IL removal from CER networks, thus showing the effective role of IL as a porogen. Pore sizes varied from ~20 to ~180 nm with an average pore diameter of around 45-60 nm depending on the initial IL content. The thermal stability of nanoporous CER-based films was investigated by thermogravimetric analysis.

Nanoporous Polymer Films of Cyanate Ester Resins Designed by Using Ionic Liquids as Porogens

NASA Astrophysics Data System (ADS)

Fainleib, Alexander; Vashchuk, Alina; Starostenko, Olga; Grigoryeva, Olga; Rogalsky, Sergiy; Nguyen, Thi-Thanh-Tam; Grande, Daniel

2017-02-01

Novel nanoporous film materials of thermostable cyanate ester resins (CERs) were generated by polycyclotrimerization of dicyanate ester of bisphenol E in the presence of varying amounts (from 20 to 40 wt%) of an ionic liquid (IL), i.e., 1-heptylpyridinium tetrafluoroborate, followed by its quantitative extraction after complete CER network formation. The completion of CER formation and IL extraction was assessed using gel fraction content determination, FTIR, 1H NMR, and energy-dispersive X-ray spectroscopy (EDX). SEM and DSC-based thermoporometry analyses demonstrated the formation of nanoporous structures after IL removal from CER networks, thus showing the effective role of IL as a porogen. Pore sizes varied from 20 to 180 nm with an average pore diameter of around 45-60 nm depending on the initial IL content. The thermal stability of nanoporous CER-based films was investigated by thermogravimetric analysis.

Oral administration of glucosylceramide ameliorates inflammatory dry-skin condition in chronic oxazolone-induced irritant contact dermatitis in the mouse ear.

PubMed

Yeom, Mijung; Kim, Sung-Hun; Lee, Bombi; Han, Jeong-Jun; Chung, Guk Hoon; Choi, Hee-Don; Lee, Hyejung; Hahm, Dae-Hyun

2012-08-01

Irritant contact dermatitis (ICD) is an inflammatory skin disease triggered by exposure to a chemical that is toxic or irritating to the skin. A major characteristic of chronic ICD is an inflammatory dry-skin condition with associated itching. Although glucosylceramide (GlcCer) is known to improve the skin barrier function, its mechanism of action is unknown. Using a mouse model of oxazolone-induced chronic ICD, this study investigated the effects of oral administration of GlcCer on inflammatory dry skin. Chronic ICD was induced by repeated application of oxazolone in mice. GlcCer was orally administered once daily throughout the elicitation phase. The beneficial efficacy of GlcCer on cutaneous inflammation was evaluated by assessing ear thickness, lymph node weight, histological findings, and mRNA expression of pro-inflammatory cytokines such as IL-1β and IL-6. Additionally, parameters of the itch-associated response, including scratching behavior, water content of the skin, and aquaporin-3 levels in the lesional ear, were measured. Oral GlcCer administration significantly suppressed mRNA expression of the pro-inflammatory cytokines IL-1β and IL-6. GlcCer also suppressed ear swelling, lymph node weight gains, and infiltration of leukocytes and mast cells in ICD mice. In oxazolone-induced ICD mice, GlcCer significantly inhibited irritant-related scratching behavior and dehydration of the stratum corneum, and decreased aquaporin-3 expression. Our results indicate that GlcCer suppressed inflammation not only by inhibiting cytokine production but also by repairing the skin barrier function, suggesting a potential beneficial role for GlcCer in the improvement of chronic ICD. Copyright © 2012 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

Limonoid Compounds Inhibit Sphingomyelin Biosynthesis by Preventing CERT Protein-dependent Extraction of Ceramides from the Endoplasmic Reticulum*

PubMed Central

Hullin-Matsuda, Françoise; Tomishige, Nario; Sakai, Shota; Ishitsuka, Reiko; Ishii, Kumiko; Makino, Asami; Greimel, Peter; Abe, Mitsuhiro; Laviad, Elad L.; Lagarde, Michel; Vidal, Hubert; Saito, Tamio; Osada, Hiroyuki; Hanada, Kentaro; Futerman, Anthony H.; Kobayashi, Toshihide

2012-01-01

To identify novel inhibitors of sphingomyelin (SM) metabolism, a new and selective high throughput microscopy-based screening based on the toxicity of the SM-specific toxin, lysenin, was developed. Out of a library of 2011 natural compounds, the limonoid, 3-chloro-8β-hydroxycarapin-3,8-hemiacetal (CHC), rendered cells resistant to lysenin by decreasing cell surface SM. CHC treatment selectively inhibited the de novo biosynthesis of SM without affecting glycolipid and glycerophospholipid biosynthesis. Pretreatment with brefeldin A abolished the limonoid-induced inhibition of SM synthesis suggesting that the transport of ceramide (Cer) from the endoplasmic reticulum to the Golgi apparatus is affected. Unlike the Cer transporter (CERT) inhibitor HPA-12, CHC did not change the transport of a fluorescent short chain Cer analog to the Golgi apparatus or the formation of fluorescent and short chain SM from the corresponding Cer. Nevertheless, CHC inhibited the conversion of de novo synthesized Cer to SM. We show that CHC specifically inhibited the CERT-mediated extraction of Cer from the endoplasmic reticulum membranes in vitro. Subsequent biochemical screening of 21 limonoids revealed that some of them, such as 8β-hydroxycarapin-3,8-hemiacetal and gedunin, which exhibits anti-cancer activity, inhibited SM biosynthesis and CERT-mediated extraction of Cer from membranes. Model membrane studies suggest that 8β-hydroxycarapin-3,8-hemiacetal reduced the miscibility of Cer with membrane lipids and thus induced the formation of Cer-rich membrane domains. Our study shows that certain limonoids are novel inhibitors of SM biosynthesis and suggests that some biological activities of these limonoids are related to their effect on the ceramide metabolism. PMID:22605339

Retarder action of isosorbide in a microemulsion for a targeted delivery of ceramide NP into the stratum corneum.

PubMed

Steinbach, S C; Triani, R; Bennedsen, L; Gabel, A; Haeusler, O; Wohlrab, J; Neubert, R H H

2017-08-01

Ceramide [NP] is an integral component of the stratum corneum (SC) lipid matrix and is capable of forming tough and stable lamellar structures. It was proven, that in skin diseases as psoriasis or atopic dermatitis different ceramide (CER) classes, including [NP], are degraded. It is obvious that topically application of CER on impaired skin is useful for repairing the skin barrier but a tendency for low penetration due to its poor solubility in conventional dosage forms was observed. Therefore, a stable and physiologic compatible colloidal carrier system, a microemulsion (ME), was developed and characterized. The increasing knowledge of the new colloidal systems in this last decade shows their benefits in dermal application. Isosorbide (Polysorb P) was incorporated into the ME developed. It was expected that Polysorb P has a retarder potential in order to accumulate the CER in the SC, the outermost layer of the skin. Thereby the CER [NP] would be able to interact with the affected skin layers to strengthen the skin barrier. The release and penetration behavior of the CER [NP] from the ME was assessed ex vivo in a Franz diffusion cell. The results of the study showed that CER [NP] penetrate largely in the upper layers of the skin (from SC to stratum basale), which was the desired region. A recovery in the acceptor could not be detected that underlines an accumulation in upper layers. Furthermore, significantly increased values for the SC for the ME with retarder were not received. No differences in the concentrations of CER [NP] were observed. However, the toxicity of MEs was investigated using heńs egg test chorioallantoic membrane (HET-CAM). For the isosorbide-containing ME no difference was obtained in comparison to the non-containing. The results showed that both MEs are safe to be used on the skin for the controlled penetration of CER [NP] into the skin. The isosorbide had no effect on the irritating effect as well as on the penetration of the used CER.

Inactivation of ceramide synthase 2 catalytic activity in mice affects transcription of genes involved in lipid metabolism and cell division.

PubMed

Bickert, Andreas; Kern, Paul; van Uelft, Martina; Herresthal, Stefanie; Ulas, Thomas; Gutbrod, Katharina; Breiden, Bernadette; Degen, Joachim; Sandhoff, Konrad; Schultze, Joachim L; Dörmann, Peter; Hartmann, Dieter; Bauer, Reinhard; Willecke, Klaus

2018-07-01

The replacement of two consecutive histidine residues by alanine residues in the catalytic center of ceramide synthase 2 in a new transgenic mouse mutant (CerS2 H/A) leads to inactivation of catalytic activity and reduces protein level to 60% of the WT level. We show here by qRT-PCR and transcriptome analyses that several transcripts of genes involved in lipid metabolism and cell division are differentially regulated in livers of CerS2 H/A mice. Thus, very long chain ceramides produced by CerS2 are required for transcriptional regulation of target genes. The hepatocellular carcinomata previously described in old CerS2 KO mice were already present in 8-week-old CerS2 H/A animals and thus are caused by the loss of CerS2 catalytic activity already during early life. Copyright © 2018 Elsevier B.V. All rights reserved.

CERES ERBE-like Instantaneous TOA Estimates (ES-8) in HDF (CER_ES4_TRMM-PFM_Edition1)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ERBE-like Monthly Geographical Averages (ES-4) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The ES-4 is also produced for combinations of scanner instruments. For each observed 2.5-degree spatial region, the daily average, the hourly average over the month, and the overall monthly average of shortwave and longwave fluxes at the Top-of-the-Atmosphere (TOA) from the CERES ES-9 product are spatially nested up from 2.5-degree regions to 5- and 10-degree regions, to 2.5-, 5-, and 10-degree zonal averages, and to global monthly averages. For each nested area, the albedo and net flux are given. For each region, the daily average flux is estimated from an algorithm that uses the available hourly data, scene identification data, and diurnal models. This algorithm is 'like' the algorithm used for the Earth Radiation Budget Experiment (ERBE). The following CERES ES4 data sets are currently available: CER_ES4_FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition2 CER_ES4_PFM+FM1_Edition1 CER_ES4_PFM+FM2_Edition1 CER_ES4_TRMM-PFM_Edition1 CER_ES4_TRMM-PFM_Edition2 CER_ES4_Terra-FM1_Edition1 CER_ES4_Terra-FM2_Edition1 CER_ES4_FM1+FM2_Edition2 CER_ES4_Terra-FM1_Edition2 CER_ES4_Terra-FM2_Edition2 CER_ES4_Aqua-FM3_Edition1 CER_ES4_Aqua-FM4_Edition1 CER_ES4_FM1+FM2+FM3+FM4_Edition1 CER_ES4_Aqua-FM3_Edition2 CER_ES4_Aqua-FM4_Edition2 CER_ES4_FM1+FM3_Edition2 CER_ES4_FM1+FM4_Edition2 CER_ES4_PFM+FM1_Edition2 CER_ES4_PFM+FM2_Edition2 CER_ES4_Aqua-FM3_Edition1-CV CER_ES4_Aqua-FM4_Edition1-CV CER_ES4_Terra-FM1_Edition1-CV CER_ES4_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=1998-08-31] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=2.5 degree; Longitude_Resolution=2.5 degree; Horizontal_Resolution_Range=250 km - < 500 km or approximately 2.5 degrees - < 5.0 degrees; Temporal_Resolution=1 month; Temporal_Resolution_Range=Monthly - < Annual].

CERES ERBE-like Monthly Geographical Averages (ES-4) in HDF (CER_ES4_PFM+FM1_Edition1)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ERBE-like Monthly Geographical Averages (ES-4) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The ES-4 is also produced for combinations of scanner instruments. For each observed 2.5-degree spatial region, the daily average, the hourly average over the month, and the overall monthly average of shortwave and longwave fluxes at the Top-of-the-Atmosphere (TOA) from the CERES ES-9 product are spatially nested up from 2.5-degree regions to 5- and 10-degree regions, to 2.5-, 5-, and 10-degree zonal averages, and to global monthly averages. For each nested area, the albedo and net flux are given. For each region, the daily average flux is estimated from an algorithm that uses the available hourly data, scene identification data, and diurnal models. This algorithm is 'like' the algorithm used for the Earth Radiation Budget Experiment (ERBE). The following CERES ES4 data sets are currently available: CER_ES4_FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition2 CER_ES4_PFM+FM1_Edition1 CER_ES4_PFM+FM2_Edition1 CER_ES4_TRMM-PFM_Edition1 CER_ES4_TRMM-PFM_Edition2 CER_ES4_Terra-FM1_Edition1 CER_ES4_Terra-FM2_Edition1 CER_ES4_FM1+FM2_Edition2 CER_ES4_Terra-FM1_Edition2 CER_ES4_Terra-FM2_Edition2 CER_ES4_Aqua-FM3_Edition1 CER_ES4_Aqua-FM4_Edition1 CER_ES4_FM1+FM2+FM3+FM4_Edition1 CER_ES4_Aqua-FM3_Edition2 CER_ES4_Aqua-FM4_Edition2 CER_ES4_FM1+FM3_Edition2 CER_ES4_FM1+FM4_Edition2 CER_ES4_PFM+FM1_Edition2 CER_ES4_PFM+FM2_Edition2 CER_ES4_Aqua-FM3_Edition1-CV CER_ES4_Aqua-FM4_Edition1-CV CER_ES4_Terra-FM1_Edition1-CV CER_ES4_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2000-03-31] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=2.5 degree; Longitude_Resolution=2.5 degree; Horizontal_Resolution_Range=250 km - < 500 km or approximately 2.5 degrees - < 5.0 degrees; Temporal_Resolution=1 month; Temporal_Resolution_Range=Monthly - < Annual].

CERES ERBE-like Monthly Geographical Averages (ES-4) in HDF (CER_ES4_FM1+FM4_Edition2)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ERBE-like Monthly Geographical Averages (ES-4) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The ES-4 is also produced for combinations of scanner instruments. For each observed 2.5-degree spatial region, the daily average, the hourly average over the month, and the overall monthly average of shortwave and longwave fluxes at the Top-of-the-Atmosphere (TOA) from the CERES ES-9 product are spatially nested up from 2.5-degree regions to 5- and 10-degree regions, to 2.5-, 5-, and 10-degree zonal averages, and to global monthly averages. For each nested area, the albedo and net flux are given. For each region, the daily average flux is estimated from an algorithm that uses the available hourly data, scene identification data, and diurnal models. This algorithm is 'like' the algorithm used for the Earth Radiation Budget Experiment (ERBE). The following CERES ES4 data sets are currently available: CER_ES4_FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition2 CER_ES4_PFM+FM1_Edition1 CER_ES4_PFM+FM2_Edition1 CER_ES4_TRMM-PFM_Edition1 CER_ES4_TRMM-PFM_Edition2 CER_ES4_Terra-FM1_Edition1 CER_ES4_Terra-FM2_Edition1 CER_ES4_FM1+FM2_Edition2 CER_ES4_Terra-FM1_Edition2 CER_ES4_Terra-FM2_Edition2 CER_ES4_Aqua-FM3_Edition1 CER_ES4_Aqua-FM4_Edition1 CER_ES4_FM1+FM2+FM3+FM4_Edition1 CER_ES4_Aqua-FM3_Edition2 CER_ES4_Aqua-FM4_Edition2 CER_ES4_FM1+FM3_Edition2 CER_ES4_FM1+FM4_Edition2 CER_ES4_PFM+FM1_Edition2 CER_ES4_PFM+FM2_Edition2 CER_ES4_Aqua-FM3_Edition1-CV CER_ES4_Aqua-FM4_Edition1-CV CER_ES4_Terra-FM1_Edition1-CV CER_ES4_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2005-03-31] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=2.5 degree; Longitude_Resolution=2.5 degree; Horizontal_Resolution_Range=250 km - < 500 km or approximately 2.5 degrees - < 5.0 degrees; Temporal_Resolution=1 month; Temporal_Resolution_Range=Monthly - < Annual].

CERES ERBE-like Monthly Geographical Averages (ES-4) in HDF (CER_ES4_Terra-FM2_Edition1-CV)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ERBE-like Monthly Geographical Averages (ES-4) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The ES-4 is also produced for combinations of scanner instruments. For each observed 2.5-degree spatial region, the daily average, the hourly average over the month, and the overall monthly average of shortwave and longwave fluxes at the Top-of-the-Atmosphere (TOA) from the CERES ES-9 product are spatially nested up from 2.5-degree regions to 5- and 10-degree regions, to 2.5-, 5-, and 10-degree zonal averages, and to global monthly averages. For each nested area, the albedo and net flux are given. For each region, the daily average flux is estimated from an algorithm that uses the available hourly data, scene identification data, and diurnal models. This algorithm is 'like' the algorithm used for the Earth Radiation Budget Experiment (ERBE). The following CERES ES4 data sets are currently available: CER_ES4_FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition2 CER_ES4_PFM+FM1_Edition1 CER_ES4_PFM+FM2_Edition1 CER_ES4_TRMM-PFM_Edition1 CER_ES4_TRMM-PFM_Edition2 CER_ES4_Terra-FM1_Edition1 CER_ES4_Terra-FM2_Edition1 CER_ES4_FM1+FM2_Edition2 CER_ES4_Terra-FM1_Edition2 CER_ES4_Terra-FM2_Edition2 CER_ES4_Aqua-FM3_Edition1 CER_ES4_Aqua-FM4_Edition1 CER_ES4_FM1+FM2+FM3+FM4_Edition1 CER_ES4_Aqua-FM3_Edition2 CER_ES4_Aqua-FM4_Edition2 CER_ES4_FM1+FM3_Edition2 CER_ES4_FM1+FM4_Edition2 CER_ES4_PFM+FM1_Edition2 CER_ES4_PFM+FM2_Edition2 CER_ES4_Aqua-FM3_Edition1-CV CER_ES4_Aqua-FM4_Edition1-CV CER_ES4_Terra-FM1_Edition1-CV CER_ES4_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2006-10-31] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=2.5 degree; Longitude_Resolution=2.5 degree; Horizontal_Resolution_Range=250 km - < 500 km or approximately 2.5 degrees - < 5.0 degrees; Temporal_Resolution=1 month; Temporal_Resolution_Range=Monthly - < Annual].

CERES ERBE-like Monthly Geographical Averages (ES-4) in HDF (CER_ES4_Aqua-FM3_Edition1)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ERBE-like Monthly Geographical Averages (ES-4) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The ES-4 is also produced for combinations of scanner instruments. For each observed 2.5-degree spatial region, the daily average, the hourly average over the month, and the overall monthly average of shortwave and longwave fluxes at the Top-of-the-Atmosphere (TOA) from the CERES ES-9 product are spatially nested up from 2.5-degree regions to 5- and 10-degree regions, to 2.5-, 5-, and 10-degree zonal averages, and to global monthly averages. For each nested area, the albedo and net flux are given. For each region, the daily average flux is estimated from an algorithm that uses the available hourly data, scene identification data, and diurnal models. This algorithm is 'like' the algorithm used for the Earth Radiation Budget Experiment (ERBE). The following CERES ES4 data sets are currently available: CER_ES4_FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition2 CER_ES4_PFM+FM1_Edition1 CER_ES4_PFM+FM2_Edition1 CER_ES4_TRMM-PFM_Edition1 CER_ES4_TRMM-PFM_Edition2 CER_ES4_Terra-FM1_Edition1 CER_ES4_Terra-FM2_Edition1 CER_ES4_FM1+FM2_Edition2 CER_ES4_Terra-FM1_Edition2 CER_ES4_Terra-FM2_Edition2 CER_ES4_Aqua-FM3_Edition1 CER_ES4_Aqua-FM4_Edition1 CER_ES4_FM1+FM2+FM3+FM4_Edition1 CER_ES4_Aqua-FM3_Edition2 CER_ES4_Aqua-FM4_Edition2 CER_ES4_FM1+FM3_Edition2 CER_ES4_FM1+FM4_Edition2 CER_ES4_PFM+FM1_Edition2 CER_ES4_PFM+FM2_Edition2 CER_ES4_Aqua-FM3_Edition1-CV CER_ES4_Aqua-FM4_Edition1-CV CER_ES4_Terra-FM1_Edition1-CV CER_ES4_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2005-10-31] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=2.5 degree; Longitude_Resolution=2.5 degree; Horizontal_Resolution_Range=250 km - < 500 km or approximately 2.5 degrees - < 5.0 degrees; Temporal_Resolution=1 month; Temporal_Resolution_Range=Monthly - < Annual].

CERES ERBE-like Monthly Geographical Averages (ES-4) in HDF (CER_ES4_Aqua-FM3_Edition2)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ERBE-like Monthly Geographical Averages (ES-4) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The ES-4 is also produced for combinations of scanner instruments. For each observed 2.5-degree spatial region, the daily average, the hourly average over the month, and the overall monthly average of shortwave and longwave fluxes at the Top-of-the-Atmosphere (TOA) from the CERES ES-9 product are spatially nested up from 2.5-degree regions to 5- and 10-degree regions, to 2.5-, 5-, and 10-degree zonal averages, and to global monthly averages. For each nested area, the albedo and net flux are given. For each region, the daily average flux is estimated from an algorithm that uses the available hourly data, scene identification data, and diurnal models. This algorithm is 'like' the algorithm used for the Earth Radiation Budget Experiment (ERBE). The following CERES ES4 data sets are currently available: CER_ES4_FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition2 CER_ES4_PFM+FM1_Edition1 CER_ES4_PFM+FM2_Edition1 CER_ES4_TRMM-PFM_Edition1 CER_ES4_TRMM-PFM_Edition2 CER_ES4_Terra-FM1_Edition1 CER_ES4_Terra-FM2_Edition1 CER_ES4_FM1+FM2_Edition2 CER_ES4_Terra-FM1_Edition2 CER_ES4_Terra-FM2_Edition2 CER_ES4_Aqua-FM3_Edition1 CER_ES4_Aqua-FM4_Edition1 CER_ES4_FM1+FM2+FM3+FM4_Edition1 CER_ES4_Aqua-FM3_Edition2 CER_ES4_Aqua-FM4_Edition2 CER_ES4_FM1+FM3_Edition2 CER_ES4_FM1+FM4_Edition2 CER_ES4_PFM+FM1_Edition2 CER_ES4_PFM+FM2_Edition2 CER_ES4_Aqua-FM3_Edition1-CV CER_ES4_Aqua-FM4_Edition1-CV CER_ES4_Terra-FM1_Edition1-CV CER_ES4_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2005-12-31] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=2.5 degree; Longitude_Resolution=2.5 degree; Horizontal_Resolution_Range=250 km - < 500 km or approximately 2.5 degrees - < 5.0 degrees; Temporal_Resolution=1 month; Temporal_Resolution_Range=Monthly - < Annual].

CERES ERBE-like Monthly Geographical Averages (ES-4) in HDF (CER_ES4_Aqua-FM4_Edition1)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ERBE-like Monthly Geographical Averages (ES-4) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The ES-4 is also produced for combinations of scanner instruments. For each observed 2.5-degree spatial region, the daily average, the hourly average over the month, and the overall monthly average of shortwave and longwave fluxes at the Top-of-the-Atmosphere (TOA) from the CERES ES-9 product are spatially nested up from 2.5-degree regions to 5- and 10-degree regions, to 2.5-, 5-, and 10-degree zonal averages, and to global monthly averages. For each nested area, the albedo and net flux are given. For each region, the daily average flux is estimated from an algorithm that uses the available hourly data, scene identification data, and diurnal models. This algorithm is 'like' the algorithm used for the Earth Radiation Budget Experiment (ERBE). The following CERES ES4 data sets are currently available: CER_ES4_FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition2 CER_ES4_PFM+FM1_Edition1 CER_ES4_PFM+FM2_Edition1 CER_ES4_TRMM-PFM_Edition1 CER_ES4_TRMM-PFM_Edition2 CER_ES4_Terra-FM1_Edition1 CER_ES4_Terra-FM2_Edition1 CER_ES4_FM1+FM2_Edition2 CER_ES4_Terra-FM1_Edition2 CER_ES4_Terra-FM2_Edition2 CER_ES4_Aqua-FM3_Edition1 CER_ES4_Aqua-FM4_Edition1 CER_ES4_FM1+FM2+FM3+FM4_Edition1 CER_ES4_Aqua-FM3_Edition2 CER_ES4_Aqua-FM4_Edition2 CER_ES4_FM1+FM3_Edition2 CER_ES4_FM1+FM4_Edition2 CER_ES4_PFM+FM1_Edition2 CER_ES4_PFM+FM2_Edition2 CER_ES4_Aqua-FM3_Edition1-CV CER_ES4_Aqua-FM4_Edition1-CV CER_ES4_Terra-FM1_Edition1-CV CER_ES4_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2005-03-29] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=2.5 degree; Longitude_Resolution=2.5 degree; Horizontal_Resolution_Range=250 km - < 500 km or approximately 2.5 degrees - < 5.0 degrees; Temporal_Resolution=1 month; Temporal_Resolution_Range=Monthly - < Annual].

CERES ERBE-like Monthly Geographical Averages (ES-4) in HDF (CER_ES4_FM1+FM2_Edition1)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ERBE-like Monthly Geographical Averages (ES-4) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The ES-4 is also produced for combinations of scanner instruments. For each observed 2.5-degree spatial region, the daily average, the hourly average over the month, and the overall monthly average of shortwave and longwave fluxes at the Top-of-the-Atmosphere (TOA) from the CERES ES-9 product are spatially nested up from 2.5-degree regions to 5- and 10-degree regions, to 2.5-, 5-, and 10-degree zonal averages, and to global monthly averages. For each nested area, the albedo and net flux are given. For each region, the daily average flux is estimated from an algorithm that uses the available hourly data, scene identification data, and diurnal models. This algorithm is 'like' the algorithm used for the Earth Radiation Budget Experiment (ERBE). The following CERES ES4 data sets are currently available: CER_ES4_FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition2 CER_ES4_PFM+FM1_Edition1 CER_ES4_PFM+FM2_Edition1 CER_ES4_TRMM-PFM_Edition1 CER_ES4_TRMM-PFM_Edition2 CER_ES4_Terra-FM1_Edition1 CER_ES4_Terra-FM2_Edition1 CER_ES4_FM1+FM2_Edition2 CER_ES4_Terra-FM1_Edition2 CER_ES4_Terra-FM2_Edition2 CER_ES4_Aqua-FM3_Edition1 CER_ES4_Aqua-FM4_Edition1 CER_ES4_FM1+FM2+FM3+FM4_Edition1 CER_ES4_Aqua-FM3_Edition2 CER_ES4_Aqua-FM4_Edition2 CER_ES4_FM1+FM3_Edition2 CER_ES4_FM1+FM4_Edition2 CER_ES4_PFM+FM1_Edition2 CER_ES4_PFM+FM2_Edition2 CER_ES4_Aqua-FM3_Edition1-CV CER_ES4_Aqua-FM4_Edition1-CV CER_ES4_Terra-FM1_Edition1-CV CER_ES4_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2003-12-31] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=2.5 degree; Longitude_Resolution=2.5 degree; Horizontal_Resolution_Range=250 km - < 500 km or approximately 2.5 degrees - < 5.0 degrees; Temporal_Resolution=1 month; Temporal_Resolution_Range=Monthly - < Annual].

CERES ERBE-like Monthly Geographical Averages (ES-4) in HDF (CER_ES4_Terra-FM1_Edition2)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ERBE-like Monthly Geographical Averages (ES-4) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The ES-4 is also produced for combinations of scanner instruments. For each observed 2.5-degree spatial region, the daily average, the hourly average over the month, and the overall monthly average of shortwave and longwave fluxes at the Top-of-the-Atmosphere (TOA) from the CERES ES-9 product are spatially nested up from 2.5-degree regions to 5- and 10-degree regions, to 2.5-, 5-, and 10-degree zonal averages, and to global monthly averages. For each nested area, the albedo and net flux are given. For each region, the daily average flux is estimated from an algorithm that uses the available hourly data, scene identification data, and diurnal models. This algorithm is 'like' the algorithm used for the Earth Radiation Budget Experiment (ERBE). The following CERES ES4 data sets are currently available: CER_ES4_FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition2 CER_ES4_PFM+FM1_Edition1 CER_ES4_PFM+FM2_Edition1 CER_ES4_TRMM-PFM_Edition1 CER_ES4_TRMM-PFM_Edition2 CER_ES4_Terra-FM1_Edition1 CER_ES4_Terra-FM2_Edition1 CER_ES4_FM1+FM2_Edition2 CER_ES4_Terra-FM1_Edition2 CER_ES4_Terra-FM2_Edition2 CER_ES4_Aqua-FM3_Edition1 CER_ES4_Aqua-FM4_Edition1 CER_ES4_FM1+FM2+FM3+FM4_Edition1 CER_ES4_Aqua-FM3_Edition2 CER_ES4_Aqua-FM4_Edition2 CER_ES4_FM1+FM3_Edition2 CER_ES4_FM1+FM4_Edition2 CER_ES4_PFM+FM1_Edition2 CER_ES4_PFM+FM2_Edition2 CER_ES4_Aqua-FM3_Edition1-CV CER_ES4_Aqua-FM4_Edition1-CV CER_ES4_Terra-FM1_Edition1-CV CER_ES4_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2005-12-31] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=2.5 degree; Longitude_Resolution=2.5 degree; Horizontal_Resolution_Range=250 km - < 500 km or approximately 2.5 degrees - < 5.0 degrees; Temporal_Resolution=1 month; Temporal_Resolution_Range=Monthly - < Annual].

CERES ERBE-like Monthly Geographical Averages (ES-4) in HDF (CER_ES4_Aqua-FM4_Edition2)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ERBE-like Monthly Geographical Averages (ES-4) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The ES-4 is also produced for combinations of scanner instruments. For each observed 2.5-degree spatial region, the daily average, the hourly average over the month, and the overall monthly average of shortwave and longwave fluxes at the Top-of-the-Atmosphere (TOA) from the CERES ES-9 product are spatially nested up from 2.5-degree regions to 5- and 10-degree regions, to 2.5-, 5-, and 10-degree zonal averages, and to global monthly averages. For each nested area, the albedo and net flux are given. For each region, the daily average flux is estimated from an algorithm that uses the available hourly data, scene identification data, and diurnal models. This algorithm is 'like' the algorithm used for the Earth Radiation Budget Experiment (ERBE). The following CERES ES4 data sets are currently available: CER_ES4_FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition2 CER_ES4_PFM+FM1_Edition1 CER_ES4_PFM+FM2_Edition1 CER_ES4_TRMM-PFM_Edition1 CER_ES4_TRMM-PFM_Edition2 CER_ES4_Terra-FM1_Edition1 CER_ES4_Terra-FM2_Edition1 CER_ES4_FM1+FM2_Edition2 CER_ES4_Terra-FM1_Edition2 CER_ES4_Terra-FM2_Edition2 CER_ES4_Aqua-FM3_Edition1 CER_ES4_Aqua-FM4_Edition1 CER_ES4_FM1+FM2+FM3+FM4_Edition1 CER_ES4_Aqua-FM3_Edition2 CER_ES4_Aqua-FM4_Edition2 CER_ES4_FM1+FM3_Edition2 CER_ES4_FM1+FM4_Edition2 CER_ES4_PFM+FM1_Edition2 CER_ES4_PFM+FM2_Edition2 CER_ES4_Aqua-FM3_Edition1-CV CER_ES4_Aqua-FM4_Edition1-CV CER_ES4_Terra-FM1_Edition1-CV CER_ES4_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2005-03-29] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=2.5 degree; Longitude_Resolution=2.5 degree; Horizontal_Resolution_Range=250 km - < 500 km or approximately 2.5 degrees - < 5.0 degrees; Temporal_Resolution=1 month; Temporal_Resolution_Range=Monthly - < Annual].

CERES ERBE-like Monthly Geographical Averages (ES-4) in HDF (CER_ES4_Aqua-FM4_Edition1-CV)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ERBE-like Monthly Geographical Averages (ES-4) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The ES-4 is also produced for combinations of scanner instruments. For each observed 2.5-degree spatial region, the daily average, the hourly average over the month, and the overall monthly average of shortwave and longwave fluxes at the Top-of-the-Atmosphere (TOA) from the CERES ES-9 product are spatially nested up from 2.5-degree regions to 5- and 10-degree regions, to 2.5-, 5-, and 10-degree zonal averages, and to global monthly averages. For each nested area, the albedo and net flux are given. For each region, the daily average flux is estimated from an algorithm that uses the available hourly data, scene identification data, and diurnal models. This algorithm is 'like' the algorithm used for the Earth Radiation Budget Experiment (ERBE). The following CERES ES4 data sets are currently available: CER_ES4_FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition2 CER_ES4_PFM+FM1_Edition1 CER_ES4_PFM+FM2_Edition1 CER_ES4_TRMM-PFM_Edition1 CER_ES4_TRMM-PFM_Edition2 CER_ES4_Terra-FM1_Edition1 CER_ES4_Terra-FM2_Edition1 CER_ES4_FM1+FM2_Edition2 CER_ES4_Terra-FM1_Edition2 CER_ES4_Terra-FM2_Edition2 CER_ES4_Aqua-FM3_Edition1 CER_ES4_Aqua-FM4_Edition1 CER_ES4_FM1+FM2+FM3+FM4_Edition1 CER_ES4_Aqua-FM3_Edition2 CER_ES4_Aqua-FM4_Edition2 CER_ES4_FM1+FM3_Edition2 CER_ES4_FM1+FM4_Edition2 CER_ES4_PFM+FM1_Edition2 CER_ES4_PFM+FM2_Edition2 CER_ES4_Aqua-FM3_Edition1-CV CER_ES4_Aqua-FM4_Edition1-CV CER_ES4_Terra-FM1_Edition1-CV CER_ES4_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2005-03-29] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=2.5 degree; Longitude_Resolution=2.5 degree; Horizontal_Resolution_Range=250 km - < 500 km or approximately 2.5 degrees - < 5.0 degrees; Temporal_Resolution=1 month; Temporal_Resolution_Range=Monthly - < Annual].

CERES ERBE-like Monthly Geographical Averages (ES-4) in HDF (CER_ES4_Terra-FM2_Edition1)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ERBE-like Monthly Geographical Averages (ES-4) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The ES-4 is also produced for combinations of scanner instruments. For each observed 2.5-degree spatial region, the daily average, the hourly average over the month, and the overall monthly average of shortwave and longwave fluxes at the Top-of-the-Atmosphere (TOA) from the CERES ES-9 product are spatially nested up from 2.5-degree regions to 5- and 10-degree regions, to 2.5-, 5-, and 10-degree zonal averages, and to global monthly averages. For each nested area, the albedo and net flux are given. For each region, the daily average flux is estimated from an algorithm that uses the available hourly data, scene identification data, and diurnal models. This algorithm is 'like' the algorithm used for the Earth Radiation Budget Experiment (ERBE). The following CERES ES4 data sets are currently available: CER_ES4_FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition2 CER_ES4_PFM+FM1_Edition1 CER_ES4_PFM+FM2_Edition1 CER_ES4_TRMM-PFM_Edition1 CER_ES4_TRMM-PFM_Edition2 CER_ES4_Terra-FM1_Edition1 CER_ES4_Terra-FM2_Edition1 CER_ES4_FM1+FM2_Edition2 CER_ES4_Terra-FM1_Edition2 CER_ES4_Terra-FM2_Edition2 CER_ES4_Aqua-FM3_Edition1 CER_ES4_Aqua-FM4_Edition1 CER_ES4_FM1+FM2+FM3+FM4_Edition1 CER_ES4_Aqua-FM3_Edition2 CER_ES4_Aqua-FM4_Edition2 CER_ES4_FM1+FM3_Edition2 CER_ES4_FM1+FM4_Edition2 CER_ES4_PFM+FM1_Edition2 CER_ES4_PFM+FM2_Edition2 CER_ES4_Aqua-FM3_Edition1-CV CER_ES4_Aqua-FM4_Edition1-CV CER_ES4_Terra-FM1_Edition1-CV CER_ES4_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2005-10-31] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=2.5 degree; Longitude_Resolution=2.5 degree; Horizontal_Resolution_Range=250 km - < 500 km or approximately 2.5 degrees - < 5.0 degrees; Temporal_Resolution=1 month; Temporal_Resolution_Range=Monthly - < Annual].

CERES ERBE-like Monthly Geographical Averages (ES-4) in HDF (CER_ES4_Terra-FM1_Edition1)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ERBE-like Monthly Geographical Averages (ES-4) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The ES-4 is also produced for combinations of scanner instruments. For each observed 2.5-degree spatial region, the daily average, the hourly average over the month, and the overall monthly average of shortwave and longwave fluxes at the Top-of-the-Atmosphere (TOA) from the CERES ES-9 product are spatially nested up from 2.5-degree regions to 5- and 10-degree regions, to 2.5-, 5-, and 10-degree zonal averages, and to global monthly averages. For each nested area, the albedo and net flux are given. For each region, the daily average flux is estimated from an algorithm that uses the available hourly data, scene identification data, and diurnal models. This algorithm is 'like' the algorithm used for the Earth Radiation Budget Experiment (ERBE). The following CERES ES4 data sets are currently available: CER_ES4_FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition2 CER_ES4_PFM+FM1_Edition1 CER_ES4_PFM+FM2_Edition1 CER_ES4_TRMM-PFM_Edition1 CER_ES4_TRMM-PFM_Edition2 CER_ES4_Terra-FM1_Edition1 CER_ES4_Terra-FM2_Edition1 CER_ES4_FM1+FM2_Edition2 CER_ES4_Terra-FM1_Edition2 CER_ES4_Terra-FM2_Edition2 CER_ES4_Aqua-FM3_Edition1 CER_ES4_Aqua-FM4_Edition1 CER_ES4_FM1+FM2+FM3+FM4_Edition1 CER_ES4_Aqua-FM3_Edition2 CER_ES4_Aqua-FM4_Edition2 CER_ES4_FM1+FM3_Edition2 CER_ES4_FM1+FM4_Edition2 CER_ES4_PFM+FM1_Edition2 CER_ES4_PFM+FM2_Edition2 CER_ES4_Aqua-FM3_Edition1-CV CER_ES4_Aqua-FM4_Edition1-CV CER_ES4_Terra-FM1_Edition1-CV CER_ES4_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2005-10-31] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=2.5 degree; Longitude_Resolution=2.5 degree; Horizontal_Resolution_Range=250 km - < 500 km or approximately 2.5 degrees - < 5.0 degrees; Temporal_Resolution=1 month; Temporal_Resolution_Range=Monthly - < Annual].

CERES ERBE-like Monthly Geographical Averages (ES-4) in HDF (CER_ES4_PFM+FM2_Edition1)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ERBE-like Monthly Geographical Averages (ES-4) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The ES-4 is also produced for combinations of scanner instruments. For each observed 2.5-degree spatial region, the daily average, the hourly average over the month, and the overall monthly average of shortwave and longwave fluxes at the Top-of-the-Atmosphere (TOA) from the CERES ES-9 product are spatially nested up from 2.5-degree regions to 5- and 10-degree regions, to 2.5-, 5-, and 10-degree zonal averages, and to global monthly averages. For each nested area, the albedo and net flux are given. For each region, the daily average flux is estimated from an algorithm that uses the available hourly data, scene identification data, and diurnal models. This algorithm is 'like' the algorithm used for the Earth Radiation Budget Experiment (ERBE). The following CERES ES4 data sets are currently available: CER_ES4_FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition2 CER_ES4_PFM+FM1_Edition1 CER_ES4_PFM+FM2_Edition1 CER_ES4_TRMM-PFM_Edition1 CER_ES4_TRMM-PFM_Edition2 CER_ES4_Terra-FM1_Edition1 CER_ES4_Terra-FM2_Edition1 CER_ES4_FM1+FM2_Edition2 CER_ES4_Terra-FM1_Edition2 CER_ES4_Terra-FM2_Edition2 CER_ES4_Aqua-FM3_Edition1 CER_ES4_Aqua-FM4_Edition1 CER_ES4_FM1+FM2+FM3+FM4_Edition1 CER_ES4_Aqua-FM3_Edition2 CER_ES4_Aqua-FM4_Edition2 CER_ES4_FM1+FM3_Edition2 CER_ES4_FM1+FM4_Edition2 CER_ES4_PFM+FM1_Edition2 CER_ES4_PFM+FM2_Edition2 CER_ES4_Aqua-FM3_Edition1-CV CER_ES4_Aqua-FM4_Edition1-CV CER_ES4_Terra-FM1_Edition1-CV CER_ES4_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2000-03-31] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=2.5 degree; Longitude_Resolution=2.5 degree; Horizontal_Resolution_Range=250 km - < 500 km or approximately 2.5 degrees - < 5.0 degrees; Temporal_Resolution=1 month; Temporal_Resolution_Range=Monthly - < Annual].

CERES ERBE-like Monthly Geographical Averages (ES-4) in HDF (CER_ES4_FM1+FM2_Edition2)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ERBE-like Monthly Geographical Averages (ES-4) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The ES-4 is also produced for combinations of scanner instruments. For each observed 2.5-degree spatial region, the daily average, the hourly average over the month, and the overall monthly average of shortwave and longwave fluxes at the Top-of-the-Atmosphere (TOA) from the CERES ES-9 product are spatially nested up from 2.5-degree regions to 5- and 10-degree regions, to 2.5-, 5-, and 10-degree zonal averages, and to global monthly averages. For each nested area, the albedo and net flux are given. For each region, the daily average flux is estimated from an algorithm that uses the available hourly data, scene identification data, and diurnal models. This algorithm is 'like' the algorithm used for the Earth Radiation Budget Experiment (ERBE). The following CERES ES4 data sets are currently available: CER_ES4_FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition2 CER_ES4_PFM+FM1_Edition1 CER_ES4_PFM+FM2_Edition1 CER_ES4_TRMM-PFM_Edition1 CER_ES4_TRMM-PFM_Edition2 CER_ES4_Terra-FM1_Edition1 CER_ES4_Terra-FM2_Edition1 CER_ES4_FM1+FM2_Edition2 CER_ES4_Terra-FM1_Edition2 CER_ES4_Terra-FM2_Edition2 CER_ES4_Aqua-FM3_Edition1 CER_ES4_Aqua-FM4_Edition1 CER_ES4_FM1+FM2+FM3+FM4_Edition1 CER_ES4_Aqua-FM3_Edition2 CER_ES4_Aqua-FM4_Edition2 CER_ES4_FM1+FM3_Edition2 CER_ES4_FM1+FM4_Edition2 CER_ES4_PFM+FM1_Edition2 CER_ES4_PFM+FM2_Edition2 CER_ES4_Aqua-FM3_Edition1-CV CER_ES4_Aqua-FM4_Edition1-CV CER_ES4_Terra-FM1_Edition1-CV CER_ES4_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2002-12-31] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=2.5 degree; Longitude_Resolution=2.5 degree; Horizontal_Resolution_Range=250 km - < 500 km or approximately 2.5 degrees - < 5.0 degrees; Temporal_Resolution=1 month; Temporal_Resolution_Range=Monthly - < Annual].

CERES ERBE-like Monthly Geographical Averages (ES-4) in HDF (CER_ES4_FM1+FM3_Edition2)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ERBE-like Monthly Geographical Averages (ES-4) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The ES-4 is also produced for combinations of scanner instruments. For each observed 2.5-degree spatial region, the daily average, the hourly average over the month, and the overall monthly average of shortwave and longwave fluxes at the Top-of-the-Atmosphere (TOA) from the CERES ES-9 product are spatially nested up from 2.5-degree regions to 5- and 10-degree regions, to 2.5-, 5-, and 10-degree zonal averages, and to global monthly averages. For each nested area, the albedo and net flux are given. For each region, the daily average flux is estimated from an algorithm that uses the available hourly data, scene identification data, and diurnal models. This algorithm is 'like' the algorithm used for the Earth Radiation Budget Experiment (ERBE). The following CERES ES4 data sets are currently available: CER_ES4_FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition1 CER_ES4_PFM+FM1+FM2_Edition2 CER_ES4_PFM+FM1_Edition1 CER_ES4_PFM+FM2_Edition1 CER_ES4_TRMM-PFM_Edition1 CER_ES4_TRMM-PFM_Edition2 CER_ES4_Terra-FM1_Edition1 CER_ES4_Terra-FM2_Edition1 CER_ES4_FM1+FM2_Edition2 CER_ES4_Terra-FM1_Edition2 CER_ES4_Terra-FM2_Edition2 CER_ES4_Aqua-FM3_Edition1 CER_ES4_Aqua-FM4_Edition1 CER_ES4_FM1+FM2+FM3+FM4_Edition1 CER_ES4_Aqua-FM3_Edition2 CER_ES4_Aqua-FM4_Edition2 CER_ES4_FM1+FM3_Edition2 CER_ES4_FM1+FM4_Edition2 CER_ES4_PFM+FM1_Edition2 CER_ES4_PFM+FM2_Edition2 CER_ES4_Aqua-FM3_Edition1-CV CER_ES4_Aqua-FM4_Edition1-CV CER_ES4_Terra-FM1_Edition1-CV CER_ES4_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2005-12-31] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=2.5 degree; Longitude_Resolution=2.5 degree; Horizontal_Resolution_Range=250 km - < 500 km or approximately 2.5 degrees - < 5.0 degrees; Temporal_Resolution=1 month; Temporal_Resolution_Range=Monthly - < Annual].

Concerted functions of HDAC1 and microRNA-574-5p repress alternatively spliced ceramide synthase 1 expression in human cancer cells

PubMed Central

Meyers-Needham, Marisa; Ponnusamy, Suriyan; Gencer, Salih; Jiang, Wenhui; Thomas, Raquela J; Senkal, Can E; Ogretmen, Besim

2012-01-01

Histone deacetylases (HDACs) and microRNAs (miRs) have pro-survival roles, but the mechanism behind this is unclear. Repression of ceramide synthase 1 (CerS1), altering C18-ceramide generation, was linked to drug resistance and metastasis. Here we report that the CerS1 promoter was repressed by HDAC1-dependent inhibition of Sp1 recruitment to two specific GC-boxes spanning the −177 and −139 region. Moreover, an alternatively spliced variant CerS1 mRNA (CerS1-2) was detected mainly in cancer cells or primary tumour tissues compared to controls, which was targeted by miR-574-5p for degradation. A specific 3′UTR-targeting site, localized within the retained intron between exons 6 and 7, was identified, and its mutation, or miR-574-5p knockdown prevented the degradation of CerS1-2 mRNA. Interference with HDAC1 and miR-574-5p reconstituted CerS1-2 expression and C18-ceramide generation in multiple human cancer cell lines, which subsequently inhibited proliferation and anchorage-independent growth. Accordingly, knockdown of CerS1 partially protected cancer cells from MS-275/miR-574-5p siRNA-mediated growth inhibition. Thus, these data suggest that the HDAC1/miR-574-5p axis might provide a novel therapeutic target to reconstitute tumour suppressor CerS1/ceramide signalling. PMID:22180294

Re-Orientation of Clinical Research in Traumatic Brain Injury: Report of an International Workshop on Comparative Effectiveness Research

PubMed Central

Menon, David K.; Lingsma, Hester F.; Pineda, Jose A.; Sandel, M. Elizabeth; Manley, Geoffrey T.

2012-01-01

Abstract During the National Neurotrauma Symposium 2010, the DG Research of the European Commission and the National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) organized a workshop on comparative effectiveness research (CER) in traumatic brain injury (TBI). This workshop reviewed existing approaches to improve outcomes of TBI patients. It had two main outcomes: First, it initiated a process of re-orientation of clinical research in TBI. Second, it provided ideas for a potential collaboration between the European Commission and the NIH/NINDS to stimulate research in TBI. Advances in provision of care for TBI patients have resulted from observational studies, guideline development, and meta-analyses of individual patient data. In contrast, randomized controlled trials have not led to any identifiable major advances. Rigorous protocols and tightly selected populations constrain generalizability. The workshop addressed additional research approaches, summarized the greatest unmet needs, and highlighted priorities for future research. The collection of high-quality clinical databases, associated with systems biology and CER, offers substantial opportunities. Systems biology aims to identify multiple factors contributing to a disease and addresses complex interactions. Effectiveness research aims to measure benefits and risks of systems of care and interventions in ordinary settings and broader populations. These approaches have great potential for TBI research. Although not new, they still need to be introduced to and accepted by TBI researchers as instruments for clinical research. As with therapeutic targets in individual patient management, so it is with research tools: one size does not fit all. PMID:21545277

An eceriferum locus, cer-zv, is associated with a defect in cutin responsible for water retention in barley (Hordeum vulgare) leaves.

PubMed

Li, Chao; Wang, Aidong; Ma, Xiaoying; Pourkheirandish, Mohammad; Sakuma, Shun; Wang, Ning; Ning, Shunzong; Nevo, Eviatar; Nawrath, Christiane; Komatsuda, Takao; Chen, Guoxiong

2013-03-01

Drought limits plant growth and threatens crop productivity. A barley (Hordeum vulgare) ethylene imine-induced monogenic recessive mutant cer-zv, which is sensitive to drought, was characterized and genetically mapped in the present study. Detached leaves of cer-zv lost 34.2 % of their initial weight after 1 h of dehydration. The transpiration was much higher in cer-zv leaves than in wild-type leaves under both light and dark conditions. The stomata of cer-zv leaves functioned normally, but the cuticle of cer-zv leaves showed increased permeability to ethanol and toluidine blue dye. There was a 50-90 % reduction in four major cutin monomers, but no reduction in wax loads was found in the cer-zv mutant as compared with the wild type. Two F(2) mapping populations were established by the crosses of 23-19 × cer-zv and cer-zv × OUH602. More polymorphisms were found in EST sequences between cer-zv and OUH602 than between cer-zv and 23-19. cer-zv was located in a pericentromeric region on chromosome 4H in a 10.8 cM interval in the 23-19 × cer-zv map based on 186 gametes tested and a 1.7 cM interval in the cer-zv × OUH602 map based on 176 gametes tested. It co-segregated with EST marker AK251484 in both maps. The results indicated that the cer-zv mutant is defective in cutin, which might be responsible for the increased transpiration rate and drought sensitivity, and that the F(2) of cer-zv × OUH602 might better facilitate high resolution mapping of cer-zv.

Effect of serial infusions of reconstituted high-density lipoprotein (CER-001) on coronary atherosclerosis: rationale and design of the CARAT study.

PubMed

Andrews, Jordan; Janssan, Alex; Nguyen, Tracy; Pisaniello, Anthony D; Scherer, Daniel J; Kastelein, John J P; Merkely, Bela; Nissen, Steven E; Ray, Kausik; Schwartz, Gregory G; Worthley, Stephen G; Keyserling, Connie; Dasseux, Jean-Louis; Butters, Julie; Girardi, Jacinta; Miller, Rosemary; Nicholls, Stephen J

2017-02-01

High-density lipoprotein (HDL) is believed to have atheroprotective properties, but an effective HDL-based therapy remains elusive. Early studies have suggested that infusion of reconstituted HDL promotes reverse cholesterol transport and vascular reactivity. The CER-001 Atherosclerosis Regression Acute Coronary Syndrome Trial (CARAT) is investigating the impact of infusing an engineered pre-beta HDL mimetic containing sphingomyelin (SM) and dipalmitoyl phosphatidlyglycerol (CER-001) on coronary atheroma volume in patients with a recent acute coronary syndrome (ACS). The CARAT is a phase 2, multicenter trial in which 292 patients with an ACS undergoing intracoronary ultrasonography and showing percent atheroma volume (PAV) greater than 30% are randomly assigned to treatment with ten infusions of CER-001 3 mg/kg or matching placebo, administered at weekly intervals. Intracoronary ultrasonography is repeated at the end of the treatment period. The primary endpoint is the nominal change in PAV. Safety and tolerability will also be evaluated. CARAT will establish whether serial 3 mg/kg infusions of an engineered pre-beta HDL mimetic containing SM and dipalmitoyl phosphatidlyglycerol (CER-001) will regress atherosclerotic plaque in patients with a recent ACS.

Could Intermittent Energy Restriction and Intermittent Fasting Reduce Rates of Cancer in Obese, Overweight, and Normal-Weight Subjects? A Summary of Evidence.

PubMed

Harvie, Michelle N; Howell, Tony

2016-07-01

Animal studies and human observational data link energy restriction (ER) to reduced rates of carcinogenesis. Most of these studies have involved continuous energy restriction (CER), but there is increasing public and scientific interest in the potential health and anticancer effects of intermittent energy restriction (IER) or intermittent fasting (IF), which comprise periods of marked ER or total fasting interspersed with periods of normal eating. This review summarizes animal studies that assessed tumor rates with IER and IF compared with CER or ad libitum feed consumption. The relevance of these animal data to human cancer is also considered by summarizing available human studies of the effects of IER or IF compared with CER on cancer biomarkers in obese, overweight, and normal-weight subjects. IER regimens that include periods of ER alternating with ad libitum feed consumption for 1, 2, or 3 wk have been reported to be superior to CER in reducing tumor rates in most spontaneous mice tumor models. Limited human data from short-term studies (≤6 mo) in overweight and obese subjects have shown that IER can lead to greater improvements in insulin sensitivity (homeostasis model assessment) than can CER, with comparable reductions in adipokines and inflammatory markers and minor changes in the insulin-like growth factor axis. There are currently no data comparing IER or IF with CER in normal-weight subjects. The benefits of IER in these short-term trials are of interest, but not sufficient evidence to recommend the use of IER above CER. Longer-term human studies of adherence to and efficacy and safety of IER are required in obese and overweight subjects, as well as normal-weight subjects. © 2016 American Society for Nutrition.

Could Intermittent Energy Restriction and Intermittent Fasting Reduce Rates of Cancer in Obese, Overweight, and Normal-Weight Subjects? A Summary of Evidence12

PubMed Central

2016-01-01

Animal studies and human observational data link energy restriction (ER) to reduced rates of carcinogenesis. Most of these studies have involved continuous energy restriction (CER), but there is increasing public and scientific interest in the potential health and anticancer effects of intermittent energy restriction (IER) or intermittent fasting (IF), which comprise periods of marked ER or total fasting interspersed with periods of normal eating. This review summarizes animal studies that assessed tumor rates with IER and IF compared with CER or ad libitum feed consumption. The relevance of these animal data to human cancer is also considered by summarizing available human studies of the effects of IER or IF compared with CER on cancer biomarkers in obese, overweight, and normal-weight subjects. IER regimens that include periods of ER alternating with ad libitum feed consumption for 1, 2, or 3 wk have been reported to be superior to CER in reducing tumor rates in most spontaneous mice tumor models. Limited human data from short-term studies (≤6 mo) in overweight and obese subjects have shown that IER can lead to greater improvements in insulin sensitivity (homeostasis model assessment) than can CER, with comparable reductions in adipokines and inflammatory markers and minor changes in the insulin-like growth factor axis. There are currently no data comparing IER or IF with CER in normal-weight subjects. The benefits of IER in these short-term trials are of interest, but not sufficient evidence to recommend the use of IER above CER. Longer-term human studies of adherence to and efficacy and safety of IER are required in obese and overweight subjects, as well as normal-weight subjects. PMID:27422504

CERES ERBE-like Monthly Regional Averages (ES-9) in HDF (CER_ES9_Aqua-FM3_Edition1)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ERBE-like Monthly Regional Averages (ES-9) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The ES-9 is also produced for combinations of scanner instruments. All instantaneous shortwave and longwave fluxes at the Top-of-the-Atmosphere (TOA) from the CERES ES-8 product for a month are sorted by 2.5-degree spatial regions, by day number, and by the local hour of observation. The mean of the instantaneous fluxes for a given region-day-hour bin is determined and recorded on the ES-9 along with other flux statistics and scene information. For each region, the daily average flux is estimated from an algorithm that uses the available hourly data, scene identification data, and diurnal models. This algorithm is 'like' the algorithm used for the Earth Radiation Budget Experiment (ERBE). The ES-9 also contains hourly average fluxes for the month and an overall monthly average for each region. These average fluxes are given for both clear-sky and total-sky scenes. The following CERES ES9 data sets are currently available: CER_ES9_FM1+FM2_Edition1 CER_ES9_PFM+FM1+FM2_Edition1 CER_ES9_PFM+FM1+FM2_Edition2 CER_ES9_PFM+FM1_Edition1 CER_ES9_PFM+FM2_Edition1 CER_ES9_PFM+FM1_Edition2 CER_ES9_PFM+FM2_Edition2 CER_ES9_TRMM-PFM_Edition1 CER_ES9_TRMM-PFM_Edition2 CER_ES9_Terra-FM1_Edition1 CER_ES9_Terra-FM2_Edition1 CER_ES9_FM1+FM2_Edition2 CER_ES9_Terra-FM1_Edition2 CER_ES9_Terra-FM2_Edition2 CER_ES9_Aqua-FM3_Edition1 CER_ES9_Aqua-FM4_Edition1 CER_ES9_FM1+FM2+FM3+FM4_Edition1 CER_ES9_Aqua-FM3_Edition2 CER_ES9_Aqua-FM4_Edition2 CER_ES9_FM1+FM3_Edition2 CER_ES9_FM1+FM4_Edition2 CER_ES9_Aqua-FM3_Edition1-CV CER_ES9_Aqua-FM4_Edition1-CV CER_ES9_Terra-FM1_Edition1-CV CER_ES9_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2005-10-31] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=2.5 degree; Longitude_Resolution=2.5 degree; Horizontal_Resolution_Range=250 km - < 500 km or approximately 2.5 degrees - < 5.0 degrees; Temporal_Resolution=hourly, daily, monthly; Temporal_Resolution_Range=Hourly - < Daily, Daily - < Weekly, Monthly - < Annual].

CERES ERBE-like Monthly Regional Averages (ES-9) in HDF (CER_ES9_FM1+FM4_Edition2)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ERBE-like Monthly Regional Averages (ES-9) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The ES-9 is also produced for combinations of scanner instruments. All instantaneous shortwave and longwave fluxes at the Top-of-the-Atmosphere (TOA) from the CERES ES-8 product for a month are sorted by 2.5-degree spatial regions, by day number, and by the local hour of observation. The mean of the instantaneous fluxes for a given region-day-hour bin is determined and recorded on the ES-9 along with other flux statistics and scene information. For each region, the daily average flux is estimated from an algorithm that uses the available hourly data, scene identification data, and diurnal models. This algorithm is 'like' the algorithm used for the Earth Radiation Budget Experiment (ERBE). The ES-9 also contains hourly average fluxes for the month and an overall monthly average for each region. These average fluxes are given for both clear-sky and total-sky scenes. The following CERES ES9 data sets are currently available: CER_ES9_FM1+FM2_Edition1 CER_ES9_PFM+FM1+FM2_Edition1 CER_ES9_PFM+FM1+FM2_Edition2 CER_ES9_PFM+FM1_Edition1 CER_ES9_PFM+FM2_Edition1 CER_ES9_PFM+FM1_Edition2 CER_ES9_PFM+FM2_Edition2 CER_ES9_TRMM-PFM_Edition1 CER_ES9_TRMM-PFM_Edition2 CER_ES9_Terra-FM1_Edition1 CER_ES9_Terra-FM2_Edition1 CER_ES9_FM1+FM2_Edition2 CER_ES9_Terra-FM1_Edition2 CER_ES9_Terra-FM2_Edition2 CER_ES9_Aqua-FM3_Edition1 CER_ES9_Aqua-FM4_Edition1 CER_ES9_FM1+FM2+FM3+FM4_Edition1 CER_ES9_Aqua-FM3_Edition2 CER_ES9_Aqua-FM4_Edition2 CER_ES9_FM1+FM3_Edition2 CER_ES9_FM1+FM4_Edition2 CER_ES9_Aqua-FM3_Edition1-CV CER_ES9_Aqua-FM4_Edition1-CV CER_ES9_Terra-FM1_Edition1-CV CER_ES9_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2005-03-31] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=2.5 degree; Longitude_Resolution=2.5 degree; Horizontal_Resolution_Range=250 km - < 500 km or approximately 2.5 degrees - < 5.0 degrees; Temporal_Resolution=hourly, daily, monthly; Temporal_Resolution_Range=Hourly - < Daily, Daily - < Weekly, Monthly - < Annual].

CERES ERBE-like Monthly Regional Averages (ES-9) in HDF ( CER_ES9_Aqua-FM4_Edition1-CV)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ERBE-like Monthly Regional Averages (ES-9) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The ES-9 is also produced for combinations of scanner instruments. All instantaneous shortwave and longwave fluxes at the Top-of-the-Atmosphere (TOA) from the CERES ES-8 product for a month are sorted by 2.5-degree spatial regions, by day number, and by the local hour of observation. The mean of the instantaneous fluxes for a given region-day-hour bin is determined and recorded on the ES-9 along with other flux statistics and scene information. For each region, the daily average flux is estimated from an algorithm that uses the available hourly data, scene identification data, and diurnal models. This algorithm is 'like' the algorithm used for the Earth Radiation Budget Experiment (ERBE). The ES-9 also contains hourly average fluxes for the month and an overall monthly average for each region. These average fluxes are given for both clear-sky and total-sky scenes. The following CERES ES9 data sets are currently available: CER_ES9_FM1+FM2_Edition1 CER_ES9_PFM+FM1+FM2_Edition1 CER_ES9_PFM+FM1+FM2_Edition2 CER_ES9_PFM+FM1_Edition1 CER_ES9_PFM+FM2_Edition1 CER_ES9_PFM+FM1_Edition2 CER_ES9_PFM+FM2_Edition2 CER_ES9_TRMM-PFM_Edition1 CER_ES9_TRMM-PFM_Edition2 CER_ES9_Terra-FM1_Edition1 CER_ES9_Terra-FM2_Edition1 CER_ES9_FM1+FM2_Edition2 CER_ES9_Terra-FM1_Edition2 CER_ES9_Terra-FM2_Edition2 CER_ES9_Aqua-FM3_Edition1 CER_ES9_Aqua-FM4_Edition1 CER_ES9_FM1+FM2+FM3+FM4_Edition1 CER_ES9_Aqua-FM3_Edition2 CER_ES9_Aqua-FM4_Edition2 CER_ES9_FM1+FM3_Edition2 CER_ES9_FM1+FM4_Edition2 CER_ES9_Aqua-FM3_Edition1-CV CER_ES9_Aqua-FM4_Edition1-CV CER_ES9_Terra-FM1_Edition1-CV CER_ES9_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2005-03-29] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=2.5 degree; Longitude_Resolution=2.5 degree; Horizontal_Resolution_Range=250 km - < 500 km or approximately 2.5 degrees - < 5.0 degrees; Temporal_Resolution=hourly, daily, monthly; Temporal_Resolution_Range=Hourly - < Daily, Daily - < Weekly, Monthly - < Annual].

CERES ERBE-like Monthly Regional Averages (ES-9) in HDF ( CER_ES9_Terra-FM1_Edition1-CV)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ERBE-like Monthly Regional Averages (ES-9) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The ES-9 is also produced for combinations of scanner instruments. All instantaneous shortwave and longwave fluxes at the Top-of-the-Atmosphere (TOA) from the CERES ES-8 product for a month are sorted by 2.5-degree spatial regions, by day number, and by the local hour of observation. The mean of the instantaneous fluxes for a given region-day-hour bin is determined and recorded on the ES-9 along with other flux statistics and scene information. For each region, the daily average flux is estimated from an algorithm that uses the available hourly data, scene identification data, and diurnal models. This algorithm is 'like' the algorithm used for the Earth Radiation Budget Experiment (ERBE). The ES-9 also contains hourly average fluxes for the month and an overall monthly average for each region. These average fluxes are given for both clear-sky and total-sky scenes. The following CERES ES9 data sets are currently available: CER_ES9_FM1+FM2_Edition1 CER_ES9_PFM+FM1+FM2_Edition1 CER_ES9_PFM+FM1+FM2_Edition2 CER_ES9_PFM+FM1_Edition1 CER_ES9_PFM+FM2_Edition1 CER_ES9_PFM+FM1_Edition2 CER_ES9_PFM+FM2_Edition2 CER_ES9_TRMM-PFM_Edition1 CER_ES9_TRMM-PFM_Edition2 CER_ES9_Terra-FM1_Edition1 CER_ES9_Terra-FM2_Edition1 CER_ES9_FM1+FM2_Edition2 CER_ES9_Terra-FM1_Edition2 CER_ES9_Terra-FM2_Edition2 CER_ES9_Aqua-FM3_Edition1 CER_ES9_Aqua-FM4_Edition1 CER_ES9_FM1+FM2+FM3+FM4_Edition1 CER_ES9_Aqua-FM3_Edition2 CER_ES9_Aqua-FM4_Edition2 CER_ES9_FM1+FM3_Edition2 CER_ES9_FM1+FM4_Edition2 CER_ES9_Aqua-FM3_Edition1-CV CER_ES9_Aqua-FM4_Edition1-CV CER_ES9_Terra-FM1_Edition1-CV CER_ES9_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2006-09-30] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=2.5 degree; Longitude_Resolution=2.5 degree; Horizontal_Resolution_Range=250 km - < 500 km or approximately 2.5 degrees - < 5.0 degrees; Temporal_Resolution=hourly, daily, monthly; Temporal_Resolution_Range=Hourly - < Daily, Daily - < Weekly, Monthly - < Annual].

CERES ERBE-like Monthly Regional Averages (ES-9) in HDF (CER_ES9_TRMM-PFM_Edition1)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ERBE-like Monthly Regional Averages (ES-9) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The ES-9 is also produced for combinations of scanner instruments. All instantaneous shortwave and longwave fluxes at the Top-of-the-Atmosphere (TOA) from the CERES ES-8 product for a month are sorted by 2.5-degree spatial regions, by day number, and by the local hour of observation. The mean of the instantaneous fluxes for a given region-day-hour bin is determined and recorded on the ES-9 along with other flux statistics and scene information. For each region, the daily average flux is estimated from an algorithm that uses the available hourly data, scene identification data, and diurnal models. This algorithm is 'like' the algorithm used for the Earth Radiation Budget Experiment (ERBE). The ES-9 also contains hourly average fluxes for the month and an overall monthly average for each region. These average fluxes are given for both clear-sky and total-sky scenes. The following CERES ES9 data sets are currently available: CER_ES9_FM1+FM2_Edition1 CER_ES9_PFM+FM1+FM2_Edition1 CER_ES9_PFM+FM1+FM2_Edition2 CER_ES9_PFM+FM1_Edition1 CER_ES9_PFM+FM2_Edition1 CER_ES9_PFM+FM1_Edition2 CER_ES9_PFM+FM2_Edition2 CER_ES9_TRMM-PFM_Edition1 CER_ES9_TRMM-PFM_Edition2 CER_ES9_Terra-FM1_Edition1 CER_ES9_Terra-FM2_Edition1 CER_ES9_FM1+FM2_Edition2 CER_ES9_Terra-FM1_Edition2 CER_ES9_Terra-FM2_Edition2 CER_ES9_Aqua-FM3_Edition1 CER_ES9_Aqua-FM4_Edition1 CER_ES9_FM1+FM2+FM3+FM4_Edition1 CER_ES9_Aqua-FM3_Edition2 CER_ES9_Aqua-FM4_Edition2 CER_ES9_FM1+FM3_Edition2 CER_ES9_FM1+FM4_Edition2 CER_ES9_Aqua-FM3_Edition1-CV CER_ES9_Aqua-FM4_Edition1-CV CER_ES9_Terra-FM1_Edition1-CV CER_ES9_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=1998-08-31] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=2.5 degree; Longitude_Resolution=2.5 degree; Horizontal_Resolution_Range=250 km - < 500 km or approximately 2.5 degrees - < 5.0 degrees; Temporal_Resolution=hourly, daily, monthly; Temporal_Resolution_Range=Hourly - < Daily, Daily - < Weekly, Monthly - < Annual].

CERES ERBE-like Monthly Regional Averages (ES-9) in HDF (CER_ES9_Aqua-FM4_Edition1)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ERBE-like Monthly Regional Averages (ES-9) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The ES-9 is also produced for combinations of scanner instruments. All instantaneous shortwave and longwave fluxes at the Top-of-the-Atmosphere (TOA) from the CERES ES-8 product for a month are sorted by 2.5-degree spatial regions, by day number, and by the local hour of observation. The mean of the instantaneous fluxes for a given region-day-hour bin is determined and recorded on the ES-9 along with other flux statistics and scene information. For each region, the daily average flux is estimated from an algorithm that uses the available hourly data, scene identification data, and diurnal models. This algorithm is 'like' the algorithm used for the Earth Radiation Budget Experiment (ERBE). The ES-9 also contains hourly average fluxes for the month and an overall monthly average for each region. These average fluxes are given for both clear-sky and total-sky scenes. The following CERES ES9 data sets are currently available: CER_ES9_FM1+FM2_Edition1 CER_ES9_PFM+FM1+FM2_Edition1 CER_ES9_PFM+FM1+FM2_Edition2 CER_ES9_PFM+FM1_Edition1 CER_ES9_PFM+FM2_Edition1 CER_ES9_PFM+FM1_Edition2 CER_ES9_PFM+FM2_Edition2 CER_ES9_TRMM-PFM_Edition1 CER_ES9_TRMM-PFM_Edition2 CER_ES9_Terra-FM1_Edition1 CER_ES9_Terra-FM2_Edition1 CER_ES9_FM1+FM2_Edition2 CER_ES9_Terra-FM1_Edition2 CER_ES9_Terra-FM2_Edition2 CER_ES9_Aqua-FM3_Edition1 CER_ES9_Aqua-FM4_Edition1 CER_ES9_FM1+FM2+FM3+FM4_Edition1 CER_ES9_Aqua-FM3_Edition2 CER_ES9_Aqua-FM4_Edition2 CER_ES9_FM1+FM3_Edition2 CER_ES9_FM1+FM4_Edition2 CER_ES9_Aqua-FM3_Edition1-CV CER_ES9_Aqua-FM4_Edition1-CV CER_ES9_Terra-FM1_Edition1-CV CER_ES9_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2005-03-29] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=2.5 degree; Longitude_Resolution=2.5 degree; Horizontal_Resolution_Range=250 km - < 500 km or approximately 2.5 degrees - < 5.0 degrees; Temporal_Resolution=hourly, daily, monthly; Temporal_Resolution_Range=Hourly - < Daily, Daily - < Weekly, Monthly - < Annual].

CERES ERBE-like Monthly Regional Averages (ES-9) in HDF (CER_ES9_PFM+FM2_Edition1)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ERBE-like Monthly Regional Averages (ES-9) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The ES-9 is also produced for combinations of scanner instruments. All instantaneous shortwave and longwave fluxes at the Top-of-the-Atmosphere (TOA) from the CERES ES-8 product for a month are sorted by 2.5-degree spatial regions, by day number, and by the local hour of observation. The mean of the instantaneous fluxes for a given region-day-hour bin is determined and recorded on the ES-9 along with other flux statistics and scene information. For each region, the daily average flux is estimated from an algorithm that uses the available hourly data, scene identification data, and diurnal models. This algorithm is 'like' the algorithm used for the Earth Radiation Budget Experiment (ERBE). The ES-9 also contains hourly average fluxes for the month and an overall monthly average for each region. These average fluxes are given for both clear-sky and total-sky scenes. The following CERES ES9 data sets are currently available: CER_ES9_FM1+FM2_Edition1 CER_ES9_PFM+FM1+FM2_Edition1 CER_ES9_PFM+FM1+FM2_Edition2 CER_ES9_PFM+FM1_Edition1 CER_ES9_PFM+FM2_Edition1 CER_ES9_PFM+FM1_Edition2 CER_ES9_PFM+FM2_Edition2 CER_ES9_TRMM-PFM_Edition1 CER_ES9_TRMM-PFM_Edition2 CER_ES9_Terra-FM1_Edition1 CER_ES9_Terra-FM2_Edition1 CER_ES9_FM1+FM2_Edition2 CER_ES9_Terra-FM1_Edition2 CER_ES9_Terra-FM2_Edition2 CER_ES9_Aqua-FM3_Edition1 CER_ES9_Aqua-FM4_Edition1 CER_ES9_FM1+FM2+FM3+FM4_Edition1 CER_ES9_Aqua-FM3_Edition2 CER_ES9_Aqua-FM4_Edition2 CER_ES9_FM1+FM3_Edition2 CER_ES9_FM1+FM4_Edition2 CER_ES9_Aqua-FM3_Edition1-CV CER_ES9_Aqua-FM4_Edition1-CV CER_ES9_Terra-FM1_Edition1-CV CER_ES9_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2000-03-31] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=2.5 degree; Longitude_Resolution=2.5 degree; Horizontal_Resolution_Range=250 km - < 500 km or approximately 2.5 degrees - < 5.0 degrees; Temporal_Resolution=hourly, daily, monthly; Temporal_Resolution_Range=Hourly - < Daily, Daily - < Weekly, Monthly - < Annual].

CERES ERBE-like Monthly Regional Averages (ES-9) in HDF (CER_ES9_Terra-FM1_Edition1)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ERBE-like Monthly Regional Averages (ES-9) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The ES-9 is also produced for combinations of scanner instruments. All instantaneous shortwave and longwave fluxes at the Top-of-the-Atmosphere (TOA) from the CERES ES-8 product for a month are sorted by 2.5-degree spatial regions, by day number, and by the local hour of observation. The mean of the instantaneous fluxes for a given region-day-hour bin is determined and recorded on the ES-9 along with other flux statistics and scene information. For each region, the daily average flux is estimated from an algorithm that uses the available hourly data, scene identification data, and diurnal models. This algorithm is 'like' the algorithm used for the Earth Radiation Budget Experiment (ERBE). The ES-9 also contains hourly average fluxes for the month and an overall monthly average for each region. These average fluxes are given for both clear-sky and total-sky scenes. The following CERES ES9 data sets are currently available: CER_ES9_FM1+FM2_Edition1 CER_ES9_PFM+FM1+FM2_Edition1 CER_ES9_PFM+FM1+FM2_Edition2 CER_ES9_PFM+FM1_Edition1 CER_ES9_PFM+FM2_Edition1 CER_ES9_PFM+FM1_Edition2 CER_ES9_PFM+FM2_Edition2 CER_ES9_TRMM-PFM_Edition1 CER_ES9_TRMM-PFM_Edition2 CER_ES9_Terra-FM1_Edition1 CER_ES9_Terra-FM2_Edition1 CER_ES9_FM1+FM2_Edition2 CER_ES9_Terra-FM1_Edition2 CER_ES9_Terra-FM2_Edition2 CER_ES9_Aqua-FM3_Edition1 CER_ES9_Aqua-FM4_Edition1 CER_ES9_FM1+FM2+FM3+FM4_Edition1 CER_ES9_Aqua-FM3_Edition2 CER_ES9_Aqua-FM4_Edition2 CER_ES9_FM1+FM3_Edition2 CER_ES9_FM1+FM4_Edition2 CER_ES9_Aqua-FM3_Edition1-CV CER_ES9_Aqua-FM4_Edition1-CV CER_ES9_Terra-FM1_Edition1-CV CER_ES9_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2005-10-31] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=2.5 degree; Longitude_Resolution=2.5 degree; Horizontal_Resolution_Range=250 km - < 500 km or approximately 2.5 degrees - < 5.0 degrees; Temporal_Resolution=hourly, daily, monthly; Temporal_Resolution_Range=Hourly - < Daily, Daily - < Weekly, Monthly - < Annual].

CERES ERBE-like Monthly Regional Averages (ES-9) in HDF (CERES:CER_ES9_PFM+FM1_Edition2)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ERBE-like Monthly Regional Averages (ES-9) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The ES-9 is also produced for combinations of scanner instruments. All instantaneous shortwave and longwave fluxes at the Top-of-the-Atmosphere (TOA) from the CERES ES-8 product for a month are sorted by 2.5-degree spatial regions, by day number, and by the local hour of observation. The mean of the instantaneous fluxes for a given region-day-hour bin is determined and recorded on the ES-9 along with other flux statistics and scene information. For each region, the daily average flux is estimated from an algorithm that uses the available hourly data, scene identification data, and diurnal models. This algorithm is 'like' the algorithm used for the Earth Radiation Budget Experiment (ERBE). The ES-9 also contains hourly average fluxes for the month and an overall monthly average for each region. These average fluxes are given for both clear-sky and total-sky scenes. The following CERES ES9 data sets are currently available: CER_ES9_FM1+FM2_Edition1 CER_ES9_PFM+FM1+FM2_Edition1 CER_ES9_PFM+FM1+FM2_Edition2 CER_ES9_PFM+FM1_Edition1 CER_ES9_PFM+FM2_Edition1 CER_ES9_PFM+FM1_Edition2 CER_ES9_PFM+FM2_Edition2 CER_ES9_TRMM-PFM_Edition1 CER_ES9_TRMM-PFM_Edition2 CER_ES9_Terra-FM1_Edition1 CER_ES9_Terra-FM2_Edition1 CER_ES9_FM1+FM2_Edition2 CER_ES9_Terra-FM1_Edition2 CER_ES9_Terra-FM2_Edition2 CER_ES9_Aqua-FM3_Edition1 CER_ES9_Aqua-FM4_Edition1 CER_ES9_FM1+FM2+FM3+FM4_Edition1 CER_ES9_Aqua-FM3_Edition2 CER_ES9_Aqua-FM4_Edition2 CER_ES9_FM1+FM3_Edition2 CER_ES9_FM1+FM4_Edition2 CER_ES9_Aqua-FM3_Edition1-CV CER_ES9_Aqua-FM4_Edition1-CV CER_ES9_Terra-FM1_Edition1-CV CER_ES9_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2000-03-31] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=2.5 degree; Longitude_Resolution=2.5 degree; Horizontal_Resolution_Range=250 km - < 500 km or approximately 2.5 degrees - < 5.0 degrees; Temporal_Resolution=hourly, daily, monthly; Temporal_Resolution_Range=Hourly - < Daily, Daily - < Weekly, Monthly - < Annual].

CERES ERBE-like Monthly Regional Averages (ES-9) in HDF (CER_ES9_Aqua-FM4_Edition2)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ERBE-like Monthly Regional Averages (ES-9) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The ES-9 is also produced for combinations of scanner instruments. All instantaneous shortwave and longwave fluxes at the Top-of-the-Atmosphere (TOA) from the CERES ES-8 product for a month are sorted by 2.5-degree spatial regions, by day number, and by the local hour of observation. The mean of the instantaneous fluxes for a given region-day-hour bin is determined and recorded on the ES-9 along with other flux statistics and scene information. For each region, the daily average flux is estimated from an algorithm that uses the available hourly data, scene identification data, and diurnal models. This algorithm is 'like' the algorithm used for the Earth Radiation Budget Experiment (ERBE). The ES-9 also contains hourly average fluxes for the month and an overall monthly average for each region. These average fluxes are given for both clear-sky and total-sky scenes. The following CERES ES9 data sets are currently available: CER_ES9_FM1+FM2_Edition1 CER_ES9_PFM+FM1+FM2_Edition1 CER_ES9_PFM+FM1+FM2_Edition2 CER_ES9_PFM+FM1_Edition1 CER_ES9_PFM+FM2_Edition1 CER_ES9_PFM+FM1_Edition2 CER_ES9_PFM+FM2_Edition2 CER_ES9_TRMM-PFM_Edition1 CER_ES9_TRMM-PFM_Edition2 CER_ES9_Terra-FM1_Edition1 CER_ES9_Terra-FM2_Edition1 CER_ES9_FM1+FM2_Edition2 CER_ES9_Terra-FM1_Edition2 CER_ES9_Terra-FM2_Edition2 CER_ES9_Aqua-FM3_Edition1 CER_ES9_Aqua-FM4_Edition1 CER_ES9_FM1+FM2+FM3+FM4_Edition1 CER_ES9_Aqua-FM3_Edition2 CER_ES9_Aqua-FM4_Edition2 CER_ES9_FM1+FM3_Edition2 CER_ES9_FM1+FM4_Edition2 CER_ES9_Aqua-FM3_Edition1-CV CER_ES9_Aqua-FM4_Edition1-CV CER_ES9_Terra-FM1_Edition1-CV CER_ES9_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2005-03-29] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=2.5 degree; Longitude_Resolution=2.5 degree; Horizontal_Resolution_Range=250 km - < 500 km or approximately 2.5 degrees - < 5.0 degrees; Temporal_Resolution=hourly, daily, monthly; Temporal_Resolution_Range=Hourly - < Daily, Daily - < Weekly, Monthly - < Annual].

CERES ERBE-like Monthly Regional Averages (ES-9) in HDF (CER_ES9_PFM+FM1_Edition1)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ERBE-like Monthly Regional Averages (ES-9) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The ES-9 is also produced for combinations of scanner instruments. All instantaneous shortwave and longwave fluxes at the Top-of-the-Atmosphere (TOA) from the CERES ES-8 product for a month are sorted by 2.5-degree spatial regions, by day number, and by the local hour of observation. The mean of the instantaneous fluxes for a given region-day-hour bin is determined and recorded on the ES-9 along with other flux statistics and scene information. For each region, the daily average flux is estimated from an algorithm that uses the available hourly data, scene identification data, and diurnal models. This algorithm is 'like' the algorithm used for the Earth Radiation Budget Experiment (ERBE). The ES-9 also contains hourly average fluxes for the month and an overall monthly average for each region. These average fluxes are given for both clear-sky and total-sky scenes. The following CERES ES9 data sets are currently available: CER_ES9_FM1+FM2_Edition1 CER_ES9_PFM+FM1+FM2_Edition1 CER_ES9_PFM+FM1+FM2_Edition2 CER_ES9_PFM+FM1_Edition1 CER_ES9_PFM+FM2_Edition1 CER_ES9_PFM+FM1_Edition2 CER_ES9_PFM+FM2_Edition2 CER_ES9_TRMM-PFM_Edition1 CER_ES9_TRMM-PFM_Edition2 CER_ES9_Terra-FM1_Edition1 CER_ES9_Terra-FM2_Edition1 CER_ES9_FM1+FM2_Edition2 CER_ES9_Terra-FM1_Edition2 CER_ES9_Terra-FM2_Edition2 CER_ES9_Aqua-FM3_Edition1 CER_ES9_Aqua-FM4_Edition1 CER_ES9_FM1+FM2+FM3+FM4_Edition1 CER_ES9_Aqua-FM3_Edition2 CER_ES9_Aqua-FM4_Edition2 CER_ES9_FM1+FM3_Edition2 CER_ES9_FM1+FM4_Edition2 CER_ES9_Aqua-FM3_Edition1-CV CER_ES9_Aqua-FM4_Edition1-CV CER_ES9_Terra-FM1_Edition1-CV CER_ES9_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2000-03-31] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=2.5 degree; Longitude_Resolution=2.5 degree; Horizontal_Resolution_Range=250 km - < 500 km or approximately 2.5 degrees - < 5.0 degrees; Temporal_Resolution=hourly, daily, monthly; Temporal_Resolution_Range=Hourly - < Daily, Daily - < Weekly, Monthly - < Annual].

CERES ERBE-like Monthly Regional Averages (ES-9) in HDF ( CER_ES9_Aqua-FM3_Edition1-CV)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ERBE-like Monthly Regional Averages (ES-9) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The ES-9 is also produced for combinations of scanner instruments. All instantaneous shortwave and longwave fluxes at the Top-of-the-Atmosphere (TOA) from the CERES ES-8 product for a month are sorted by 2.5-degree spatial regions, by day number, and by the local hour of observation. The mean of the instantaneous fluxes for a given region-day-hour bin is determined and recorded on the ES-9 along with other flux statistics and scene information. For each region, the daily average flux is estimated from an algorithm that uses the available hourly data, scene identification data, and diurnal models. This algorithm is 'like' the algorithm used for the Earth Radiation Budget Experiment (ERBE). The ES-9 also contains hourly average fluxes for the month and an overall monthly average for each region. These average fluxes are given for both clear-sky and total-sky scenes. The following CERES ES9 data sets are currently available: CER_ES9_FM1+FM2_Edition1 CER_ES9_PFM+FM1+FM2_Edition1 CER_ES9_PFM+FM1+FM2_Edition2 CER_ES9_PFM+FM1_Edition1 CER_ES9_PFM+FM2_Edition1 CER_ES9_PFM+FM1_Edition2 CER_ES9_PFM+FM2_Edition2 CER_ES9_TRMM-PFM_Edition1 CER_ES9_TRMM-PFM_Edition2 CER_ES9_Terra-FM1_Edition1 CER_ES9_Terra-FM2_Edition1 CER_ES9_FM1+FM2_Edition2 CER_ES9_Terra-FM1_Edition2 CER_ES9_Terra-FM2_Edition2 CER_ES9_Aqua-FM3_Edition1 CER_ES9_Aqua-FM4_Edition1 CER_ES9_FM1+FM2+FM3+FM4_Edition1 CER_ES9_Aqua-FM3_Edition2 CER_ES9_Aqua-FM4_Edition2 CER_ES9_FM1+FM3_Edition2 CER_ES9_FM1+FM4_Edition2 CER_ES9_Aqua-FM3_Edition1-CV CER_ES9_Aqua-FM4_Edition1-CV CER_ES9_Terra-FM1_Edition1-CV CER_ES9_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2006-10-31] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=2.5 degree; Longitude_Resolution=2.5 degree; Horizontal_Resolution_Range=250 km - < 500 km or approximately 2.5 degrees - < 5.0 degrees; Temporal_Resolution=hourly, daily, monthly; Temporal_Resolution_Range=Hourly - < Daily, Daily - < Weekly, Monthly - < Annual].

CERES ERBE-like Monthly Regional Averages (ES-9) in HDF (CER_ES9_Terra-FM2_Edition1)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ERBE-like Monthly Regional Averages (ES-9) product contains a month of space and time averaged Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The ES-9 is also produced for combinations of scanner instruments. All instantaneous shortwave and longwave fluxes at the Top-of-the-Atmosphere (TOA) from the CERES ES-8 product for a month are sorted by 2.5-degree spatial regions, by day number, and by the local hour of observation. The mean of the instantaneous fluxes for a given region-day-hour bin is determined and recorded on the ES-9 along with other flux statistics and scene information. For each region, the daily average flux is estimated from an algorithm that uses the available hourly data, scene identification data, and diurnal models. This algorithm is 'like' the algorithm used for the Earth Radiation Budget Experiment (ERBE). The ES-9 also contains hourly average fluxes for the month and an overall monthly average for each region. These average fluxes are given for both clear-sky and total-sky scenes. The following CERES ES9 data sets are currently available: CER_ES9_FM1+FM2_Edition1 CER_ES9_PFM+FM1+FM2_Edition1 CER_ES9_PFM+FM1+FM2_Edition2 CER_ES9_PFM+FM1_Edition1 CER_ES9_PFM+FM2_Edition1 CER_ES9_PFM+FM1_Edition2 CER_ES9_PFM+FM2_Edition2 CER_ES9_TRMM-PFM_Edition1 CER_ES9_TRMM-PFM_Edition2 CER_ES9_Terra-FM1_Edition1 CER_ES9_Terra-FM2_Edition1 CER_ES9_FM1+FM2_Edition2 CER_ES9_Terra-FM1_Edition2 CER_ES9_Terra-FM2_Edition2 CER_ES9_Aqua-FM3_Edition1 CER_ES9_Aqua-FM4_Edition1 CER_ES9_FM1+FM2+FM3+FM4_Edition1 CER_ES9_Aqua-FM3_Edition2 CER_ES9_Aqua-FM4_Edition2 CER_ES9_FM1+FM3_Edition2 CER_ES9_FM1+FM4_Edition2 CER_ES9_Aqua-FM3_Edition1-CV CER_ES9_Aqua-FM4_Edition1-CV CER_ES9_Terra-FM1_Edition1-CV CER_ES9_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2005-10-31] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Latitude_Resolution=2.5 degree; Longitude_Resolution=2.5 degree; Horizontal_Resolution_Range=250 km - < 500 km or approximately 2.5 degrees - < 5.0 degrees; Temporal_Resolution=hourly, daily, monthly; Temporal_Resolution_Range=Hourly - < Daily, Daily - < Weekly, Monthly - < Annual].

Hidden Wolbachia diversity in field populations of the European cherry fruit fly, Rhagoletis cerasi (Diptera, Tephritidae).

PubMed

Arthofer, Wolfgang; Riegler, Markus; Schneider, Daniela; Krammer, Martin; Miller, Wolfgang J; Stauffer, Christian

2009-09-01

The European cherry fruit fly Rhagoletis cerasi has been a field model for cytoplasmic incompatibility since the mid 1970s. Two Wolbachia strains were detected in this tephritid species and wCer2 was described as the CI inducing agent dividing European populations into two unidirectional incompatible groups, i.e. southern females produce viable offspring with northern males, whereas the reciprocal cross results in incompatibility. We detected three new Wolbachia strains by sequencing a multitude of plasmids derived from Wolbachia surface protein gene (wsp) polymerase chain reaction (PCR) products. Strain-specific primers were developed allowing individual diagnosis without need for cloning. Hybridization of specific PCR products with a wsp oligonucleotide enhanced the detection limit significantly and revealed the presence of low-titre infections in some strains, in different ontogenetic stages and in adults of different age. We then performed a survey of strain prevalence and infection frequency in eight European regions. wCer1 was fixed in all populations, whereas wCer2 was detected only in the South. wCer3 frequency was the lowest without a clear distribution pattern. The abundance of wCer4 was homogenous across Europe. Like wCer2, wCer5 showed significant differences in spatial distribution. Our new findings of previously undetected and recombinant Wolbachia strains in R. cerasi reveal a major caveat to the research community not to overlook hidden Wolbachia diversity in field populations. Low-titres and geographical variability in Wolbachia diversity are expected to influence the outcome of Wolbachia population dynamics and Wolbachia-based insect population control and may create invasion barriers for expanding and artificially introduced Wolbachia strains.

[Effects, safety and cost-benefit analysis of Down syndrome screening in first trimester].

PubMed

Shengmou, Lin; Min, Chen; Chenhong, Wang; Shengli, Li; Jiansheng, Xie; Hui, Yuan; Dinghao, Lin; Xiaoxia, Wu; Wei, Wang; Hongyun, Zhang; Haiyan, Tang

2014-05-01

To investigate the effects, safety and cost-benefit analysis of Down syndrome screening in first trimester. From January 2009 to December 2012, 43 729 pregnant women undergoing 3 methods of Down syndrome traditional screening strategies in Shenzhen Maternity and Child Healthcare Hospital were studied retrospectively, including in 17 502 cases in pregnancy associated plasma protein A (PAPP-A) and free β-hCG measured biochemistry screening, 14 080 cases in nuchal translucency (NT) screening and 12 147 cases in combined screening, meanwhile, 7 389 cases on non-invasive fetal trisomy test (NIFTY) were performed in Huada Gene Research Institute(BGI). The effects and safety of four screening strategies were assessed throughout a decision tree. The economical characters of each screening strategy were compared by cost-effectiveness analysis as well as cost-benefit analysis. (1) The effects of four strategies are: NIFTY > combined screening > NT screening > biochemistry screening. (2) The safety of four strategies are: NIFTY > combined screening > NT screening > biochemistry screening. (3) Cost-effectiveness analysis and cost-benefit analysis:the biochemistry screening has lowest cost-effectiveness ratio (CER) and highest cost-benefit ratio (CBR), which performed a better economical efficiency. The incremental CER of three traditional screening strategies are all less than the economical burden of Down syndrome.NIFTY has highest CER and negative net present value (NPV), NPV would be positive and CBR would be more than 1 if the price of NIFTY reduce to 1 434 Yuan. Combined screening possess best screening efficiency, while biochemistry screening was demonstrated more economical in traditional screening.NIFTY is the future of Down syndrome screening.

Expression of Shiga toxin 2e glycosphingolipid receptors of primary porcine brain endothelial cells and toxin-mediated breakdown of the blood-brain barrier.

PubMed

Meisen, Iris; Rosenbrück, Regina; Galla, Hans-Joachim; Hüwel, Sabine; Kouzel, Ivan U; Mormann, Michael; Karch, Helge; Müthing, Johannes

2013-06-01

Shiga toxin (Stx) 2e, released by certain Stx-producing Escherichia coli, is presently the best characterized virulence factor responsible for pig edema disease, which is characterized by hemorrhagic lesions, neurological disorders and often fatal outcomes. Although Stx2e-mediated brain vascular injury is the key event in development of neurologic signs, the glycosphingolipid (GSL) receptors of Stx2e and toxin-mediated impairment of pig brain endothelial cells have not been investigated so far. Here, we report on the detailed structural characterization of Stx2e receptors globotriaosylceramide (Gb3Cer) and globotetraosylceramide (Gb4Cer), which make up the major neutral GSLs in primary porcine brain capillary endothelial cells (PBCECs). Various Gb3Cer and Gb4Cer lipoforms harboring sphingenine (d18:1) or sphinganine (d18:0) and mostly a long-chain fatty acid (C20-C24) were detected. A notable batch-to-batch heterogeneity of primary endothelial cells was observed regarding the extent of ceramide hydroxylation of Gb3Cer or Gb4Cer species. Gb3Cer, Gb4Cer and sphingomyelin preferentially distribute to detergent-resistant membrane fractions and can be considered lipid raft markers in PBCECs. Moreover, we employed an in vitro model of the blood-brain barrier (BBB), which exhibited strong cytotoxic effects of Stx2e on the endothelial monolayer and a rapid collapse of the BBB. These data strongly suggest the involvement of Stx2e in cerebral vascular damage with resultant neurological disturbance characteristic of edema disease.

CERAMIDE SYNTHASE 1 IS REGULATED BY PROTEASOMAL MEDIATED TURNOVER

PubMed Central

Sridevi, Priya; Alexander, Hannah; Laviad, Elad L.; Pewzner-Jung, Yael; Hannink, Mark; Futerman, Anthony H.; Alexander, Stephen

2009-01-01

Ceramide is an important bioactive lipid, intimately involved in many cellular functions, including the regulation of cell death, and in cancer and chemotherapy. Ceramide is synthesized de novo from sphinganine and acyl CoA via a family of 6 ceramide synthase enzymes, each having a unique preference for different fatty acyl CoA substrates and a unique tissue distribution. However, little is known regarding the regulation of these important enzymes. In this study we focus on ceramide synthase 1 (CerS1) which is the most structurally and functionally distinct of the enzymes, and describe a regulatory mechanism that specifically controls the level of CerS1 via ubiquitination and proteasome dependent protein turnover. We show that both endogenous and ectopically expressed CerS1 have rapid basal turnover and that diverse stresses including chemotherapeutic drugs, UV light and DTT can induce CerS1 turnover. The turnover requires CerS1 activity and is regulated by the opposing actions of p38 MAP kinase and protein kinase C (PKC). p38 MAP kinase is a positive regulator of turnover, while PKC is a negative regulator of turnover. CerS1 is phosphorylated in vivo and activation of PKC increases the phosphorylation of the protein. This study reveals a novel and highly specific mechanism by which CerS1 protein levels are regulated and which directly impacts ceramide homeostasis. PMID:19393694

CERES ERBE-like Instantaneous TOA Estimates (ES-8) in HDF (CER_ES8_Terra-FM1_Edition2)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ES-8 archival data product contains a 24-hour, single-satellite, instantaneous view of scanner fluxes at the top-of-atmosphere (TOA) reduced from spacecraft altitude unfiltered radiances using Earth Radiation Budget Experiment (ERBE) scanner Inversion algorithms and the ERBE shortwave (SW) and longwave (LW) Angular Distribution Models (ADMs). The ES-8 also includes the total (TOT), SW, LW, and window (WN) channel radiometric data; SW, LW, and WN unfiltered radiance values; and the ERBE scene identification for each measurement. These data are organized according to the CERES 3.3-second scan into 6.6-second records. As long as there is one valid scanner measurement within a record, the ES-8 record will be generated. The following CERES ES8 data sets are currently available: CER_ES8_TRMM-PFM_Edition1 CER_ES8_TRMM-PFM_Edition2 CER_ES8_TRMM-PFM_Transient-Ops2 CER_ES8_Terra-FM1_Edition1 CER_ES8_Terra-FM2_Edition1 CER_ES8_Terra-FM1_Edition2 CER_ES8_Terra-FM2_Edition2 CER_ES8_Aqua-FM3_Edition1 CER_ES8_Aqua-FM4_Edition1 CER_ES8_Aqua-FM3_Edition2 CER_ES8_Aqua-FM4_Edition2 CER_ES8_Aqua-FM3_Edition1-CV CER_ES8_Aqua-FM4_Edition1-CV CER_ES8_Terra-FM1_Edition1-CV CER_ES8_Terra-FM1_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1997-12-27; Stop_Date=2006-01-01] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Temporal_Resolution=1 day; Temporal_Resolution_Range=Daily - < Weekly].

CERES ERBE-like Instantaneous TOA Estimates (ES-8) in HDF (CER_ES8_Terra-FM1_Edition1-CV)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ES-8 archival data product contains a 24-hour, single-satellite, instantaneous view of scanner fluxes at the top-of-atmosphere (TOA) reduced from spacecraft altitude unfiltered radiances using Earth Radiation Budget Experiment (ERBE) scanner Inversion algorithms and the ERBE shortwave (SW) and longwave (LW) Angular Distribution Models (ADMs). The ES-8 also includes the total (TOT), SW, LW, and window (WN) channel radiometric data; SW, LW, and WN unfiltered radiance values; and the ERBE scene identification for each measurement. These data are organized according to the CERES 3.3-second scan into 6.6-second records. As long as there is one valid scanner measurement within a record, the ES-8 record will be generated. The following CERES ES8 data sets are currently available: CER_ES8_TRMM-PFM_Edition1 CER_ES8_TRMM-PFM_Edition2 CER_ES8_TRMM-PFM_Transient-Ops2 CER_ES8_Terra-FM1_Edition1 CER_ES8_Terra-FM2_Edition1 CER_ES8_Terra-FM1_Edition2 CER_ES8_Terra-FM2_Edition2 CER_ES8_Aqua-FM3_Edition1 CER_ES8_Aqua-FM4_Edition1 CER_ES8_Aqua-FM3_Edition2 CER_ES8_Aqua-FM4_Edition2 CER_ES8_Aqua-FM3_Edition1-CV CER_ES8_Aqua-FM4_Edition1-CV CER_ES8_Terra-FM1_Edition1-CV CER_ES8_Terra-FM1_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1997-12-27; Stop_Date=2006-09-30] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Temporal_Resolution=1 day; Temporal_Resolution_Range=Daily - < Weekly].

CERES ERBE-like Instantaneous TOA Estimates (ES-8) in HDF (CER_ES8_Aqua-FM4_Edition1-CV)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ES-8 archival data product contains a 24-hour, single-satellite, instantaneous view of scanner fluxes at the top-of-atmosphere (TOA) reduced from spacecraft altitude unfiltered radiances using Earth Radiation Budget Experiment (ERBE) scanner Inversion algorithms and the ERBE shortwave (SW) and longwave (LW) Angular Distribution Models (ADMs). The ES-8 also includes the total (TOT), SW, LW, and window (WN) channel radiometric data; SW, LW, and WN unfiltered radiance values; and the ERBE scene identification for each measurement. These data are organized according to the CERES 3.3-second scan into 6.6-second records. As long as there is one valid scanner measurement within a record, the ES-8 record will be generated. The following CERES ES8 data sets are currently available: CER_ES8_TRMM-PFM_Edition1 CER_ES8_TRMM-PFM_Edition2 CER_ES8_TRMM-PFM_Transient-Ops2 CER_ES8_Terra-FM1_Edition1 CER_ES8_Terra-FM2_Edition1 CER_ES8_Terra-FM1_Edition2 CER_ES8_Terra-FM2_Edition2 CER_ES8_Aqua-FM3_Edition1 CER_ES8_Aqua-FM4_Edition1 CER_ES8_Aqua-FM3_Edition2 CER_ES8_Aqua-FM4_Edition2 CER_ES8_Aqua-FM3_Edition1-CV CER_ES8_Aqua-FM4_Edition1-CV CER_ES8_Terra-FM1_Edition1-CV CER_ES8_Terra-FM1_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1997-12-27; Stop_Date=2005-03-29] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Temporal_Resolution=1 day; Temporal_Resolution_Range=Daily - < Weekly].

CERES ERBE-like Instantaneous TOA Estimates (ES-8) in HDF (CER_ES8_Terra-FM2_Edition1)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ES-8 archival data product contains a 24-hour, single-satellite, instantaneous view of scanner fluxes at the top-of-atmosphere (TOA) reduced from spacecraft altitude unfiltered radiances using Earth Radiation Budget Experiment (ERBE) scanner Inversion algorithms and the ERBE shortwave (SW) and longwave (LW) Angular Distribution Models (ADMs). The ES-8 also includes the total (TOT), SW, LW, and window (WN) channel radiometric data; SW, LW, and WN unfiltered radiance values; and the ERBE scene identification for each measurement. These data are organized according to the CERES 3.3-second scan into 6.6-second records. As long as there is one valid scanner measurement within a record, the ES-8 record will be generated. The following CERES ES8 data sets are currently available: CER_ES8_TRMM-PFM_Edition1 CER_ES8_TRMM-PFM_Edition2 CER_ES8_TRMM-PFM_Transient-Ops2 CER_ES8_Terra-FM1_Edition1 CER_ES8_Terra-FM2_Edition1 CER_ES8_Terra-FM1_Edition2 CER_ES8_Terra-FM2_Edition2 CER_ES8_Aqua-FM3_Edition1 CER_ES8_Aqua-FM4_Edition1 CER_ES8_Aqua-FM3_Edition2 CER_ES8_Aqua-FM4_Edition2 CER_ES8_Aqua-FM3_Edition1-CV CER_ES8_Aqua-FM4_Edition1-CV CER_ES8_Terra-FM1_Edition1-CV CER_ES8_Terra-FM1_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1997-12-27; Stop_Date=2005-11-01] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Temporal_Resolution=1 day; Temporal_Resolution_Range=Daily - < Weekly].

CERES ERBE-like Instantaneous TOA Estimates (ES-8) in HDF (CER_ES8_TRMM-PFM_Edition2)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ES-8 archival data product contains a 24-hour, single-satellite, instantaneous view of scanner fluxes at the top-of-atmosphere (TOA) reduced from spacecraft altitude unfiltered radiances using Earth Radiation Budget Experiment (ERBE) scanner Inversion algorithms and the ERBE shortwave (SW) and longwave (LW) Angular Distribution Models (ADMs). The ES-8 also includes the total (TOT), SW, LW, and window (WN) channel radiometric data; SW, LW, and WN unfiltered radiance values; and the ERBE scene identification for each measurement. These data are organized according to the CERES 3.3-second scan into 6.6-second records. As long as there is one valid scanner measurement within a record, the ES-8 record will be generated. The following CERES ES8 data sets are currently available: CER_ES8_TRMM-PFM_Edition1 CER_ES8_TRMM-PFM_Edition2 CER_ES8_TRMM-PFM_Transient-Ops2 CER_ES8_Terra-FM1_Edition1 CER_ES8_Terra-FM2_Edition1 CER_ES8_Terra-FM1_Edition2 CER_ES8_Terra-FM2_Edition2 CER_ES8_Aqua-FM3_Edition1 CER_ES8_Aqua-FM4_Edition1 CER_ES8_Aqua-FM3_Edition2 CER_ES8_Aqua-FM4_Edition2 CER_ES8_Aqua-FM3_Edition1-CV CER_ES8_Aqua-FM4_Edition1-CV CER_ES8_Terra-FM1_Edition1-CV CER_ES8_Terra-FM1_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1997-12-27; Stop_Date=2000-03-31] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Temporal_Resolution=1 day; Temporal_Resolution_Range=Daily - < Weekly].

CERES ERBE-like Instantaneous TOA Estimates (ES-8) in HDF (CER_ES8_Aqua-FM3_Edition2)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The ES-8 archival data product contains a 24-hour, single-satellite, instantaneous view of scanner fluxes at the top-of-atmosphere (TOA) reduced from spacecraft altitude unfiltered radiances using Earth Radiation Budget Experiment (ERBE) scanner Inversion algorithms and the ERBE shortwave (SW) and longwave (LW) Angular Distribution Models (ADMs). The ES-8 also includes the total (TOT), SW, LW, and window (WN) channel radiometric data; SW, LW, and WN unfiltered radiance values; and the ERBE scene identification for each measurement. These data are organized according to the CERES 3.3-second scan into 6.6-second records. As long as there is one valid scanner measurement within a record, the ES-8 record will be generated. The following CERES ES8 data sets are currently available: CER_ES8_TRMM-PFM_Edition1 CER_ES8_TRMM-PFM_Edition2 CER_ES8_TRMM-PFM_Transient-Ops2 CER_ES8_Terra-FM1_Edition1 CER_ES8_Terra-FM2_Edition1 CER_ES8_Terra-FM1_Edition2 CER_ES8_Terra-FM2_Edition2 CER_ES8_Aqua-FM3_Edition1 CER_ES8_Aqua-FM4_Edition1 CER_ES8_Aqua-FM3_Edition2 CER_ES8_Aqua-FM4_Edition2 CER_ES8_Aqua-FM3_Edition1-CV CER_ES8_Aqua-FM4_Edition1-CV CER_ES8_Terra-FM1_Edition1-CV CER_ES8_Terra-FM1_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1997-12-27; Stop_Date=2005-12-31] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Temporal_Resolution=1 day; Temporal_Resolution_Range=Daily - < Weekly].

Concurrent and Construct Validity of Three Counselor Social Influence Instruments.

ERIC Educational Resources Information Center

Wilson, F. Robert; Yager, Geoffrey G.

1990-01-01

Conducted factor analytic investigation of Counselor Rating Form, Counselor Rating Form-Short Form, and Counselor Effectiveness Rating Scale (CERS) using data from 160 undergraduate students. Analysis revealed two oblique factors (expertness and attractiveness-trustworthiness), whereas CERS produced single, global evaluative factor. Oblique…

Effects of Asterias amurensis-derived Sphingoid Bases on the de novo Ceramide Synthesis in Cultured Normal Human Epidermal Keratinocytes.

PubMed

Mikami, Daisuke; Sakai, Shota; Sasaki, Shigefumi; Igarashi, Yasuyuki

2016-08-01

Asterias amurensis starfish provide several bioactive species in addition to being fishery waste. Glucosyl ceramides (GlcCers) were extracted from the viscera of these starfish and were isolated by silica gel column chromatography. Degraded GlcCers generated A. amurensis sphingoid bases (ASBs) that mainly consisted of the triene-type bases d18:3 and 9-methyl-d18:3. The effect of these bases on ceramide synthesis and content were analyzed using normal human epidermal keratinocytes (NHEKs). The bases significantly enhanced the de novo ceramide synthesis and gene expression in NHEKs for proteins, such as serine-palmitoyltransferase and ceramide synthase. Total ceramide, GlcCer, and sphingomyelin contents increased dramatically upon ASB treatment. In particular, GlcCer bearing very-long-chain fatty acids (≥C28) exhibited a significant content increase. These ASB-induced enhancements on de novo ceramide synthesis were only observed in undifferentiated NHEKs. This stimulation of the de novo sphingolipid synthesis may improve skin barrier functions.

The cost effectiveness of occupational health interventions: preventing occupational back pain.

PubMed

Lahiri, Supriya; Markkanen, Pia; Levenstein, Charles

2005-12-01

Occupational back pain exacts a toll on society with concomitant economic losses; it is imperative to evaluate the cost-effectiveness of interventions to reduce the relevant ergonomic stressors at work. This study estimates and evaluates the average and incremental cost-effectiveness ratios (CERs) of specific interventions for the prevention of occupationally induced back pain for the World Health Organization (WHO) defined subregions of the world. Four back-pain interventions were selected from the literature: training (T), engineering controls (EC), engineering controls and training (EC&T), and a comprehensive full ergonomics program (EP) for evaluation. A simulation model for a 100-year time horizon, developed by the WHO CHOICE initiative project was used to estimate the effectiveness of the interventions in healthy year equivalents. The intervention costs were adjusted for all WHO subregions. In all of the subregions, training was the most cost-effective with CERs varying from 74 dollars per healthy life years gained in the subregion comprising of Egypt, Iraq, Morocco, Yemen (EMROD) to approximately 567 dollars in the subregion covering Canada and the United States (AMROA). Training is considered to be very cost-effective and would be the first choice option where resources are scarce. However, the overall effectiveness of training is low. Although other interventions such as engineering controls and total ergonomic interventions are relatively more expensive, the addition to health outcome through these interventions is much higher. The difference in the CERs for training and other engineering controls and full ergonomic interventions is relatively small for most of the industrialized regions of the world. It is clear from the ranked CERs and incremental CERs over the different subregions that in most of the industrialized regions of the world additional resources, if they become available, should go straight to the full ergonomics program. The model results based on CERs show that worker training is a low cost, feasible first step toward reducing back pain/injury incidence. However, all of the average CERs for the different interventions, for each of the regions, fall well within their GDP per capita estimates [World Bank, 2001]. According to the WHO Commission on Macroeconomics and Health any intervention that costs less than three times GDP per capita for saving a healthy year equivalent should be considered worthwhile and good value for money [WHO, 2002]. Given this criterion, the engineering controls interventions as well as the full ergonomics program look very cost effective for all of the WHO subregions. 2005 Wiley-Liss, Inc.

Tumor Necrosis Factor-α (TNFα)-induced Ceramide Generation via Ceramide Synthases Regulates Loss of Focal Adhesion Kinase (FAK) and Programmed Cell Death.

PubMed

Hernández-Corbacho, María José; Canals, Daniel; Adada, Mohamad M; Liu, Mengling; Senkal, Can E; Yi, Jae Kyo; Mao, Cungui; Luberto, Chiara; Hannun, Yusuf A; Obeid, Lina M

2015-10-16

Ceramide synthases (CerS1-CerS6), which catalyze the N-acylation of the (dihydro)sphingosine backbone to produce (dihydro)ceramide in both the de novo and the salvage or recycling pathway of ceramide generation, have been implicated in the control of programmed cell death. However, the regulation of the de novo pathway compared with the salvage pathway is not fully understood. In the current study, we have found that late accumulation of multiple ceramide and dihydroceramide species in MCF-7 cells treated with TNFα occurred by up-regulation of both pathways of ceramide synthesis. Nevertheless, fumonisin B1 but not myriocin was able to protect from TNFα-induced cell death, suggesting that ceramide synthase activity is crucial for the progression of cell death and that the pool of ceramide involved derives from the salvage pathway rather than de novo biosynthesis. Furthermore, compared with control cells, TNFα-treated cells exhibited reduced focal adhesion kinase and subsequent plasma membrane permeabilization, which was blocked exclusively by fumonisin B1. In addition, exogenously added C6-ceramide mimicked the effects of TNFα that lead to cell death, which were inhibited by fumonisin B1. Knockdown of individual ceramide synthases identified CerS6 and its product C16-ceramide as the ceramide synthase isoform essential for the regulation of cell death. In summary, our data suggest a novel role for CerS6/C16-ceramide as an upstream effector of the loss of focal adhesion protein and plasma membrane permeabilization, via the activation of caspase-7, and identify the salvage pathway as the critical mechanism of ceramide generation that controls cell death. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Positive relationship between liquid cloud droplet effective radius and aerosol optical depth over Eastern China from satellite data

NASA Astrophysics Data System (ADS)

Tang, Jinping; Wang, Pucai; Mickley, Loretta J.; Xia, Xiangao; Liao, Hong; Yue, Xu; Sun, Li; Xia, Junrong

2014-02-01

Correlations between water cloud effective radius (CER) and aerosol optical depth (AOD) from the Moderate Resolution Imaging Spectroradiometer (MODIS) are examined over seven sub-regions in Eastern China for 2003-2012. Water phase cloud is defined as having a cloud top pressure greater than 800 hPa. Significant negative correlation coefficients (r = -0.79 ˜ -0.94) between AOD and CER are derived over the East Sea and the South China Sea for grid cells with AOD < 0.3. However, positive correlations (r = 0.01-0.91) are calculated for cells with AOD > 0.3. In contrast, significant positive correlations (r = 0.67-0.95) are derived over the Eastern China mainland and Yellow Sea. Further analysis for North China Plain shows that variations in wind speed and relative humidity may account for such positive correlations. Southerly winds carry high levels of pollutants and abundant water vapor, resulting in coincident increases in both AOD and CER in North China Plain, while the northerly winds transport dry and clean air from high latitudes, leading to decreases in AOD and CER. Both processes contribute to the positive correlations between AOD and CER over Eastern China, suggesting that the influence of background weather conditions need to be considered when studying the interactions between aerosol and cloud.

CERES BiDirectional Scans (BDS) data in HDF (CER_BDS_Terra-FM1_Edition1)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

Each BiDirectional Scans (BDS) data product contains twenty-four hours of Level-1b data for each CERES scanner instrument mounted on each spacecraft. The BDS includes samples taken in normal and short Earth scan elevation profiles in both fixed and rotating azimuth scan modes (including space, internal calibration, and solar calibration views). The BDS contains Level-0 raw (unconverted) science and instrument data as well as the geolocated converted science and instrument data. The BDS contains additional data not found in the Level-0 input file, including converted satellite position and velocity data, celestial data, converted digital status data, and parameters used in the radiance count conversion equations. The following CERES BDS data sets are currently available: CER_BDS_TRMM-PFM_Edition1 CER_BDS_Terra-FM1_Edition1 CER_BDS_Terra-FM2_Edition1 CER_BDS_Terra-FM1_Edition2 CER_BDS_Terra-FM2_Edition2 CER_BDS_Aqua-FM3_Edition1 CER_BDS_Aqua-FM4_Edition1 CER_BDS_Aqua-FM3_Edition2 CER_BDS_Aqua-FM4_Edition2 CER_BDS_Aqua-FM3_Edition1-CV CER_BDS_Aqua-FM4_Edition1-CV CER_BDS_Terra-FM1_Edition1-CV CER_BDS_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1997-12-27; Stop_Date=2005-11-02] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Temporal_Resolution=1 day; Temporal_Resolution_Range=Daily - < Weekly].

CERES BiDirectional Scans (BDS) data in HDF (CER_BDS_Aqua-FM4_Edition1)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

Each BiDirectional Scans (BDS) data product contains twenty-four hours of Level-1b data for each CERES scanner instrument mounted on each spacecraft. The BDS includes samples taken in normal and short Earth scan elevation profiles in both fixed and rotating azimuth scan modes (including space, internal calibration, and solar calibration views). The BDS contains Level-0 raw (unconverted) science and instrument data as well as the geolocated converted science and instrument data. The BDS contains additional data not found in the Level-0 input file, including converted satellite position and velocity data, celestial data, converted digital status data, and parameters used in the radiance count conversion equations. The following CERES BDS data sets are currently available: CER_BDS_TRMM-PFM_Edition1 CER_BDS_Terra-FM1_Edition1 CER_BDS_Terra-FM2_Edition1 CER_BDS_Terra-FM1_Edition2 CER_BDS_Terra-FM2_Edition2 CER_BDS_Aqua-FM3_Edition1 CER_BDS_Aqua-FM4_Edition1 CER_BDS_Aqua-FM3_Edition2 CER_BDS_Aqua-FM4_Edition2 CER_BDS_Aqua-FM3_Edition1-CV CER_BDS_Aqua-FM4_Edition1-CV CER_BDS_Terra-FM1_Edition1-CV CER_BDS_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1997-12-27; Stop_Date=2005-04-02] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Temporal_Resolution=1 day; Temporal_Resolution_Range=Daily - < Weekly].

CERES BiDirectional Scans (BDS) data in HDF (CER_BDS_Terra-FM1_Edition1-CV)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

Each BiDirectional Scans (BDS) data product contains twenty-four hours of Level-1b data for each CERES scanner instrument mounted on each spacecraft. The BDS includes samples taken in normal and short Earth scan elevation profiles in both fixed and rotating azimuth scan modes (including space, internal calibration, and solar calibration views). The BDS contains Level-0 raw (unconverted) science and instrument data as well as the geolocated converted science and instrument data. The BDS contains additional data not found in the Level-0 input file, including converted satellite position and velocity data, celestial data, converted digital status data, and parameters used in the radiance count conversion equations. The following CERES BDS data sets are currently available: CER_BDS_TRMM-PFM_Edition1 CER_BDS_Terra-FM1_Edition1 CER_BDS_Terra-FM2_Edition1 CER_BDS_Terra-FM1_Edition2 CER_BDS_Terra-FM2_Edition2 CER_BDS_Aqua-FM3_Edition1 CER_BDS_Aqua-FM4_Edition1 CER_BDS_Aqua-FM3_Edition2 CER_BDS_Aqua-FM4_Edition2 CER_BDS_Aqua-FM3_Edition1-CV CER_BDS_Aqua-FM4_Edition1-CV CER_BDS_Terra-FM1_Edition1-CV CER_BDS_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1997-12-27; Stop_Date=2006-11-02] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Temporal_Resolution=1 day; Temporal_Resolution_Range=Daily - < Weekly].

CERES BiDirectional Scans (BDS) data in HDF (CER_BDS_Terra-FM2_Edition2)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

Each BiDirectional Scans (BDS) data product contains twenty-four hours of Level-1b data for each CERES scanner instrument mounted on each spacecraft. The BDS includes samples taken in normal and short Earth scan elevation profiles in both fixed and rotating azimuth scan modes (including space, internal calibration, and solar calibration views). The BDS contains Level-0 raw (unconverted) science and instrument data as well as the geolocated converted science and instrument data. The BDS contains additional data not found in the Level-0 input file, including converted satellite position and velocity data, celestial data, converted digital status data, and parameters used in the radiance count conversion equations. The following CERES BDS data sets are currently available: CER_BDS_TRMM-PFM_Edition1 CER_BDS_Terra-FM1_Edition1 CER_BDS_Terra-FM2_Edition1 CER_BDS_Terra-FM1_Edition2 CER_BDS_Terra-FM2_Edition2 CER_BDS_Aqua-FM3_Edition1 CER_BDS_Aqua-FM4_Edition1 CER_BDS_Aqua-FM3_Edition2 CER_BDS_Aqua-FM4_Edition2 CER_BDS_Aqua-FM3_Edition1-CV CER_BDS_Aqua-FM4_Edition1-CV CER_BDS_Terra-FM1_Edition1-CV CER_BDS_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1997-12-27; Stop_Date=2006-01-01] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Temporal_Resolution=1 day; Temporal_Resolution_Range=Daily - < Weekly].

CERES BiDirectional Scans (BDS) data in HDF (CER_BDS_Aqua-FM3_Edition1)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

Each BiDirectional Scans (BDS) data product contains twenty-four hours of Level-1b data for each CERES scanner instrument mounted on each spacecraft. The BDS includes samples taken in normal and short Earth scan elevation profiles in both fixed and rotating azimuth scan modes (including space, internal calibration, and solar calibration views). The BDS contains Level-0 raw (unconverted) science and instrument data as well as the geolocated converted science and instrument data. The BDS contains additional data not found in the Level-0 input file, including converted satellite position and velocity data, celestial data, converted digital status data, and parameters used in the radiance count conversion equations. The following CERES BDS data sets are currently available: CER_BDS_TRMM-PFM_Edition1 CER_BDS_Terra-FM1_Edition1 CER_BDS_Terra-FM2_Edition1 CER_BDS_Terra-FM1_Edition2 CER_BDS_Terra-FM2_Edition2 CER_BDS_Aqua-FM3_Edition1 CER_BDS_Aqua-FM4_Edition1 CER_BDS_Aqua-FM3_Edition2 CER_BDS_Aqua-FM4_Edition2 CER_BDS_Aqua-FM3_Edition1-CV CER_BDS_Aqua-FM4_Edition1-CV CER_BDS_Terra-FM1_Edition1-CV CER_BDS_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1997-12-27; Stop_Date=2005-11-02] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Temporal_Resolution=1 day; Temporal_Resolution_Range=Daily - < Weekly].

CERES BiDirectional Scans (BDS) data in HDF (CER_BDS_TRMM-PFM_Edition1)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

Each BiDirectional Scans (BDS) data product contains twenty-four hours of Level-1b data for each CERES scanner instrument mounted on each spacecraft. The BDS includes samples taken in normal and short Earth scan elevation profiles in both fixed and rotating azimuth scan modes (including space, internal calibration, and solar calibration views). The BDS contains Level-0 raw (unconverted) science and instrument data as well as the geolocated converted science and instrument data. The BDS contains additional data not found in the Level-0 input file, including converted satellite position and velocity data, celestial data, converted digital status data, and parameters used in the radiance count conversion equations. The following CERES BDS data sets are currently available: CER_BDS_TRMM-PFM_Edition1 CER_BDS_Terra-FM1_Edition1 CER_BDS_Terra-FM2_Edition1 CER_BDS_Terra-FM1_Edition2 CER_BDS_Terra-FM2_Edition2 CER_BDS_Aqua-FM3_Edition1 CER_BDS_Aqua-FM4_Edition1 CER_BDS_Aqua-FM3_Edition2 CER_BDS_Aqua-FM4_Edition2 CER_BDS_Aqua-FM3_Edition1-CV CER_BDS_Aqua-FM4_Edition1-CV CER_BDS_Terra-FM1_Edition1-CV CER_BDS_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1997-12-27; Stop_Date=2000-12-31] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Temporal_Resolution=1 day; Temporal_Resolution_Range=Daily - < Weekly].

CERES BiDirectional Scans (BDS) data in HDF (CER_BDS_Aqua-FM4_Edition2)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

Each BiDirectional Scans (BDS) data product contains twenty-four hours of Level-1b data for each CERES scanner instrument mounted on each spacecraft. The BDS includes samples taken in normal and short Earth scan elevation profiles in both fixed and rotating azimuth scan modes (including space, internal calibration, and solar calibration views). The BDS contains Level-0 raw (unconverted) science and instrument data as well as the geolocated converted science and instrument data. The BDS contains additional data not found in the Level-0 input file, including converted satellite position and velocity data, celestial data, converted digital status data, and parameters used in the radiance count conversion equations. The following CERES BDS data sets are currently available: CER_BDS_TRMM-PFM_Edition1 CER_BDS_Terra-FM1_Edition1 CER_BDS_Terra-FM2_Edition1 CER_BDS_Terra-FM1_Edition2 CER_BDS_Terra-FM2_Edition2 CER_BDS_Aqua-FM3_Edition1 CER_BDS_Aqua-FM4_Edition1 CER_BDS_Aqua-FM3_Edition2 CER_BDS_Aqua-FM4_Edition2 CER_BDS_Aqua-FM3_Edition1-CV CER_BDS_Aqua-FM4_Edition1-CV CER_BDS_Terra-FM1_Edition1-CV CER_BDS_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1997-12-27; Stop_Date=2005-03-29] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Temporal_Resolution=1 day; Temporal_Resolution_Range=Daily - < Weekly].

CERES BiDirectional Scans (BDS) data in HDF (CER_BDS_Aqua-FM3_Edition2)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

Each BiDirectional Scans (BDS) data product contains twenty-four hours of Level-1b data for each CERES scanner instrument mounted on each spacecraft. The BDS includes samples taken in normal and short Earth scan elevation profiles in both fixed and rotating azimuth scan modes (including space, internal calibration, and solar calibration views). The BDS contains Level-0 raw (unconverted) science and instrument data as well as the geolocated converted science and instrument data. The BDS contains additional data not found in the Level-0 input file, including converted satellite position and velocity data, celestial data, converted digital status data, and parameters used in the radiance count conversion equations. The following CERES BDS data sets are currently available: CER_BDS_TRMM-PFM_Edition1 CER_BDS_Terra-FM1_Edition1 CER_BDS_Terra-FM2_Edition1 CER_BDS_Terra-FM1_Edition2 CER_BDS_Terra-FM2_Edition2 CER_BDS_Aqua-FM3_Edition1 CER_BDS_Aqua-FM4_Edition1 CER_BDS_Aqua-FM3_Edition2 CER_BDS_Aqua-FM4_Edition2 CER_BDS_Aqua-FM3_Edition1-CV CER_BDS_Aqua-FM4_Edition1-CV CER_BDS_Terra-FM1_Edition1-CV CER_BDS_Terra-FM2_Edition1-CV. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1997-12-27; Stop_Date=2006-01-01] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Temporal_Resolution=1 day; Temporal_Resolution_Range=Daily - < Weekly].

ECERIFERUM2-LIKE proteins have unique biochemical and physiological functions in very-long-chain fatty acid elongation.

PubMed

Haslam, Tegan M; Haslam, Richard; Thoraval, Didier; Pascal, Stéphanie; Delude, Camille; Domergue, Frédéric; Fernández, Aurora Mañas; Beaudoin, Frédéric; Napier, Johnathan A; Kunst, Ljerka; Joubès, Jérôme

2015-03-01

The extension of very-long-chain fatty acids (VLCFAs) for the synthesis of specialized apoplastic lipids requires unique biochemical machinery. Condensing enzymes catalyze the first reaction in fatty acid elongation and determine the chain length of fatty acids accepted and produced by the fatty acid elongation complex. Although necessary for the elongation of all VLCFAs, known condensing enzymes cannot efficiently synthesize VLCFAs longer than 28 carbons, despite the prevalence of C28 to C34 acyl lipids in cuticular wax and the pollen coat. The eceriferum2 (cer2) mutant of Arabidopsis (Arabidopsis thaliana) was previously shown to have a specific deficiency in cuticular waxes longer than 28 carbons, and heterologous expression of CER2 in yeast (Saccharomyces cerevisiae) demonstrated that it can modify the acyl chain length produced by a condensing enzyme from 28 to 30 carbon atoms. Here, we report the physiological functions and biochemical specificities of the CER2 homologs CER2-LIKE1 and CER2-LIKE2 by mutant analysis and heterologous expression in yeast. We demonstrate that all three CER2-LIKEs function with the same small subset of condensing enzymes, and that they have different effects on the substrate specificity of the same condensing enzyme. Finally, we show that the changes in acyl chain length caused by each CER2-LIKE protein are of substantial importance for cuticle formation and pollen coat function. © 2015 American Society of Plant Biologists. All Rights Reserved.

ECERIFERUM2-LIKE Proteins Have Unique Biochemical and Physiological Functions in Very-Long-Chain Fatty Acid Elongation1[OPEN

PubMed Central

Haslam, Tegan M.; Haslam, Richard; Thoraval, Didier; Pascal, Stéphanie; Delude, Camille; Domergue, Frédéric; Fernández, Aurora Mañas; Beaudoin, Frédéric; Napier, Johnathan A.; Kunst, Ljerka; Joubès, Jérôme

2015-01-01

The extension of very-long-chain fatty acids (VLCFAs) for the synthesis of specialized apoplastic lipids requires unique biochemical machinery. Condensing enzymes catalyze the first reaction in fatty acid elongation and determine the chain length of fatty acids accepted and produced by the fatty acid elongation complex. Although necessary for the elongation of all VLCFAs, known condensing enzymes cannot efficiently synthesize VLCFAs longer than 28 carbons, despite the prevalence of C28 to C34 acyl lipids in cuticular wax and the pollen coat. The eceriferum2 (cer2) mutant of Arabidopsis (Arabidopsis thaliana) was previously shown to have a specific deficiency in cuticular waxes longer than 28 carbons, and heterologous expression of CER2 in yeast (Saccharomyces cerevisiae) demonstrated that it can modify the acyl chain length produced by a condensing enzyme from 28 to 30 carbon atoms. Here, we report the physiological functions and biochemical specificities of the CER2 homologs CER2-LIKE1 and CER2-LIKE2 by mutant analysis and heterologous expression in yeast. We demonstrate that all three CER2-LIKEs function with the same small subset of condensing enzymes, and that they have different effects on the substrate specificity of the same condensing enzyme. Finally, we show that the changes in acyl chain length caused by each CER2-LIKE protein are of substantial importance for cuticle formation and pollen coat function. PMID:25596184

Seasonal changes in epidermal ceramides are linked to impaired barrier function in acne patients.

PubMed

Pappas, Apostolos; Kendall, Alexandra C; Brownbridge, Luke C; Batchvarova, Nikoleta; Nicolaou, Anna

2018-01-21

Acne skin demonstrates increased transepidermal water loss (TEWL) compared with healthy skin, which may be due, in part, to altered ceramide (CER) levels. We analysed ceramides in the stratum corneum of healthy and acne skin, and studied seasonal variation over the course of a year. Using ultraperformance liquid chromatography with electrospray ionisation and tandem mass spectrometry (UPLC/ESI-MS/MS), we identified 283 ceramides. Acne-affected skin demonstrated overall lower levels of ceramides, with notable reductions in CER[NH] and CER[AH] ceramides, as well as the acylceramides CER[EOS] and CER[EOH]; these differences were more apparent in the winter months. Lower ceramide levels reflected an increase in TEWL in acne, compared with healthy skin, which partly resolves in the summer. Individual ceramide species with 18-carbon 6-hydroxysphingosine (H) bases (including CER[N(24)H(18)], CER[N(26)H(18)], CER[A(24)H(18)], CER[A(26)H(18)]) were significantly reduced in acne skin, suggesting that CER[NH] and CER[AH] species may be particularly important in a healthy skin barrier. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Diastereomer-specific quantification of bioactive hexosylceramides from bacteria and mammals.

PubMed

von Gerichten, Johanna; Schlosser, Kerstin; Lamprecht, Dominic; Morace, Ivan; Eckhardt, Matthias; Wachten, Dagmar; Jennemann, Richard; Gröne, Hermann-Josef; Mack, Matthias; Sandhoff, Roger

2017-06-01

Mammals synthesize, cell-type specifically, the diastereomeric hexosylceramides, β-galactosylceramide (GalCer) and β-glucosylceramide (GlcCer), which are involved in several diseases, such as sphingolipidosis, diabetes, chronic kidney diseases, or cancer. In contrast, Bacteroides fragilis , a member of the human gut microbiome, and the marine sponge, Agelas mauritianus , produce α-GalCer, one of the most potent stimulators for invariant natural killer T cells. To dissect the contribution of these individual stereoisomers to pathologies, we established a novel hydrophilic interaction chromatography-based LC-MS 2 method and separated ( R > 1.5) corresponding diastereomers from each other, independent of their lipid anchors. Testing various bacterial and mammalian samples, we could separate, identify (including the lipid anchor composition), and quantify endogenous β-GlcCer, β-GalCer, and α-GalCer isomers without additional derivatization steps. Thereby, we show a selective decrease of β-GlcCers versus β-GalCers in cell-specific models of GlcCer synthase-deficiency and an increase of specific β-GlcCers due to loss of β-glucoceramidase 2 activity. Vice versa, β-GalCer increased specifically when cerebroside sulfotransferase ( Gal3st1 ) was deleted. We further confirm β-GalCer as substrate of globotriaosylceramide synthase for galabiaosylceramide synthesis and identify additional members of the human gut microbiome to contain immunogenic α-GalCers. Finally, this method is shown to separate corresponding hexosylsphingosine standards, promoting its applicability in further investigations. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

[Palliative care: an example of Comparative Effectiveness Research?].

PubMed

Schmacke, Norbert

2012-01-01

Comparative Effectiveness Research (CER) seeks to establish treatment objectives and concepts striving to achieve patient relevant progress in therapy on the basis of published evidence. Using the example of palliative medicine and palliative care, respectively, it will be demonstrated that these two are under-researched areas of care. In addition, it will become clear that the success of this interdisciplinary treatment concept for the seriously ill must be weighed in the light of traditional clinical research - far beyond the cancer diagnosis. The current distinction between curative and palliative research and care urgently needs to be reconsidered. Copyright © 2012. Published by Elsevier GmbH.

The Cer-cqu gene cluster determines three key players in a β-diketone synthase polyketide pathway synthesizing aliphatics in epicuticular waxes.

PubMed

Schneider, Lizette M; Adamski, Nikolai M; Christensen, Caspar Elo; Stuart, David B; Vautrin, Sonia; Hansson, Mats; Uauy, Cristobal; von Wettstein-Knowles, Penny

2016-03-09

Aliphatic compounds on plant surfaces, called epicuticular waxes, are the first line of defense against pathogens and pests, contribute to reducing water loss and determine other important phenotypes. Aliphatics can form crystals affecting light refraction, resulting in a color change and allowing identification of mutants in their synthesis or transport. The present study discloses three such Eceriferum (cer) genes in barley - Cer-c, Cer-q and Cer-u - known to be tightly linked and functioning in a biochemical pathway forming dominating amounts of β-diketone and hydroxy-β-diketones plus some esterified alkan-2-ols. These aliphatics are present in many Triticeae as well as dicotyledons such as Eucalyptus and Dianthus. Recently developed genomic resources and mapping populations in barley defined these genes to a small region on chromosome arm 2HS. Exploiting Cer-c and -u potential functions pinpointed five candidates, of which three were missing in apparent cer-cqu triple mutants. Sequencing more than 50 independent mutants for each gene confirmed their identification. Cer-c is a chalcone synthase-like polyketide synthase, designated diketone synthase (DKS), Cer-q is a lipase/carboxyl transferase and Cer-u is a P450 enzyme. All were highly expressed in pertinent leaf sheath tissue of wild type. A physical map revealed the order Cer-c, Cer-u, Cer-q with the flanking genes 101kb apart, confirming they are a gene cluster, Cer-cqu. Homology-based modeling suggests that many of the mutant alleles affect overall protein structure or specific active site residues. The rich diversity of identified mutations will facilitate future studies of three key enzymes involved in synthesis of plant apoplast waxes. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology.

The Cer-cqu gene cluster determines three key players in a β-diketone synthase polyketide pathway synthesizing aliphatics in epicuticular waxes

PubMed Central

Schneider, Lizette M; Adamski, Nikolai M; Christensen, Caspar Elo; Stuart, David B; Vautrin, Sonia; Hansson, Mats; Uauy, Cristobal; von Wettstein-Knowles, Penny

2016-01-01

Aliphatic compounds on plant surfaces, called epicuticular waxes, are the first line of defense against pathogens and pests, contribute to reducing water loss and determine other important phenotypes. Aliphatics can form crystals affecting light refraction, resulting in a color change and allowing identification of mutants in their synthesis or transport. The present study discloses three such Eceriferum (cer) genes in barley – Cer-c, Cer-q and Cer-u – known to be tightly linked and functioning in a biochemical pathway forming dominating amounts of β-diketone and hydroxy-β-diketones plus some esterified alkan-2-ols. These aliphatics are present in many Triticeae as well as dicotyledons such as Eucalyptus and Dianthus. Recently developed genomic resources and mapping populations in barley defined these genes to a small region on chromosome arm 2HS. Exploiting Cer-c and -u potential functions pinpointed five candidates, of which three were missing in apparent cer-cqu triple mutants. Sequencing more than 50 independent mutants for each gene confirmed their identification. Cer-c is a chalcone synthase-like polyketide synthase, designated diketone synthase (DKS), Cer-q is a lipase/carboxyl transferase and Cer-u is a P450 enzyme. All were highly expressed in pertinent leaf sheath tissue of wild type. A physical map revealed the order Cer-c, Cer-u, Cer-q with the flanking genes 101kb apart, confirming they are a gene cluster, Cer-cqu. Homology-based modeling suggests that many of the mutant alleles affect overall protein structure or specific active site residues. The rich diversity of identified mutations will facilitate future studies of three key enzymes involved in synthesis of plant apoplast waxes. PMID:26962211

Variations in the ceramide profile in different seasons and regions of the body contribute to stratum corneum functions.

PubMed

Ishikawa, Junko; Shimotoyodome, Yoshie; Ito, Shotaro; Miyauchi, Yuki; Fujimura, Tsutomu; Kitahara, Takashi; Hase, Tadashi

2013-03-01

The objective of this study was to clarify variations of the ceramide (CER) profile in human stratum corneum (SC) in different seasons and in different regions of the body and to estimate the contributions of CERs to the SC barrier and water-holding functions. Based on the information that there are great variations of SC functions among body sites, we compared the CER profiles obtained from ten different anatomical sites in healthy Japanese males in four seasons. Not only the physiological parameters of skin but also the CER profile showed body region and seasonal variations. The total CER level, the CER composition and the C34-CER[NS] species displayed strong correlations with the values of transepidermal water loss and capacitance throughout the body. Especially in the cheek, a strong correlation between the capacitance and the CER profile was observed. There were seasonal variations of the CER profile in the lip, upper arm and palm. Our results indicate that regional and seasonal variations of the CER profile may contribute to SC functions.

The role of private industry in pragmatic comparative effectiveness trials.

PubMed

Buesching, Don P; Luce, Bryan R; Berger, Marc L

2012-03-01

Comparative effectiveness research (CER) includes pragmatic clinical trials (PCTs) to address 'real-world' effectiveness. CER interest would be expected to stimulate biopharmaceutical manufacturer PCT investment; however, this does not seem to be the case. In this article we identify all industry-sponsored PCT studies from 1996 to 2010; analyze them across a variety of characteristics, including sponsor, research question, design, comparators and results; and suggest methodological and policy changes to spur future manufacturer PCT investment. Nine 'naturalistic', head-to-head versus standard of care or similar agent PCTs were identified. Two included a 'usual care' arm. Chronic care trials' length averaged 12 months (range: 6-24 months), six of which reported equivocal or no difference in effectiveness; results of two chronic and the single acute care PCTs favored the sponsor drug. None reported the sponsor drug inferior. Of seven that evaluated utilization or costs, six reported no differences and four of five studies comparing brand-generic drugs reported no difference. Whereas private investment in PCTs is in the public interest, manufacturers apparently have not yet seen the business case. To induce investment, we propose several methodological and regulatory policy innovations designed to reduce business risk by decreasing outcome variability and increasing trial efficiency, flexibility and market applicability.

Intra-Peritoneal Hyperthermia Combining α-Galactosylceramide in the Treatment of Ovarian Cancer

PubMed Central

Hsu, Yun-Ting; Huang, Jung-Tang; Wu, T. -C; Hung, Chien-Fu; Yang, Yuh-Cheng; Chang, Chih-Long

2013-01-01

The purpose of this study was to investigate the anti-tumor effect and potential mechanisms of i.p. hyperthermia in combination with α-galactosylceramide (α-GalCer) for the treatment of ovarian cancer. In this study, immuno-competent tumor models were established using murine ovarian cancer cell lines and treated with i.p. hyperthermia combining α-GalCer. Th1/Th2 cytokine expression profiles in the serum, NK cell cytotoxicity and phagocytic activities of dendritic cells (DCs) were assayed. We also analyzed the number of CD8+/IFN-γ+ tumor specific cytotoxic T cells, as well as the tumor growth based on depletion of lymphocyte sub-population. Therapeutic effect on those ovarian tumors was monitored by a non-invasive luminescent imaging system. Intra-peritoneal hyperthermia induced significant pro-inflammatory cytokines expression, and sustained the response of NK and DCs induced by α-GalCer treatment. The combination treatment enhanced the cytotoxic T lymphocyte (CTL) immune response in two mouse ovarian cancer models. This novel treatment modality by combination of hyperthermia and glycolipid provides a pronounced anti-tumor immune response and better survival. In conclusion, intra-peritoneal hyperthermia enhanced the pro-inflammatory cytokine secretion and phagocytic activity of DCs stimulated by α-GalCer. The subsequent CTL immune response induced by α-GalCer was further strengthened by combining with i.p. hyperthermia. Both innate and adaptive immunities were involved and resulted in a superior therapeutic effect in treating the ovarian cancer. PMID:23935988

Efficacy of a Cream Containing Ceramides and Magnesium in the Treatment of Mild to Moderate Atopic Dermatitis: A Randomized, Double-blind, Emollient- and Hydrocortisone-controlled Trial.

PubMed

Koppes, Sjors A; Charles, Frank; Lammers, Laureen; Frings-Dresen, Monique; Kezic, Sanja; Rustemeyer, Thomas

2016-11-02

The aim of this randomized controlled trial was to assess the efficacy of a cream containing ceramides and magnesium (Cer-Mg) in the treatment of mild to moderate atopic dermatitis and to compare it with hydrocortisone and a commonly used emollient (unguentum leniens; cold cream). A total of 100 patients, randomized into 2 groups, were treated for 6 weeks simultaneously (left vs. right side of the body) with either Cer-Mg and hydrocortisone (group I) or Cer-Mg and emollient (group II). The primary outcome was a reduction in severity of lesions as assessed by (local) SCORAD (SCORing Atopic Dermatitis). Levels of trans-epidermal water loss (TEWL), skin hydration, and natural moisturizing factors (NMF) were then measured. After 6 weeks, group I showed comparable significant improvement in SCORAD and TEWL, while in group II, the decrease in SCORAD and TEWL was significantly greater after Cer-Mg compared with emollient. Finally, Cer-Mg cream was more effective in improving skin hydration and maintenance of levels of NMF than hydrocortisone and emollient.

VARIATIONS IN RECRUITMENT YIELD, COSTS, SPEED AND PARTICIPANT DIVERSITY ACROSS INTERNET PLATFORMS IN A GLOBAL STUDY EXAMINING THE EFFICACY OF AN HIV/AIDS AND HIV TESTING ANIMATED AND LIVE-ACTION VIDEO AMONG ENGLISH- OR SPANISH-SPEAKING INTERNET OR SOCIAL MEDIA USERS

PubMed Central

Shao, Winnie; Guan, Wentao; Clark, Melissa A.; Liu, Tao; Santelices, Claudia; Cortés, Dharma E.; Merchant, Roland C.

2016-01-01

For a world-wide, Internet-based study on HIV/AIDS and HIV testing knowledge, we compared the yields, speed and costs of recruitment and participant diversity across free postings on 13 Internet or social media platforms, paid advertising or postings on 3 platforms, and separate free postings and paid advertisements on Facebook. Platforms were compared by study completions (yield), time to completion, completion to enrollment ratios (CERs), and costs/ completion; and by participants’ demographic characteristics, HIV testing history, and health literacy levels. Of the 482 English-speaking participants, Amazon Mechanical Turk yielded the most participants, recruited participants at the fastest rate and had the highest CER (0.78) and lowest costs / completion. Of the 335 Spanish-speaking participants, Facebook yielded the most participants and recruited participants at the fastest rate, although Amazon Mechanical Turk had the highest CER (0.72) and lowest costs/completion. Across platforms participants differed substantially according to their demographic characteristics, HIV testing history and health literay skills. The study results highlight the need for researchers to strongly consider choice of Internet or social media plaforms when conducting Internet-based research. Because of the sample specifications and cost restraints of studies, specific Internet/ social media or participant selection plaforms will be much more effective or appropriate than others. PMID:27330570

VARIATIONS IN RECRUITMENT YIELD, COSTS, SPEED AND PARTICIPANT DIVERSITY ACROSS INTERNET PLATFORMS IN A GLOBAL STUDY EXAMINING THE EFFICACY OF AN HIV/AIDS AND HIV TESTING ANIMATED AND LIVE-ACTION VIDEO AMONG ENGLISH- OR SPANISH-SPEAKING INTERNET OR SOCIAL MEDIA USERS.

PubMed

Shao, Winnie; Guan, Wentao; Clark, Melissa A; Liu, Tao; Santelices, Claudia; Cortés, Dharma E; Merchant, Roland C

For a world-wide, Internet-based study on HIV/AIDS and HIV testing knowledge, we compared the yields, speed and costs of recruitment and participant diversity across free postings on 13 Internet or social media platforms, paid advertising or postings on 3 platforms, and separate free postings and paid advertisements on Facebook. Platforms were compared by study completions (yield), time to completion, completion to enrollment ratios (CERs), and costs/ completion; and by participants' demographic characteristics, HIV testing history, and health literacy levels. Of the 482 English-speaking participants, Amazon Mechanical Turk yielded the most participants, recruited participants at the fastest rate and had the highest CER (0.78) and lowest costs / completion. Of the 335 Spanish-speaking participants, Facebook yielded the most participants and recruited participants at the fastest rate, although Amazon Mechanical Turk had the highest CER (0.72) and lowest costs/completion. Across platforms participants differed substantially according to their demographic characteristics, HIV testing history and health literay skills. The study results highlight the need for researchers to strongly consider choice of Internet or social media plaforms when conducting Internet-based research. Because of the sample specifications and cost restraints of studies, specific Internet/ social media or participant selection plaforms will be much more effective or appropriate than others.

Reconstitution of plant alkane biosynthesis in yeast demonstrates that Arabidopsis ECERIFERUM1 and ECERIFERUM3 are core components of a very-long-chain alkane synthesis complex.

PubMed

Bernard, Amélie; Domergue, Frédéric; Pascal, Stéphanie; Jetter, Reinhard; Renne, Charlotte; Faure, Jean-Denis; Haslam, Richard P; Napier, Johnathan A; Lessire, René; Joubès, Jérôme

2012-07-01

In land plants, very-long-chain (VLC) alkanes are major components of cuticular waxes that cover aerial organs, mainly acting as a waterproof barrier to prevent nonstomatal water loss. Although thoroughly investigated, plant alkane synthesis remains largely undiscovered. The Arabidopsis thaliana ECERIFERUM1 (CER1) protein has been recognized as an essential element of wax alkane synthesis; nevertheless, its function remains elusive. In this study, a screen for CER1 physical interaction partners was performed. The screen revealed that CER1 interacts with the wax-associated protein ECERIFERUM3 (CER3) and endoplasmic reticulum-localized cytochrome b5 isoforms (CYTB5s). The functional relevance of these interactions was assayed through an iterative approach using yeast as a heterologous expression system. In a yeast strain manipulated to produce VLC acyl-CoAs, a strict CER1 and CER3 coexpression resulted in VLC alkane synthesis. The additional presence of CYTB5s was found to enhance CER1/CER3 alkane production. Site-directed mutagenesis showed that CER1 His clusters are essential for alkane synthesis, whereas those of CER3 are not, suggesting that CYTB5s are specific CER1 cofactors. Collectively, our study reports the identification of plant alkane synthesis enzymatic components and supports a new model for alkane production in which CER1 interacts with both CER3 and CYTB5 to catalyze the redox-dependent synthesis of VLC alkanes from VLC acyl-CoAs.

Economic Analysis of Children's Surgical Care in Low- and Middle-Income Countries: A Systematic Review and Analysis.

PubMed

Saxton, Anthony T; Poenaru, Dan; Ozgediz, Doruk; Ameh, Emmanuel A; Farmer, Diana; Smith, Emily R; Rice, Henry E

2016-01-01

Understanding the economic value of health interventions is essential for policy makers to make informed resource allocation decisions. The objective of this systematic review was to summarize available information on the economic impact of children's surgical care in low- and middle-income countries (LMICs). We searched MEDLINE (Pubmed), Embase, and Web of Science for relevant articles published between Jan. 1996 and Jan. 2015. We summarized reported cost information for individual interventions by country, including all costs, disability weights, health outcome measurements (most commonly disability-adjusted life years [DALYs] averted) and cost-effectiveness ratios (CERs). We calculated median CER as well as societal economic benefits (using a human capital approach) by procedure group across all studies. The methodological quality of each article was assessed using the Drummond checklist and the overall quality of evidence was summarized using a scale adapted from the Agency for Healthcare Research and Quality. We identified 86 articles that met inclusion criteria, spanning 36 groups of surgical interventions. The procedure group with the lowest median CER was inguinal hernia repair ($15/DALY). The procedure group with the highest median societal economic benefit was neurosurgical procedures ($58,977). We found a wide range of study quality, with only 35% of studies having a Drummond score ≥ 7. Our findings show that many areas of children's surgical care are extremely cost-effective in LMICs, provide substantial societal benefits, and are an appropriate target for enhanced investment. Several areas, including inguinal hernia repair, trichiasis surgery, cleft lip and palate repair, circumcision, congenital heart surgery and orthopedic procedures, should be considered "Essential Pediatric Surgical Procedures" as they offer considerable economic value. However, there are major gaps in existing research quality and methodology which limit our current understanding of the economic value of surgical care.

Increased Global Interaction Across Functional Brain Modules During Cognitive Emotion Regulation.

PubMed

Brandl, Felix; Mulej Bratec, Satja; Xie, Xiyao; Wohlschläger, Afra M; Riedl, Valentin; Meng, Chun; Sorg, Christian

2017-07-13

Cognitive emotion regulation (CER) enables humans to flexibly modulate their emotions. While local theories of CER neurobiology suggest interactions between specialized local brain circuits underlying CER, e.g., in subparts of amygdala and medial prefrontal cortices (mPFC), global theories hypothesize global interaction increases among larger functional brain modules comprising local circuits. We tested the global CER hypothesis using graph-based whole-brain network analysis of functional MRI data during aversive emotional processing with and without CER. During CER, global between-module interaction across stable functional network modules increased. Global interaction increase was particularly driven by subregions of amygdala and cuneus-nodes of highest nodal participation-that overlapped with CER-specific local activations, and by mPFC and posterior cingulate as relevant connector hubs. Results provide evidence for the global nature of human CER, complementing functional specialization of embedded local brain circuits during successful CER. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Supporting Teachers to Attend to Generalisation in Science Classroom Argumentation

NASA Astrophysics Data System (ADS)

Shemwell, Jonathan T.; Gwarjanski, Kalee R.; Capps, Daniel K.; Avargil, Shirly; Meyer, Joanna L.

2015-03-01

In scientific arguments, claims must have meaning that extends beyond the immediate circumstances of an investigation. That is, claims must be generalised in some way. Therefore, teachers facilitating classroom argumentation must be prepared to support students' efforts to construct or criticise generalised claims. However, widely used argumentation support tools, for instance, the claim-evidence-reasoning (CER) framework, tend not to address generalisation. Accordingly, teachers using these kinds of tools may not be prepared to help their students negotiate issues of generalisation in arguments. We investigated this possibility in a study of professional development activities of 18 middle school teachers using CER. We compared the teachers' approach to generalisation when using a published version of CER to their approach when using an alternate form of CER that increased support for generalisation. In several different sessions, the teachers: (1) responded to survey questions when using CER, (2) critiqued student arguments, (3) used both CER and alternate CER to construct arguments, and (4) discussed the experience of using CER and alternate CER. When using the standard CER, the teachers did not explicitly attend to generalisation in student arguments or in their own arguments. With alternate CER, the teachers generalised their own arguments, and they acknowledged the need for generalisation in student arguments. We concluded that teachers using frameworks for supporting scientific argumentation could benefit from more explicit support for generalisation than CER provides. More broadly, we concluded that generalisation deserves increased attention as a pedagogical challenge within classroom scientific argumentation.

CERES Single Scanner Satellite Footprint, TOA, Surface Fluxes and Clouds (SSF) data in HDF (CER_SSF_Terra-FM2-MODIS_Edition2A)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The Single Scanner Footprint TOA/Surface Fluxes and Clouds (SSF) product contains one hour of instantaneous Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The SSF combines instantaneous CERES data with scene information from a higher-resolution imager such as Visible/Infrared Scanner (VIRS) on TRMM or Moderate-Resolution Imaging Spectroradiometer (MODIS) on Terra and Aqua. Scene identification and cloud properties are defined at the higher imager resolution and these data are averaged over the larger CERES footprint. For each CERES footprint, the SSF contains the number of cloud layers and for each layer the cloud amount, height, temperature, pressure, optical depth, emissivity, ice and liquid water path, and water particle size. The SSF also contains the CERES filtered radiances for the total, shortwave (SW), and window (WN) channels and the unfiltered SW, longwave (LW), and WN radiances. The SW, LW, and WN radiances at spacecraft altitude are converted to Top-of-the-Atmosphere (TOA) fluxes based on the imager defined scene. These TOA fluxes are used to estimate surface fluxes. Only footprints with adequate imager coverage are included on CER_SSF_TRMM-PFM-VIRS_Subset_Edition1the SSF which is much less than the full set of footprints on the CERES ES-8 product. The following CERES SSF data sets are currently available: CER_SSF_TRMM-PFM-VIRS_Edition1 CER_SSF_TRMM-PFM-VIRS_Subset_Edition1 CER_SSF_TRMM-PFM-VIRS_Edition2A CER_SSF_TRMM-SIM-VIRS_Edition2_VIRSonly CER_SSF_TRMM-PFM-VIRS_Edition2A-TransOps CER_SSF_TRMM-PFM-VIRS_Edition2B-TransOps CER_SSF_TRMM-PFM-VIRS_Edition2B CER_SSF_Terra-FM1-MODIS_Edition1A CER_SSF_Terra-FM1-MODIS_Edition1A CER_SSF_Terra-FM1-MODIS_Edition2A CER_SSF_Terra-FM2-MODIS_Edition2A CER_SSF_Terra-FM1-MODIS_Edition2B CER_SSF_Terra-FM2-MODIS_Edition2B CER_SSF_Aqua-FM4-MODIS_Beta1 CER_SSF_Aqua-FM3-MODIS_Beta2 CER_SSF_Aqua-FM4-MODIS_Beta2. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2003-12-31] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Temporal_Resolution=1 hour; Temporal_Resolution_Range=Hourly - < Daily].

CERES Single Satellite Footprint, TOA and Surface Fluxes, Clouds (SSF) data in HDF (CER_SSF_Aqua-FM4-MODIS_Edition2A)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The Single Scanner Footprint TOA/Surface Fluxes and Clouds (SSF) product contains one hour of instantaneous Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The SSF combines instantaneous CERES data with scene information from a higher-resolution imager such as Visible/Infrared Scanner (VIRS) on TRMM or Moderate-Resolution Imaging Spectroradiometer (MODIS) on Terra and Aqua. Scene identification and cloud properties are defined at the higher imager resolution and these data are averaged over the larger CERES footprint. For each CERES footprint, the SSF contains the number of cloud layers and for each layer the cloud amount, height, temperature, pressure, optical depth, emissivity, ice and liquid water path, and water particle size. The SSF also contains the CERES filtered radiances for the total, shortwave (SW), and window (WN) channels and the unfiltered SW, longwave (LW), and WN radiances. The SW, LW, and WN radiances at spacecraft altitude are converted to Top-of-the-Atmosphere (TOA) fluxes based on the imager defined scene. These TOA fluxes are used to estimate surface fluxes. Only footprints with adequate imager coverage are included on CER_SSF_TRMM-PFM-VIRS_Subset_Edition1the SSF which is much less than the full set of footprints on the CERES ES-8 product. The following CERES SSF data sets are currently available: CER_SSF_TRMM-PFM-VIRS_Edition1 CER_SSF_TRMM-PFM-VIRS_Subset_Edition1 CER_SSF_TRMM-PFM-VIRS_Edition2A CER_SSF_TRMM-SIM-VIRS_Edition2_VIRSonly CER_SSF_TRMM-PFM-VIRS_Edition2A-TransOps CER_SSF_TRMM-PFM-VIRS_Edition2B-TransOps CER_SSF_TRMM-PFM-VIRS_Edition2B CER_SSF_Terra-FM1-MODIS_Edition1A CER_SSF_Terra-FM1-MODIS_Edition1A CER_SSF_Terra-FM1-MODIS_Edition2A CER_SSF_Terra-FM2-MODIS_Edition2A CER_SSF_Terra-FM1-MODIS_Edition2B CER_SSF_Terra-FM2-MODIS_Edition2B CER_SSF_Aqua-FM4-MODIS_Beta1 CER_SSF_Aqua-FM3-MODIS_Beta2 CER_SSF_Aqua-FM4-MODIS_Beta2. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2005-09-16] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Temporal_Resolution=1 hour; Temporal_Resolution_Range=Hourly - < Daily].

CERES Single Scanner Satellite Footprint, TOA, Surface Fluxes and Clouds (SSF) data in HDF (CER_SSF_Aqua-FM4-MODIS_Edition1B)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The Single Scanner Footprint TOA/Surface Fluxes and Clouds (SSF) product contains one hour of instantaneous Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The SSF combines instantaneous CERES data with scene information from a higher-resolution imager such as Visible/Infrared Scanner (VIRS) on TRMM or Moderate-Resolution Imaging Spectroradiometer (MODIS) on Terra and Aqua. Scene identification and cloud properties are defined at the higher imager resolution and these data are averaged over the larger CERES footprint. For each CERES footprint, the SSF contains the number of cloud layers and for each layer the cloud amount, height, temperature, pressure, optical depth, emissivity, ice and liquid water path, and water particle size. The SSF also contains the CERES filtered radiances for the total, shortwave (SW), and window (WN) channels and the unfiltered SW, longwave (LW), and WN radiances. The SW, LW, and WN radiances at spacecraft altitude are converted to Top-of-the-Atmosphere (TOA) fluxes based on the imager defined scene. These TOA fluxes are used to estimate surface fluxes. Only footprints with adequate imager coverage are included on CER_SSF_TRMM-PFM-VIRS_Subset_Edition1the SSF which is much less than the full set of footprints on the CERES ES-8 product. The following CERES SSF data sets are currently available: CER_SSF_TRMM-PFM-VIRS_Edition1 CER_SSF_TRMM-PFM-VIRS_Subset_Edition1 CER_SSF_TRMM-PFM-VIRS_Edition2A CER_SSF_TRMM-SIM-VIRS_Edition2_VIRSonly CER_SSF_TRMM-PFM-VIRS_Edition2A-TransOps CER_SSF_TRMM-PFM-VIRS_Edition2B-TransOps CER_SSF_TRMM-PFM-VIRS_Edition2B CER_SSF_Terra-FM1-MODIS_Edition1A CER_SSF_Terra-FM1-MODIS_Edition1A CER_SSF_Terra-FM1-MODIS_Edition2A CER_SSF_Terra-FM2-MODIS_Edition2A CER_SSF_Terra-FM1-MODIS_Edition2B CER_SSF_Terra-FM2-MODIS_Edition2B CER_SSF_Aqua-FM4-MODIS_Beta1 CER_SSF_Aqua-FM3-MODIS_Beta2 CER_SSF_Aqua-FM4-MODIS_Beta2. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2005-03-29] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Temporal_Resolution=1 hour; Temporal_Resolution_Range=Hourly - < Daily].

CERES Single Scanner Satellite Footprint, TOA, Surface Fluxes and Clouds (SSF)- Test data in HDF (CER_SSF_TRMM-PFM-VIRS_Subset-Edition1)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The Single Scanner Footprint TOA/Surface Fluxes and Clouds (SSF) product contains one hour of instantaneous Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The SSF combines instantaneous CERES data with scene information from a higher-resolution imager such as Visible/Infrared Scanner (VIRS) on TRMM or Moderate-Resolution Imaging Spectroradiometer (MODIS) on Terra and Aqua. Scene identification and cloud properties are defined at the higher imager resolution and these data are averaged over the larger CERES footprint. For each CERES footprint, the SSF contains the number of cloud layers and for each layer the cloud amount, height, temperature, pressure, optical depth, emissivity, ice and liquid water path, and water particle size. The SSF also contains the CERES filtered radiances for the total, shortwave (SW), and window (WN) channels and the unfiltered SW, longwave (LW), and WN radiances. The SW, LW, and WN radiances at spacecraft altitude are converted to Top-of-the-Atmosphere (TOA) fluxes based on the imager defined scene. These TOA fluxes are used to estimate surface fluxes. Only footprints with adequate imager coverage are included on CER_SSF_TRMM-PFM-VIRS_Subset_Edition1the SSF which is much less than the full set of footprints on the CERES ES-8 product. The following CERES SSF data sets are currently available: CER_SSF_TRMM-PFM-VIRS_Edition1 CER_SSF_TRMM-PFM-VIRS_Subset_Edition1 CER_SSF_TRMM-PFM-VIRS_Edition2A CER_SSF_TRMM-SIM-VIRS_Edition2_VIRSonly CER_SSF_TRMM-PFM-VIRS_Edition2A-TransOps CER_SSF_TRMM-PFM-VIRS_Edition2B-TransOps CER_SSF_TRMM-PFM-VIRS_Edition2B CER_SSF_Terra-FM1-MODIS_Edition1A CER_SSF_Terra-FM1-MODIS_Edition1A CER_SSF_Terra-FM1-MODIS_Edition2A CER_SSF_Terra-FM2-MODIS_Edition2A CER_SSF_Terra-FM1-MODIS_Edition2B CER_SSF_Terra-FM2-MODIS_Edition2B CER_SSF_Aqua-FM4-MODIS_Beta1 CER_SSF_Aqua-FM3-MODIS_Beta2 CER_SSF_Aqua-FM4-MODIS_Beta2. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=1998-08-31] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Temporal_Resolution=1 hour; Temporal_Resolution_Range=Hourly - < Daily].

CERES Single Satellite Footprint, TOA and Surface Fluxes, Clouds (SSF) data in HDF (CER_SSF_Aqua-FM4-MODIS_Ed2A-NoSW)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The Single Scanner Footprint TOA/Surface Fluxes and Clouds (SSF) product contains one hour of instantaneous Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The SSF combines instantaneous CERES data with scene information from a higher-resolution imager such as Visible/Infrared Scanner (VIRS) on TRMM or Moderate-Resolution Imaging Spectroradiometer (MODIS) on Terra and Aqua. Scene identification and cloud properties are defined at the higher imager resolution and these data are averaged over the larger CERES footprint. For each CERES footprint, the SSF contains the number of cloud layers and for each layer the cloud amount, height, temperature, pressure, optical depth, emissivity, ice and liquid water path, and water particle size. The SSF also contains the CERES filtered radiances for the total, shortwave (SW), and window (WN) channels and the unfiltered SW, longwave (LW), and WN radiances. The SW, LW, and WN radiances at spacecraft altitude are converted to Top-of-the-Atmosphere (TOA) fluxes based on the imager defined scene. These TOA fluxes are used to estimate surface fluxes. Only footprints with adequate imager coverage are included on CER_SSF_TRMM-PFM-VIRS_Subset_Edition1the SSF which is much less than the full set of footprints on the CERES ES-8 product. The following CERES SSF data sets are currently available: CER_SSF_TRMM-PFM-VIRS_Edition1 CER_SSF_TRMM-PFM-VIRS_Subset_Edition1 CER_SSF_TRMM-PFM-VIRS_Edition2A CER_SSF_TRMM-SIM-VIRS_Edition2_VIRSonly CER_SSF_TRMM-PFM-VIRS_Edition2A-TransOps CER_SSF_TRMM-PFM-VIRS_Edition2B-TransOps CER_SSF_TRMM-PFM-VIRS_Edition2B CER_SSF_Terra-FM1-MODIS_Edition1A CER_SSF_Terra-FM1-MODIS_Edition1A CER_SSF_Terra-FM1-MODIS_Edition2A CER_SSF_Terra-FM2-MODIS_Edition2A CER_SSF_Terra-FM1-MODIS_Edition2B CER_SSF_Terra-FM2-MODIS_Edition2B CER_SSF_Aqua-FM4-MODIS_Beta1 CER_SSF_Aqua-FM3-MODIS_Beta2 CER_SSF_Aqua-FM4-MODIS_Beta2. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2006-01-01] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Temporal_Resolution=1 hour; Temporal_Resolution_Range=Hourly - < Daily].

CERES Single Scanner Satellite Footprint, TOA, Surface Fluxes and Clouds (SSF) data in HDF (CER_SSF_Terra-FM2-MODIS_Edition2B)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The Single Scanner Footprint TOA/Surface Fluxes and Clouds (SSF) product contains one hour of instantaneous Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The SSF combines instantaneous CERES data with scene information from a higher-resolution imager such as Visible/Infrared Scanner (VIRS) on TRMM or Moderate-Resolution Imaging Spectroradiometer (MODIS) on Terra and Aqua. Scene identification and cloud properties are defined at the higher imager resolution and these data are averaged over the larger CERES footprint. For each CERES footprint, the SSF contains the number of cloud layers and for each layer the cloud amount, height, temperature, pressure, optical depth, emissivity, ice and liquid water path, and water particle size. The SSF also contains the CERES filtered radiances for the total, shortwave (SW), and window (WN) channels and the unfiltered SW, longwave (LW), and WN radiances. The SW, LW, and WN radiances at spacecraft altitude are converted to Top-of-the-Atmosphere (TOA) fluxes based on the imager defined scene. These TOA fluxes are used to estimate surface fluxes. Only footprints with adequate imager coverage are included on CER_SSF_TRMM-PFM-VIRS_Subset_Edition1the SSF which is much less than the full set of footprints on the CERES ES-8 product. The following CERES SSF data sets are currently available: CER_SSF_TRMM-PFM-VIRS_Edition1 CER_SSF_TRMM-PFM-VIRS_Subset_Edition1 CER_SSF_TRMM-PFM-VIRS_Edition2A CER_SSF_TRMM-SIM-VIRS_Edition2_VIRSonly CER_SSF_TRMM-PFM-VIRS_Edition2A-TransOps CER_SSF_TRMM-PFM-VIRS_Edition2B-TransOps CER_SSF_TRMM-PFM-VIRS_Edition2B CER_SSF_Terra-FM1-MODIS_Edition1A CER_SSF_Terra-FM1-MODIS_Edition1A CER_SSF_Terra-FM1-MODIS_Edition2A CER_SSF_Terra-FM2-MODIS_Edition2A CER_SSF_Terra-FM1-MODIS_Edition2B CER_SSF_Terra-FM2-MODIS_Edition2B CER_SSF_Aqua-FM4-MODIS_Beta1 CER_SSF_Aqua-FM3-MODIS_Beta2 CER_SSF_Aqua-FM4-MODIS_Beta2. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2006-01-01] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Temporal_Resolution=1 hour; Temporal_Resolution_Range=Hourly - < Daily].

CERES Single Scanner Satellite Footprint, TOA, Surface Fluxes and Clouds (SSF) data in HDF (CER_SSF_TRMM-PFM-VIRS_Edition1)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The Single Scanner Footprint TOA/Surface Fluxes and Clouds (SSF) product contains one hour of instantaneous Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The SSF combines instantaneous CERES data with scene information from a higher-resolution imager such as Visible/Infrared Scanner (VIRS) on TRMM or Moderate-Resolution Imaging Spectroradiometer (MODIS) on Terra and Aqua. Scene identification and cloud properties are defined at the higher imager resolution and these data are averaged over the larger CERES footprint. For each CERES footprint, the SSF contains the number of cloud layers and for each layer the cloud amount, height, temperature, pressure, optical depth, emissivity, ice and liquid water path, and water particle size. The SSF also contains the CERES filtered radiances for the total, shortwave (SW), and window (WN) channels and the unfiltered SW, longwave (LW), and WN radiances. The SW, LW, and WN radiances at spacecraft altitude are converted to Top-of-the-Atmosphere (TOA) fluxes based on the imager defined scene. These TOA fluxes are used to estimate surface fluxes. Only footprints with adequate imager coverage are included on CER_SSF_TRMM-PFM-VIRS_Subset_Edition1the SSF which is much less than the full set of footprints on the CERES ES-8 product. The following CERES SSF data sets are currently available: CER_SSF_TRMM-PFM-VIRS_Edition1 CER_SSF_TRMM-PFM-VIRS_Subset_Edition1 CER_SSF_TRMM-PFM-VIRS_Edition2A CER_SSF_TRMM-SIM-VIRS_Edition2_VIRSonly CER_SSF_TRMM-PFM-VIRS_Edition2A-TransOps CER_SSF_TRMM-PFM-VIRS_Edition2B-TransOps CER_SSF_TRMM-PFM-VIRS_Edition2B CER_SSF_Terra-FM1-MODIS_Edition1A CER_SSF_Terra-FM1-MODIS_Edition1A CER_SSF_Terra-FM1-MODIS_Edition2A CER_SSF_Terra-FM2-MODIS_Edition2A CER_SSF_Terra-FM1-MODIS_Edition2B CER_SSF_Terra-FM2-MODIS_Edition2B CER_SSF_Aqua-FM4-MODIS_Beta1 CER_SSF_Aqua-FM3-MODIS_Beta2 CER_SSF_Aqua-FM4-MODIS_Beta2. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2000-03-31] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Temporal_Resolution=1 hour; Temporal_Resolution_Range=Hourly - < Daily].

CERES Single Scanner Satellite Footprint, TOA, Surface Fluxes and Clouds (SSF) data in HDF (CER_SSF_Terra-FM1-MODIS_Edition2A)

NASA Technical Reports Server (NTRS)

Wielicki, Bruce A. (Principal Investigator)

The Single Scanner Footprint TOA/Surface Fluxes and Clouds (SSF) product contains one hour of instantaneous Clouds and the Earth's Radiant Energy System (CERES) data for a single scanner instrument. The SSF combines instantaneous CERES data with scene information from a higher-resolution imager such as Visible/Infrared Scanner (VIRS) on TRMM or Moderate-Resolution Imaging Spectroradiometer (MODIS) on Terra and Aqua. Scene identification and cloud properties are defined at the higher imager resolution and these data are averaged over the larger CERES footprint. For each CERES footprint, the SSF contains the number of cloud layers and for each layer the cloud amount, height, temperature, pressure, optical depth, emissivity, ice and liquid water path, and water particle size. The SSF also contains the CERES filtered radiances for the total, shortwave (SW), and window (WN) channels and the unfiltered SW, longwave (LW), and WN radiances. The SW, LW, and WN radiances at spacecraft altitude are converted to Top-of-the-Atmosphere (TOA) fluxes based on the imager defined scene. These TOA fluxes are used to estimate surface fluxes. Only footprints with adequate imager coverage are included on CER_SSF_TRMM-PFM-VIRS_Subset_Edition1the SSF which is much less than the full set of footprints on the CERES ES-8 product. The following CERES SSF data sets are currently available: CER_SSF_TRMM-PFM-VIRS_Edition1 CER_SSF_TRMM-PFM-VIRS_Subset_Edition1 CER_SSF_TRMM-PFM-VIRS_Edition2A CER_SSF_TRMM-SIM-VIRS_Edition2_VIRSonly CER_SSF_TRMM-PFM-VIRS_Edition2A-TransOps CER_SSF_TRMM-PFM-VIRS_Edition2B-TransOps CER_SSF_TRMM-PFM-VIRS_Edition2B CER_SSF_Terra-FM1-MODIS_Edition1A CER_SSF_Terra-FM1-MODIS_Edition1A CER_SSF_Terra-FM1-MODIS_Edition2A CER_SSF_Terra-FM2-MODIS_Edition2A CER_SSF_Terra-FM1-MODIS_Edition2B CER_SSF_Terra-FM2-MODIS_Edition2B CER_SSF_Aqua-FM4-MODIS_Beta1 CER_SSF_Aqua-FM3-MODIS_Beta2 CER_SSF_Aqua-FM4-MODIS_Beta2. [Location=GLOBAL] [Temporal_Coverage: Start_Date=1998-01-01; Stop_Date=2003-12-31] [Spatial_Coverage: Southernmost_Latitude=-90; Northernmost_Latitude=90; Westernmost_Longitude=-180; Easternmost_Longitude=180] [Data_Resolution: Temporal_Resolution=1 hour; Temporal_Resolution_Range=Hourly - < Daily].

HDL and CER-001 Inverse-Dose Dependent Inhibition of Atherosclerotic Plaque Formation in apoE-/- Mice: Evidence of ABCA1 Down-Regulation

PubMed Central

Tardy, Claudine; Goffinet, Marine; Boubekeur, Nadia; Cholez, Guy; Ackermann, Rose; Sy, Gavin; Keyserling, Constance; Lalwani, Narendra; Paolini, John F.; Dasseux, Jean-Louis; Barbaras, Ronald; Baron, Rudi

2015-01-01

Objective CER-001 is a novel engineered HDL-mimetic comprised of recombinant human apoA-I and charged phospholipids that was designed to mimic the beneficial properties of nascent pre-ß HDL. In this study, we have evaluated the dose-dependent regulation of ABCA1 expression in vitro and in vivo in the presence of CER-001 and native HDL (HDL3). Methods and Results CER-001 induced cholesterol efflux from J774 macrophages in a dose-dependent manner similar to natural HDL. A strong down-regulation of the ATP-binding cassette A1 (ABCA1) transporter mRNA (- 50%) as well as the ABCA1 membrane protein expression (- 50%) was observed at higher doses of CER-001 and HDL3 compared to non-lipidated apoA-I. In vivo, in an apoE-/- mouse “flow cessation model,” in which the left carotid artery was ligatured to induce local inflammation, the inhibition of atherosclerotic plaque burden progression in response to a dose-range of every-other-day CER-001 or HDL in the presence of a high-fat diet for two weeks was assessed. We observed a U-shaped dose-response curve: inhibition of the plaque total cholesterol content increased with increasing doses of CER-001 or HDL3 up to a maximum inhibition (- 51%) at 5 mg/kg; however, as the dose was increased above this threshold, a progressively less pronounced inhibition of progression was observed, reaching a complete absence of inhibition of progression at doses of 20 mg/kg and over. ABCA1 protein expression in the same atherosclerotic plaque was decreased by-45% and-68% at 50 mg/kg for CER-001 and HDL respectively. Conversely, a-12% and 0% decrease in ABCA1 protein expression was observed at the 5 mg/kg dose for CER-001 and HDL respectively. Conclusions These data demonstrate that high doses of HDL and CER-001 are less effective at slowing progression of atherosclerotic plaque in apoE-/- mice compared to lower doses, following a U-shaped dose-response curve. A potential mechanism for this phenomenon is supported by the observation that high doses of HDL and CER-001 induce a rapid and strong down-regulation of ABCA1 both in vitro and in vivo. In conclusion, maximally efficient HDL- or CER-001-mediated cholesterol removal from atherosclerotic plaque is achieved by maximizing macrophage-mediated efflux from the plaque while minimizing dose-dependent down-regulation of ABCA1 expression. These observations may help define the optimal dose of HDL mimetics for testing in clinical trials of atherosclerotic burden regression. PMID:26335690

HDL and CER-001 Inverse-Dose Dependent Inhibition of Atherosclerotic Plaque Formation in apoE-/- Mice: Evidence of ABCA1 Down-Regulation.

PubMed

Tardy, Claudine; Goffinet, Marine; Boubekeur, Nadia; Cholez, Guy; Ackermann, Rose; Sy, Gavin; Keyserling, Constance; Lalwani, Narendra; Paolini, John F; Dasseux, Jean-Louis; Barbaras, Ronald; Baron, Rudi

2015-01-01

CER-001 is a novel engineered HDL-mimetic comprised of recombinant human apoA-I and charged phospholipids that was designed to mimic the beneficial properties of nascent pre-ß HDL. In this study, we have evaluated the dose-dependent regulation of ABCA1 expression in vitro and in vivo in the presence of CER-001 and native HDL (HDL3). CER-001 induced cholesterol efflux from J774 macrophages in a dose-dependent manner similar to natural HDL. A strong down-regulation of the ATP-binding cassette A1 (ABCA1) transporter mRNA (- 50%) as well as the ABCA1 membrane protein expression (- 50%) was observed at higher doses of CER-001 and HDL3 compared to non-lipidated apoA-I. In vivo, in an apoE-/- mouse "flow cessation model," in which the left carotid artery was ligatured to induce local inflammation, the inhibition of atherosclerotic plaque burden progression in response to a dose-range of every-other-day CER-001 or HDL in the presence of a high-fat diet for two weeks was assessed. We observed a U-shaped dose-response curve: inhibition of the plaque total cholesterol content increased with increasing doses of CER-001 or HDL3 up to a maximum inhibition (- 51%) at 5 mg/kg; however, as the dose was increased above this threshold, a progressively less pronounced inhibition of progression was observed, reaching a complete absence of inhibition of progression at doses of 20 mg/kg and over. ABCA1 protein expression in the same atherosclerotic plaque was decreased by-45% and-68% at 50 mg/kg for CER-001 and HDL respectively. Conversely, a-12% and 0% decrease in ABCA1 protein expression was observed at the 5 mg/kg dose for CER-001 and HDL respectively. These data demonstrate that high doses of HDL and CER-001 are less effective at slowing progression of atherosclerotic plaque in apoE-/- mice compared to lower doses, following a U-shaped dose-response curve. A potential mechanism for this phenomenon is supported by the observation that high doses of HDL and CER-001 induce a rapid and strong down-regulation of ABCA1 both in vitro and in vivo. In conclusion, maximally efficient HDL- or CER-001-mediated cholesterol removal from atherosclerotic plaque is achieved by maximizing macrophage-mediated efflux from the plaque while minimizing dose-dependent down-regulation of ABCA1 expression. These observations may help define the optimal dose of HDL mimetics for testing in clinical trials of atherosclerotic burden regression.

Plasma and ovarian tissue sphingolipids profiling in patients with advanced ovarian cancer.

PubMed

Knapp, Paweł; Bodnar, Lubomir; Błachnio-Zabielska, Agnieszka; Świderska, Magdalena; Chabowski, Adrian

2017-10-01

The role of lipids in carcinogenesis through induction of abnormal cell lines in the human body is currently undisputable. Based on the literature, bioactive sphingolipids play an essential role in the development and progression of cancer and are involved in the metastatic process. The aim of this study was to determine the concentration of selected sphingolipids in patients with advanced ovarian cancer (AOC, FIGO III/IV, high grade ovarian cancer). Seventy-four patients with ovarian cancer were enrolled. Plasma concentrations of C16-Cer, C18:1-Cer and C18-Cer were assessed by LC/MS/MS. The content of tissue sphingolipids was measured using a UHPLC/MS/MS. Plasma concentration of 3 ceramides: C16-Cer, C18:1-Cer and C18-Cer was significantly elevated in women with advanced ovarian cancer compared to control group (P=0.031; 0.022; 0.020; respectively). There were increases in concentration of 5 ceramides: C16-Cer, C18:1-Cer, C18-Cer, C24:1-Cer, C24-Cer (P=0.025; 0.049; 0.032; 0.005; 0.013, respectively) and S1P (P=0.004) in ovarian tissue of women with advanced ovarian cancer compared to healthy individuals. Importantly, significantly higher risk of ovarian cancer when the plasma concentration of C16-Cer>311.88ng/100μl (AUC: 0.76, P=0.0261); C18:1-Cer>4.75ng/100μl (AUC: 0.77, P=0.0160) and C18-Cer>100.76ng/100μl (AUC:0.77, P=0.0136) was noticed. Bioactive sphingolipids play an essential role in the development and progression of cancer and they also take part in the process of metastasizing. This study suggests that some sphingolipids can be used as potential biomarkers of advanced ovarian cancer and that they can play an important role in the pathogenesis of this disease. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Structural analysis of glucosylceramides (GlcCer) from species of the Pseudallescheria/Scedosporium complex.

PubMed

Calixto, Renata O R; Rollin-Pinheiro, Rodrigo; da Silva, Mariana I D; Liporagi-Lopes, Livia C; Vieira, Jardel M; Sassaki, Guilherme L; Barreto-Bergter, Eliana

2016-02-01

Glucosylceramides (GlcCer) are the main neutral glycosphingolipids expressed in fungal cells. In this work, glucosylceramides (GlcCer) were extracted from three strains of Scedosporium (Pseudallescheria) boydii, one strain of Pseudallescheria ellipsoidea and one strain of Pseudallescheria angusta and purified by several chromatographic steps. Using high-performance thin layer chromatography (HPTLC), we found a similarity between GlcCer obtained from all of the analysed strains. A detailed structural analysis of the P. ellipsoidea GlcCer was performed via electrospray ionization mass spectrometry (ESI-MS) and confirmed in 1- and 2-D heteronuclear NMR experiments ((1)H-(13) C HSQC). GlcCer species produced by mycelial forms of these strains displayed the same structure previously demonstrated by our group for P. boydii, Cryptococcus neoformans, Pseudallescheria minustipora, Fusarium solani, and Colletotrichum gloesporioides. A monoclonal antibody (mAb) against GlcCer was used for immunofluorescence experiments. Our results revealed that GlcCer is present on the surface of these fungi, and no difference was observed in the GlcCer structure of the present set of strains in terms of geographic or clinical origin, suggesting a conserved GlcCer structure similar to those previously described for Scedosporium apiospermum, Scedosporium aurantiacum, and P. minutispora. The surface distribution of GlcCer in these fungi is suggestive of the involvement of this molecule in fungal growth. Copyright © 2015 The British Mycological Society. Published by Elsevier Ltd. All rights reserved.

Plant surface wax affects parasitoid's response to host footprints

NASA Astrophysics Data System (ADS)

Rostás, Michael; Ruf, Daniel; Zabka, Vanessa; Hildebrandt, Ulrich

2008-10-01

The plant surface is the substrate upon which herbivorous insects and natural enemies meet and thus represents the stage for interactions between the three trophic levels. Plant surfaces are covered by an epicuticular wax layer which is highly variable depending on species, cultivar or plant part. Differences in wax chemistry may modulate ecological interactions. We explored whether caterpillars of Spodoptera frugiperda, when walking over a plant surface, leave a chemical trail (kairomones) that can be detected by the parasitoid Cotesia marginiventris. Chemistry and micromorphology of cuticular waxes of two barley eceriferum wax mutants ( cer-za.126, cer-yp.949) and wild-type cv. Bonus (wt) were assessed. The plants were then used to investigate potential surface effects on the detectability of caterpillar kairomones. Here we provide evidence that C. marginiventris responds to chemical footprints of its host. Parasitoids were able to detect the kairomone on wild-type plants and on both cer mutants but the response to cer-yp.949 (reduced wax, high aldehyde fraction) was less pronounced. Experiments with caterpillar-treated wt and mutant leaves offered simultaneously, confirmed this observation: no difference in wasp response was found when wt was tested against cer-za.126 (reduced wax, wt-like chemical composition) but wt was significantly more attractive than cer-yp.949. This demonstrates for the first time that the wax layer can modulate the detectability of host kairomones.

Identification of N-acyl-fumonisin B1 as new cytotoxic metabolites of fumonisin mycotoxins.

PubMed

Harrer, Henning; Laviad, Elad L; Humpf, Hans Ulrich; Futerman, Anthony H

2013-03-01

Fumonisins are mycotoxins produced by Fusarium species. The predominant derivative, fumonisin B1 (FB1), occurs in food and feed and is of health concern due to its hepatotoxic and carcinogenic effects. However, the role of FB1 metabolites on the mechanism of the toxicity, the inhibition of the ceramide synthesis, is unknown. The aim of this study was to identify new fumonisin metabolites and to evaluate their cytotoxic potential. MS, molecular biology, and in vitro enzyme assays were used to investigate fumonisin metabolism in mammalian cells overexpressing human ceramide synthase (CerS) genes. N-acyl-FB1 derivatives were detected as new metabolites in cultured cells at levels of up to 10 pmol/mg of protein. The N-acylation of FB1 and hydrolyzed FB1 was analyzed in several cell lines, including cells overexpressing CerS. The acyl-chain length of the N-acyl fumonisins depends on the CerS isoform acylating them. The N-acyl fumonisins are more cytotoxic than the parent fumonisin B1. The identification of N-acyl fumonisins with various acyl chain lengths together with the observed cytotoxicity of these compounds is a new aspect of fumonisin-related toxicity. Therefore, these new metabolites might play an important role in the mode of action of fumonisins. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Changes in glucosylceramide structure affect virulence and membrane biophysical properties of Cryptococcus neoformans.

PubMed

Raj, Shriya; Nazemidashtarjandi, Saeed; Kim, Jihyun; Joffe, Luna; Zhang, Xiaoxue; Singh, Ashutosh; Mor, Visesato; Desmarini, Desmarini; Djordjevic, Julianne; Raleigh, Daniel P; Rodrigues, Marcio L; London, Erwin; Del Poeta, Maurizio; Farnoud, Amir M

2017-11-01

Fungal glucosylceramide (GlcCer) is a plasma membrane sphingolipid in which the sphingosine backbone is unsaturated in carbon position 8 (C8) and methylated in carbon position 9 (C9). Studies in the fungal pathogen, Cryptococcus neoformans, have shown that loss of GlcCer synthase activity results in complete loss of virulence in the mouse model. However, whether the loss of virulence is due to the lack of the enzyme or to the loss of the sphingolipid is not known. In this study, we used genetic engineering to alter the chemical structure of fungal GlcCer and studied its effect on fungal growth and pathogenicity. Here we show that unsaturation in C8 and methylation in C9 is required for virulence in the mouse model without affecting fungal growth in vitro or common virulence factors. However, changes in GlcCer structure led to a dramatic susceptibility to membrane stressors resulting in increased cell membrane permeability and rendering the fungal mutant unable to grow within host macrophages. Biophysical studies using synthetic vesicles containing GlcCer revealed that the saturated and unmethylated sphingolipid formed vesicles with higher lipid order that were more likely to phase separate into ordered domains. Taken together, these studies show for the first time that a specific structure of GlcCer is a major regulator of membrane permeability required for fungal pathogenicity. Copyright © 2017 Elsevier B.V. All rights reserved.

Confounding adjustment in comparative effectiveness research conducted within distributed research networks.

PubMed

Toh, Sengwee; Gagne, Joshua J; Rassen, Jeremy A; Fireman, Bruce H; Kulldorff, Martin; Brown, Jeffrey S

2013-08-01

A distributed research network (DRN) of electronic health care databases, in which data reside behind the firewall of each data partner, can support a wide range of comparative effectiveness research (CER) activities. An essential component of a fully functional DRN is the capability to perform robust statistical analyses to produce valid, actionable evidence without compromising patient privacy, data security, or proprietary interests. We describe the strengths and limitations of different confounding adjustment approaches that can be considered in observational CER studies conducted within DRNs, and the theoretical and practical issues to consider when selecting among them in various study settings. Several methods can be used to adjust for multiple confounders simultaneously, either as individual covariates or as confounder summary scores (eg, propensity scores and disease risk scores), including: (1) centralized analysis of patient-level data, (2) case-centered logistic regression of risk set data, (3) stratified or matched analysis of aggregated data, (4) distributed regression analysis, and (5) meta-analysis of site-specific effect estimates. These methods require different granularities of information be shared across sites and afford investigators different levels of analytic flexibility. DRNs are growing in use and sharing of highly detailed patient-level information is not always feasible in DRNs. Methods that incorporate confounder summary scores allow investigators to adjust for a large number of confounding factors without the need to transfer potentially identifiable information in DRNs. They have the potential to let investigators perform many analyses traditionally conducted through a centralized dataset with detailed patient-level information.

Preliminary assessment of potential CDM early start projects in Brazil

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

Meyers, S.; Sathaye, J.; Lehman, B.

2000-11-01

The Brazil/US Aspen Global Forum on Climate Change Policies and Programs has facilitated a dialogue between key Brazil and US public and private sector leaders on the subject of the Clean Development Mechanism (CDM). With support from the US government, a cooperative effort between Lawrence Berkeley National Laboratory and the University of Sao Paulo conducted an assessment of a number of projects put forth by Brazilian sponsors. Initially, we gathered information and conducted a screening assessment for ten projects in the energy sector and six projects in the forestry sector. Some of the projects appeared to offer greater potential tomore » be attractive for CDM, or had better information available. We then conducted a more detailed assessment of 12 of these projects, and two other projects that were submitted after the initial screening. An important goal was to assess the potential impact of Certified Emission Reductions (CERs) on the financial performance of projects. With the exception of the two forestry-based fuel displacement projects, the impact of CERs on the internal rate of return (IRR) is fairly small. This is true for both the projects that displace grid electricity and those that displace local (diesel-based) electricity production. The relative effect of CERs is greater for projects whose IRR without CERs is low. CERs have a substantial effect on the IRR of the two short-rotation forestry energy substitution projects. One reason is that the biofuel displaces coke and oil, both of which are carbon-intensive. Another factor is that the product of these projects (charcoal and woodfuel, respectively) is relatively low value, so the revenue from carbon credits has a strong relative impact. CERs also have a substantial effect on the NPV of the carbon sequestration projects. Financial and other barriers pose a challenge for implementation of most of the projects. In most cases, the sponsor lacks sufficient capital, and loans are available only at high interest rate and with substantial guarantee. A few of the projects might go ahead without the benefit of CERs, but most probably would not. Whether the projected revenue from CERs would be sufficient to induce sponsors to proceed with the projects is an important issue that requires further investigation. All of the projects contribute to economic development in Brazil. The forestry projects in particular would create a significant number of rural jobs, and contribute income to rural communities. Some of the carbon sequestration projects would provide environmental benefits with respect to protection of biodiversity and soil.« less

Sphingolipid regulation of lung epithelial cell mitophagy and necroptosis during cigarette smoke exposure.

PubMed

Mizumura, Kenji; Justice, Matthew J; Schweitzer, Kelly S; Krishnan, Sheila; Bronova, Irina; Berdyshev, Evgeny V; Hubbard, Walter C; Pewzner-Jung, Yael; Futerman, Anthony H; Choi, Augustine M K; Petrache, Irina

2018-04-01

The mechanisms by which lung structural cells survive toxic exposures to cigarette smoke (CS) are not well defined but may involve proper disposal of damaged mitochondria by macro-autophagy (mitophagy), processes that may be influenced by pro-apoptotic ceramide (Cer) or its precursor dihydroceramide (DHC). Human lung epithelial and endothelial cells exposed to CS exhibited mitochondrial damage, signaled by phosphatase and tensin homolog-induced putative kinase 1 (PINK1) phosphorylation, autophagy, and necroptosis. Although cells responded to CS by rapid inhibition of DHC desaturase, which elevated DHC levels, palmitoyl (C16)-Cer also increased in CS-exposed cells. Whereas DHC augmentation triggered autophagy without cell death, the exogenous administration of C16-Cer was sufficient to trigger necroptosis. Inhibition of Cer-generating acid sphingomyelinase reduced both CS-induced PINK1 phosphorylation and necroptosis. When exposed to CS, Pink1-deficient ( Pink1 -/- ) mice, which are protected from airspace enlargement compared with wild-type littermates, had blunted C16-Cer elevations and less lung necroptosis. CS-exposed Pink1 -/- mice also exhibited significantly increased levels of lignoceroyl (C24)-DHC, along with increased expression of Cer synthase 2 ( CerS2), the enzyme responsible for its production. This suggested that a combination of high C24-DHC and low C16-Cer levels might protect against CS-induced necroptosis. Indeed, CerS2 -/- mice, which lack C24-DHC at the expense of increased C16-Cer, were more susceptible to CS, developing airspace enlargement following only 1 month of exposure. These results implicate DHCs, in particular, C24-DHC, as protective against CS toxicity by enhancing autophagy, whereas C16-Cer accumulation contributes to mitochondrial damage and PINK1-mediated necroptosis, which may be amplified by the inhibition of C24-DHC-producing CerS2.-Mizumura, K., Justice, M. J., Schweitzer, K. S., Krishnan, S., Bronova, I., Berdyshev, E. V., Hubbard, W. C., Pewzner-Jung, Y., Futerman, A. H., Choi, A. M. K., Petrache, I. Sphingolipid regulation of lung epithelial cell mitophagy and necroptosis during cigarette smoke exposure.

Intercomparisons of Marine Boundary Layer Cloud Properties from the ARM CAP-MBL Campaign and Two MODIS Cloud Products

NASA Technical Reports Server (NTRS)

Zhang, Zhibo; Dong, Xiquan; Xi, Baike; Song, Hua; Ma, Po-Lun; Ghan, Steven J.; Platnick, Steven; Minnis, Patrick

2017-01-01

From April 2009 to December 2010, the Department of Energy (DOE) Atmospheric Radiation Measurement (ARM) program carried out an observational field campaign on Graciosa Island, targeting the marine boundary layer (MBL) clouds over the Azores region. In this paper, we present an inter-comparison of the MBL cloud properties, namely, cloud liquid water path (LWP), cloud optical thickness (COT) and cloud-droplet effective radius (CER), among retrievals from the ARM mobile facility (AMF) and two Moderate Resolution Spectroradiometer (MODIS) cloud products (GSFC-MODIS and CERES-MODIS). A total of 63 daytime single-layer MBL cloud cases are selected for inter-comparison. Comparison of collocated retrievals indicates that the two MODIS cloud products agree well on both COT and CER retrievals, with the correlation coefficient R greater than 0.95 despite their significant difference in spatial sampling. In both MODIS products, the CER retrievals based on the 2.1 micrometers band (CER(sub 2.1)) is significantly smaller than that based on the 3.7 micrometers band (CER(sub 3.7)). The GSFC-MODIS cloud product is collocated and compared with ground-based ARM observations at several temporal spatial scales. In general, the correlation increases with more precise collocation. For the 63 selected MBL cloud cases, the GSFC-MODIS LWP and COT retrievals agree reasonably well with the ground-based observations with no apparent bias and correlation coefficient R around 0.85 and 0.70, respectively. However, GSFC-MODIS CER(sub 3.7) and CER(sub 2.1) retrievals have a lower correlation (R is approximately 0.5) with the ground-based retrievals. For the 63 selected cases, they are on average larger than ground observations by about 1.5 micrometers and 3.0 micrometers, respectively. Taking into account that the MODIS CER retrievals are only sensitive to cloud top reduces the bias only by 0.5 micrometers.

Intercomparisons of marine boundary layer cloud properties from the ARM CAP-MBL campaign and two MODIS cloud products

NASA Astrophysics Data System (ADS)

Zhang, Zhibo; Dong, Xiquan; Xi, Baike; Song, Hua; Ma, Po-Lun; Ghan, Steven J.; Platnick, Steven; Minnis, Patrick

2017-02-01

From April 2009 to December 2010, the Department of Energy Atmospheric Radiation Measurement (ARM) program carried out an observational field campaign on Graciosa Island, targeting the marine boundary layer (MBL) clouds over the Azores region. In this paper, we present an intercomparison of the MBL cloud properties, namely, cloud liquid water path (LWP), cloud optical thickness (COT), and cloud-droplet effective radius (CER), among retrievals from the ARM mobile facility and two Moderate Resolution Imaging Spectroradiometer (MODIS) cloud products (Goddard Space Flight Center (GSFC)-MODIS and Clouds and Earth's Radiant Energy System-MODIS). A total of 63 daytime single-layer MBL cloud cases are selected for intercomparison. Comparison of collocated retrievals indicates that the two MODIS cloud products agree well on both COT and CER retrievals, with the correlation coefficient R > 0.95, despite their significant difference in spatial sampling. In both MODIS products, the CER retrievals based on the 2.1 µm band (CER2.1) are significantly larger than those based on the 3.7 µm band (CER3.7). The GSFC-MODIS cloud product is collocated and compared with ground-based ARM observations at several temporal-spatial scales. In general, the correlation increases with more precise collocation. For the 63 selected MBL cloud cases, the GSFC-MODIS LWP and COT retrievals agree reasonably well with the ground-based observations with no apparent bias and correlation coefficient R around 0.85 and 0.70, respectively. However, GSFC-MODIS CER3.7 and CER2.1 retrievals have a lower correlation (R 0.5) with the ground-based retrievals. For the 63 selected cases, they are on average larger than ground observations by about 1.5 µm and 3.0 µm, respectively. Taking into account that the MODIS CER retrievals are only sensitive to cloud top reduces the bias only by 0.5 µm.

Relating quality of life to Glasgow outcome scale health states.

PubMed

Kosty, Jennifer; Macyszyn, Luke; Lai, Kevin; McCroskery, James; Park, Hae-Ran; Stein, Sherman C

2012-05-01

There has recently been a call for the adoption of comparative effectiveness research (CER) and related research approaches for studying traumatic brain injury (TBI). These methods allow researchers to compare the effectiveness of different therapies in producing patient-oriented outcomes of interest. Heretofore, the only measures by which to compare such therapies have been mortality and rate of poor outcome. Better comparisons can be made if parametric, preference-based quality-of-life (QOL) values are available for intermediate outcomes, such as those described by the Glasgow Outcome Scale Extended (GOSE). Our objective was therefore to determine QOL for the health states described by the GOSE. We interviewed community members at least 18 years of age using the standard gamble method to assess QOL for descriptions of GOSE scores of 2-7 derived from the structured interview. Linear regression analysis was also performed to assess the effect of age, gender, and years of education on QOL. One hundred and one participants between the ages of 18 and 83 were interviewed (mean age 40 ± 19 years), including 55 men and 46 women. Functional impairment and QOL showed a strong inverse relationship, as assessed by both linear regression and the Spearman rank order coefficient. No consistent effect or age, gender, or years of education was seen. As expected, QOL decreased with functional outcome as described by the GOSE. The results of this study will provide the groundwork for future groups seeking to apply CER methods to clinical studies of TBI.

Role of Intracellular Lipid Logistics in the Preferential Usage of Very Long Chain-Ceramides in Glucosylceramide.

PubMed

Yamaji, Toshiyuki; Horie, Aya; Tachida, Yuriko; Sakuma, Chisato; Suzuki, Yusuke; Kushi, Yasunori; Hanada, Kentaro

2016-10-21

Ceramide is a common precursor of sphingomyelin (SM) and glycosphingolipids (GSLs) in mammalian cells. Ceramide synthase 2 (CERS2), one of the six ceramide synthase isoforms, is responsible for the synthesis of very long chain fatty acid (C20-26 fatty acids) (VLC)-containing ceramides (VLC-Cer). It is known that the proportion of VLC species in GSLs is higher than that in SM. To address the mechanism of the VLC-preference of GSLs, we used genome editing to establish three HeLa cell mutants that expressed different amounts of CERS2 and compared the acyl chain lengths of SM and GSLs by metabolic labeling experiments. VLC-sphingolipid expression was increased along with that of CERS2, and the proportion of VLC species in glucosylceramide (GlcCer) was higher than that in SM for all expression levels of CERS2. This higher proportion was still maintained even when the proportion of C16-Cer to the total ceramides was increased by disrupting the ceramide transport protein (CERT)-dependent C16-Cer delivery pathway for SM synthesis. On the other hand, merging the Golgi apparatus and the endoplasmic reticulum (ER) by Brefeldin A decreased the proportion of VLC species in GlcCer probably due to higher accessibility of UDP-glucose ceramide glucosyltransferase (UGCG) to C16-rich ceramides. These results suggest the existence of a yet-to-be-identified mechanism rendering VLC-Cer more accessible than C16-Cer to UGCG, which is independent of CERT.

Up-regulation of tumor suppressor genes by exogenous dhC16-Cer contributes to its anti-cancer activity in primary effusion lymphoma.

PubMed

Cao, Yueyu; Qiao, Jing; Lin, Zhen; Zabaleta, Jovanny; Dai, Lu; Qin, Zhiqiang

2017-02-28

Primary effusion lymphoma (PEL) is a rare and highly aggressive B-cell malignancy with Kaposi's sarcoma-associated herpesvirus (KSHV) infection, while lack of effective therapies. Our recent data indicated that targeting the sphingolipid metabolism by either sphingosine kinase inhibitor or exogenous ceramide species induces PEL cell apoptosis and suppresses tumor progression in vivo. However, the underlying mechanisms for these exogenous ceramides "killing" PEL cells remain largely unknown. Based on the microarray analysis, we found that exogenous dhC16-Cer treatment affected the expression of many cellular genes with important functions within PEL cells such as regulation of cell cycle, cell survival/proliferation, and apoptosis/anti-apoptosis. Interestingly, we found that a subset of tumor suppressor genes (TSGs) was up-regulated from dhC16-Cer treated PEL cells. One of these elevated TSGs, Thrombospondin-1 (THBS1) was required for dhC16-Cer induced PEL cell cycle arrest. Moreover, dhC16-Cer up-regulation of THBS1 was through the suppression of multiple KSHV microRNAs expression. Our data demonstrate that exogenous ceramides display anti-cancer activities for PEL through regulation of both host and oncogenic virus factors.

iNKT-CELL ACTIVATION INDUCES LATE PRETERM BIRTH THAT IS ATTENUATED BY ROSIGLITAZONE1

PubMed Central

St Louis, Derek; Romero, Roberto; Plazyo, Olesya; Arenas-Hernandez, Marcia; Panaitescu, Bogdan; Xu, Yi; Milovic, Tatjana; Xu, Zhonghui; Bhatti, Gaurav; Qing-Sheng, Mi; Drewlo, Sascha; Tarca, Adi L.; Hassan, Sonia S.; Gomez-Lopez, Nardhy

2015-01-01

Preterm birth (PTB) is a leading cause of neonatal morbidity and mortality; however, its non-infection-related mechanisms are poorly understood. Herein, we show that the expansion of activated CD1d-restricted invariant NKT (iNKT) cells in the third trimester by administration of α-galactosylceramide (α-GalCer) induces late PTB and neonatal mortality. In vivo imaging revealed that fetuses from mice that underwent α-GalCer-induced late PTB had bradycardia and died shortly after delivery. Yet, administration of α-GalCer in the second trimester did not cause pregnancy loss. PPARγ activation, through rosiglitazone treatment, reduced the rate of α-GalCer-induced late PTB and improved neonatal survival. Administration of α-GalCer in the third trimester suppressed PPARγ activation as shown by the down-regulation of Fabp4 and Fatp4 in myometrial and decidual tissues, respectively; this suppression was rescued by rosiglitazone treatment. Administration of α-GalCer in the third trimester induced an increase in the activation of conventional CD4+ T cells in myometrial tissues and the infiltration of activated macrophages, neutrophils and mature DCs to myometrial and/or decidual tissues. All of these effects were blunted after rosiglitazone treatment. Administration of α-GalCer also up-regulated the expression of inflammatory genes at the maternal-fetal interface and systemically, and rosiglitazone treatment partially attenuated these responses. Finally, an increased infiltration of activated iNKT-like cells in human decidual tissues is associated with non-infection-related preterm labor/birth. Collectively, these results demonstrate that iNKT-cell activation in vivo leads to late PTB by initiating innate and adaptive immune responses and suggest that the PPARγ pathway has potential as a target for prevention of this syndrome. PMID:26740111

Dendritic cell internalization of α-galactosylceramide from CD8 T cells induces potent antitumor CD8 T-cell responses.

PubMed

Choi, Dong Hoon; Kim, Kwang Soon; Yang, Se Hwan; Chung, Doo Hyun; Song, Boyeong; Sprent, Jonathan; Cho, Jae Ho; Sung, Young Chul

2011-12-15

Dendritic cells (DC) present α-galactosylceramide (αGalCer) to invariant T-cell receptor-expressing natural killer T cells (iNKT) activating these cells to secrete a variety of cytokines, which in turn results in DC maturation and activation of other cell types, including NK cells, B cells, and conventional T cells. In this study, we showed that αGalCer-pulsing of antigen-activated CD8 T cells before adoptive transfer to tumor-bearing mice caused a marked increase in donor T-cell proliferation, precursor frequency, and cytotoxic lymphocyte activity. This effect was interleukin (IL)-2 dependent and involved both natural killer T cells (NKT) and DCs, as mice lacking IL-2, NKTs, and DCs lacked any enhanced response to adoptively transferred αGalCer-loaded CD8 T cells. iNKT activation was mediated by transfer of αGalCer from the cell membrane of the donor CD8 T cells onto the αGalCer receptor CD1d which is present on host DCs. αGalCer transfer was increased by prior activation of the donor CD8 T cells and required AP-2-mediated endocytosis by host DCs. In addition, host iNKT cell activation led to strong IL-2 synthesis, thereby increasing expansion and differentiation of donor CD8 T cells. Transfer of these cells led to improved therapeutic efficacy against established solid tumors in mice. Thus, our findings illustrate how αGalCer loading of CD8 T cells after antigen activation in vitro may leverage the therapeutic potential of adoptive T-cell therapies.

Human iPSC Derived GABA Ergic Precursor Cell Therapy for Chronic Epilepsy

DTIC Science & Technology

2016-10-01

chronically epileptic rats ( CERs ) would: (1) diminish the frequency and intensity of spontaneous recurrent seizures (SRS, Specific Aim 1, SA1); and (2...epileptic rats: CERs receiving hMGE-like cell grafts and cyclosporine (an immunosuppressant to promote the survival of human cell grafts in the rat brain... CERs receiving sham-grafting surgery, CERs receiving cyclosporine only and CERs receiving no treatment. The results showed that, in comparison to

Variation in Structure and Process of Care in Traumatic Brain Injury: Provider Profiles of European Neurotrauma Centers Participating in the CENTER-TBI Study.

PubMed

Cnossen, Maryse C; Polinder, Suzanne; Lingsma, Hester F; Maas, Andrew I R; Menon, David; Steyerberg, Ewout W

2016-01-01

The strength of evidence underpinning care and treatment recommendations in traumatic brain injury (TBI) is low. Comparative effectiveness research (CER) has been proposed as a framework to provide evidence for optimal care for TBI patients. The first step in CER is to map the existing variation. The aim of current study is to quantify variation in general structural and process characteristics among centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. We designed a set of 11 provider profiling questionnaires with 321 questions about various aspects of TBI care, chosen based on literature and expert opinion. After pilot testing, questionnaires were disseminated to 71 centers from 20 countries participating in the CENTER-TBI study. Reliability of questionnaires was estimated by calculating a concordance rate among 5% duplicate questions. All 71 centers completed the questionnaires. Median concordance rate among duplicate questions was 0.85. The majority of centers were academic hospitals (n = 65, 92%), designated as a level I trauma center (n = 48, 68%) and situated in an urban location (n = 70, 99%). The availability of facilities for neuro-trauma care varied across centers; e.g. 40 (57%) had a dedicated neuro-intensive care unit (ICU), 36 (51%) had an in-hospital rehabilitation unit and the organization of the ICU was closed in 64% (n = 45) of the centers. In addition, we found wide variation in processes of care, such as the ICU admission policy and intracranial pressure monitoring policy among centers. Even among high-volume, specialized neurotrauma centers there is substantial variation in structures and processes of TBI care. This variation provides an opportunity to study effectiveness of specific aspects of TBI care and to identify best practices with CER approaches.

A New Look at the Counselor Evaluation Rating Scale.

ERIC Educational Resources Information Center

Benshoff, James M.; Thomas, Wayne P.

1992-01-01

Reexamined Counselor Evaluation Rating Scale (CERS) using confirmatory factor analysis. Analyzed 185 self-rated CERs. Findings suggest that, when counselors use CERS to rate themselves, different factors may emerge from those emerging when experienced supervisors use CERS to evaluate supervisee progress and performance. (Author/NB)

The Putative E3 Ubiquitin Ligase ECERIFERUM9 Regulates Abscisic Acid Biosynthesis and Response during Seed Germination and Postgermination Growth in Arabidopsis1[W][OPEN

PubMed Central

Zhao, Huayan; Zhang, Huoming; Cui, Peng; Ding, Feng; Wang, Guangchao; Li, Rongjun; Jenks, Matthew A.; Lü, Shiyou; Xiong, Liming

2014-01-01

The ECERIFERUM9 (CER9) gene encodes a putative E3 ubiquitin ligase that functions in cuticle biosynthesis and the maintenance of plant water status. Here, we found that CER9 is also involved in abscisic acid (ABA) signaling in seeds and young seedlings of Arabidopsis (Arabidopsis thaliana). The germinated embryos of the mutants exhibited enhanced sensitivity to ABA during the transition from reversible dormancy to determinate seedling growth. Expression of the CER9 gene is closely related to ABA levels and displays a similar pattern to that of ABSCISIC ACID-INSENSITIVE5 (ABI5), which encodes a positive regulator of ABA responses in seeds. cer9 mutant seeds exhibited delayed germination that is independent of seed coat permeability. Quantitative proteomic analyses showed that cer9 seeds had a protein profile similar to that of the wild type treated with ABA. Transcriptomics analyses revealed that genes involved in ABA biosynthesis or signaling pathways were differentially regulated in cer9 seeds. Consistent with this, high levels of ABA were detected in dry seeds of cer9. Blocking ABA biosynthesis by fluridone treatment or by combining an ABA-deficient mutation with cer9 attenuated the phenotypes of cer9. Whereas introduction of the abi1-1, abi3-1, or abi4-103 mutation could completely eliminate the ABA hypersensitivity of cer9, introduction of abi5 resulted only in partial suppression. These results indicate that CER9 is a novel negative regulator of ABA biosynthesis and the ABA signaling pathway during seed germination. PMID:24812105

Moving Beyond GDP: Cost Effectiveness of Cochlear Implantation and Deaf Education in Latin America.

PubMed

Emmett, Susan D; Tucci, Debara L; Bento, Ricardo F; Garcia, Juan M; Juman, Solaiman; Chiossone-Kerdel, Juan A; Liu, Ta J; de Muñoz, Patricia Castellanos; Ullauri, Alejandra; Letort, Jose J; Mansilla, Teresita; Urquijo, Diana P; Aparicio, Maria L; Gong, Wenfeng; Francis, Howard W; Saunders, James E

2016-09-01

Cochlear implantation (CI) and deaf education are cost effective management strategies of childhood profound sensorineural hearing loss in Latin America. CI has been widely established as cost effective in North America and Europe and is considered standard of care in those regions, yet cost effectiveness in other economic environments has not been explored. With 80% of the global hearing loss burden existing in low- and middle-income countries, developing cost effective management strategies in these settings is essential. This analysis represents the continuation of a global assessment of CI and deaf education cost effectiveness. Brazil, Colombia, Ecuador, Guatemala, Paraguay, Trinidad and Tobago, and Venezuela participated in the study. A Disability Adjusted Life Years model was applied with 3% discounting and 10-year length of analysis. Experts from each country supplied cost estimates from known costs and published data. Sensitivity analysis was performed to evaluate the effect of device cost, professional salaries, annual number of implants, and probability of device failure. Cost effectiveness was determined using the World Health Organization standard of cost effectiveness ratio/gross domestic product per capita (CER/GDP)<3. Deaf education was very cost effective in all countries (CER/GDP 0.07-0.93). CI was cost effective in all countries (CER/GDP 0.69-2.96), with borderline cost effectiveness in the Guatemalan sensitivity analysis (Max CER/GDP 3.21). Both cochlear implantation and deaf education are widely cost effective in Latin America. In the lower-middle income economy of Guatemala, implant cost may have a larger impact. GDP is less influential in the middle- and high-income economies included in this study.

A core subunit of the RNA-processing/degrading exosome specifically influences cuticular wax biosynthesis in Arabidopsis.

PubMed

Hooker, Tanya S; Lam, Patricia; Zheng, Huanquan; Kunst, Ljerka

2007-03-01

The cuticle is an extracellular matrix composed of cutin polyester and waxes that covers aerial organs of land plants and protects them from environmental stresses. The Arabidopsis thaliana cer7 mutant exhibits reduced cuticular wax accumulation and contains considerably lower transcript levels of ECERIFERUM3/WAX2/YORE-YORE (CER3/WAX2/YRE), a key wax biosynthetic gene. We show here that CER7 protein is a putative 3'-5' exoribonuclease homologous to yeast Ribonuclease PH45 (RRP45p), a core subunit of the RNA processing and degrading exosome that controls the expression of CER3/WAX2/YRE. We propose that CER7 acts by degrading a specific mRNA species encoding a negative regulator of CER3/WAX2/YRE transcription. A second RRP45p homolog found in Arabidopsis, designated At RRP45a, is partially functionally redundant with CER7, and complete loss of RRP45 function in Arabidopsis is lethal. To our knowledge, CER7 is currently the only example of a core exosomal subunit specifically influencing a cellular process.

The Putative E3 Ubiquitin Ligase ECERIFERUM9 Regulates Abscisic Acid Biosynthesis and Response during Seed Germination and Postgermination Growth in Arabidopsis.

PubMed

Zhao, Huayan; Zhang, Huoming; Cui, Peng; Ding, Feng; Wang, Guangchao; Li, Rongjun; Jenks, Matthew A; Lü, Shiyou; Xiong, Liming

2014-07-01

The ECERIFERUM9 (CER9) gene encodes a putative E3 ubiquitin ligase that functions in cuticle biosynthesis and the maintenance of plant water status. Here, we found that CER9 is also involved in abscisic acid (ABA) signaling in seeds and young seedlings of Arabidopsis (Arabidopsis thaliana). The germinated embryos of the mutants exhibited enhanced sensitivity to ABA during the transition from reversible dormancy to determinate seedling growth. Expression of the CER9 gene is closely related to ABA levels and displays a similar pattern to that of ABSCISIC ACID-INSENSITIVE5 (ABI5), which encodes a positive regulator of ABA responses in seeds. cer9 mutant seeds exhibited delayed germination that is independent of seed coat permeability. Quantitative proteomic analyses showed that cer9 seeds had a protein profile similar to that of the wild type treated with ABA. Transcriptomics analyses revealed that genes involved in ABA biosynthesis or signaling pathways were differentially regulated in cer9 seeds. Consistent with this, high levels of ABA were detected in dry seeds of cer9. Blocking ABA biosynthesis by fluridone treatment or by combining an ABA-deficient mutation with cer9 attenuated the phenotypes of cer9. Whereas introduction of the abi1-1, abi3-1, or abi4-103 mutation could completely eliminate the ABA hypersensitivity of cer9, introduction of abi5 resulted only in partial suppression. These results indicate that CER9 is a novel negative regulator of ABA biosynthesis and the ABA signaling pathway during seed germination. © 2014 American Society of Plant Biologists. All Rights Reserved.

Glucosylceramide is Critical for Cell-Type Differentiation and Organogenesis, but not for Cell Viability in Arabidopsis

PubMed Central

Msanne, Joseph; Chen, Ming; Luttgeharm, Kyle D.; Bradley, Amanda M.; Mays, Elizabeth S.; Paper, Janet M.; Boyle, Daniel L.; Cahoon, Rebecca E.; Schrick, Kathrin; Cahoon, Edgar B.

2015-01-01

Summary Glucosylceramides (GlcCer), glucose-conjugated sphingolipids, are major components of the endomembrane system and plasma membrane in most eukaryote cells. Yet, the quantitative significance and cellular functions of GlcCer are not well characterized in plants and other multi-organ eukaryotes. To address this, we examined Arabidopsis lines lacking or deficient in GlcCer by insertional disruption or by RNAi suppression of the single gene for GlcCer synthase (GCS, At2g19880), the enzyme that catalyzes GlcCer synthesis. Null mutants for GCS (designated “gcs-1”) were viable as seedlings, albeit strongly reduced in size, and failed to develop beyond the seedling stage. Heterozygous plants harboring the insertion allele exhibited reduced transmission through the male gametophyte. Undifferentiated calli generated from gcs-1 seedlings and lacking GlcCer proliferated in a manner similar to calli from wild-type plants. However, gcs-1 calli, in contrast to wild-type calli, were unable to develop organs on differentiation media. Consistent with a role for GlcCer in organ-specific cell differentiation, calli from gcs-1 mutants formed roots and leaves on media supplemented with the glucosylated sphingosine glucopsychosine, which was readily converted to GlcCer independent of GCS. Underlying these phenotypes, gcs-1 cells had altered Golgi morphology and fewer cisternae per Golgi apparatus relative to wild-type cells, indicative of protein trafficking defects. Despite seedling lethality in the null mutant, GCS RNAi suppression lines with ≤2% of wild-type GlcCer levels were viable and fertile. Collectively, these results indicate that GlcCer are essential for cell-type differentiation and organogenesis, and plant cells produce GlcCer amounts in excess of that required for normal development. PMID:26313010

CER4 Encodes an Alcohol-Forming Fatty Acyl-Coenzyme A Reductase Involved in Cuticular Wax Production in Arabidopsis1[W

PubMed Central

Rowland, Owen; Zheng, Huanquan; Hepworth, Shelley R.; Lam, Patricia; Jetter, Reinhard; Kunst, Ljerka

2006-01-01

A waxy cuticle that serves as a protective barrier against uncontrolled water loss and environmental damage coats the aerial surfaces of land plants. It is composed of a cutin polymer matrix and waxes. Cuticular waxes are complex mixtures of very-long-chain fatty acids and their derivatives. We report here the molecular cloning and characterization of CER4, a wax biosynthetic gene from Arabidopsis (Arabidopsis thaliana). Arabidopsis cer4 mutants exhibit major decreases in stem primary alcohols and wax esters, and slightly elevated levels of aldehydes, alkanes, secondary alcohols, and ketones. This phenotype suggested that CER4 encoded an alcohol-forming fatty acyl-coenzyme A reductase (FAR). We identified eight FAR-like genes in Arabidopsis that are highly related to an alcohol-forming FAR expressed in seeds of jojoba (Simmondsia chinensis). Molecular characterization of CER4 alleles and genomic complementation revealed that one of these eight genes, At4g33790, encoded the FAR required for cuticular wax production. Expression of CER4 cDNA in yeast (Saccharomyces cerevisiae) resulted in the accumulation of C24:0 and C26:0 primary alcohols. Fully functional green fluorescent protein-tagged CER4 protein was localized to the endoplasmic reticulum in yeast cells by confocal microscopy. Analysis of gene expression by reverse transcription-PCR indicated that CER4 was expressed in leaves, stems, flowers, siliques, and roots. Expression of a β-glucuronidase reporter gene driven by the CER4 promoter in transgenic plants was detected in epidermal cells of leaves and stems, consistent with a dedicated role for CER4 in cuticular wax biosynthesis. CER4 was also expressed in all cell types in the elongation zone of young roots. These data indicate that CER4 is an alcohol-forming FAR that has specificity for very-long-chain fatty acids and is responsible for the synthesis of primary alcohols in the epidermal cells of aerial tissues and in roots. PMID:16980563

KCa 3.1 upregulation preserves endothelium-dependent vasorelaxation during aging and oxidative stress.

PubMed

Choi, Shinkyu; Kim, Ji Aee; Li, Hai-Yan; Shin, Kyong-Oh; Oh, Goo Taeg; Lee, Yong-Moon; Oh, Seikwan; Pewzner-Jung, Yael; Futerman, Anthony H; Suh, Suk Hyo

2016-10-01

Endothelial oxidative stress develops with aging and reactive oxygen species impair endothelium-dependent relaxation (EDR) by decreasing nitric oxide (NO) availability. Endothelial KCa 3.1, which contributes to EDR, is upregulated by H2 O2 . We investigated whether KCa 3.1 upregulation compensates for diminished EDR to NO during aging-related oxidative stress. Previous studies identified that the levels of ceramide synthase 5 (CerS5), sphingosine, and sphingosine 1-phosphate were increased in aged wild-type and CerS2 mice. In primary mouse aortic endothelial cells (MAECs) from aged wild-type and CerS2 null mice, superoxide dismutase (SOD) was upregulated, and catalase and glutathione peroxidase 1 (GPX1) were downregulated, when compared to MAECs from young and age-matched wild-type mice. Increased H2 O2 levels induced Fyn and extracellular signal-regulated kinases (ERKs) phosphorylation and KCa 3.1 upregulation. Catalase/GPX1 double knockout (catalase(-/-) /GPX1(-/-) ) upregulated KCa 3.1 in MAECs. NO production was decreased in aged wild-type, CerS2 null, and catalase(-/-) /GPX1(-/-) MAECs. However, KCa 3.1 activation-induced, N(G) -nitro-l-arginine-, and indomethacin-resistant EDR was increased without a change in acetylcholine-induced EDR in aortic rings from aged wild-type, CerS2 null, and catalase(-/-) /GPX1(-/-) mice. CerS5 transfection or exogenous application of sphingosine or sphingosine 1-phosphate induced similar changes in levels of the antioxidant enzymes and upregulated KCa 3.1. Our findings suggest that, during aging-related oxidative stress, SOD upregulation and downregulation of catalase and GPX1, which occur upon altering the sphingolipid composition or acyl chain length, generate H2 O2 and thereby upregulate KCa 3.1 expression and function via a H2 O2 /Fyn-mediated pathway. Altogether, enhanced KCa 3.1 activity may compensate for decreased NO signaling during vascular aging. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Receptor Structure for F1C Fimbriae of Uropathogenic Escherichia coli

PubMed Central

Khan, A. Salam; Kniep, Bernhard; Oelschlaeger, Tobias A.; Van Die, Irma; Korhonen, Timo; Hacker, Jörg

2000-01-01

F1C fimbriae are correlated with uropathogenic Escherichia coli strains. Although F1C fimbriae mediate binding to kidney tubular cells, their receptor is not known. In this paper, we demonstrate for the first time specific carbohydrate residues as receptor structure for F1C-fimbria-expressing E. coli. The binding of the F1C fimbriated recombinant E. coli strain HB101(pPIL110-54) and purified F1C fimbriae to reference glycolipids of different carbohydrate compositions was evaluated by using thin-layer chromatography (TLC) overlay and solid-phase binding assays. TLC fimbrial overlay analysis revealed the binding ability of purified F1C fimbriae only to glucosylceramide (GlcCer), β1-linked galactosylceramide 2 (GalCer2) with nonhydroxy fatty acids, lactosylceramide, globotriaosylceramide, paragloboside (nLc4Cer), lactotriaosylceramide, gangliotriaosylceramide (asialo-GM2 [GgO3Cer]) and gangliotetraosylceramide (asialo-GM1 [GgO4Cer]). The binding of purified F1C fimbriae as well as F1C fimbriated recombinant E. coli strain HB101(pPIL110-54) was optimal to microtiter plates coated with asialo-GM2 (GgO3Cer). The bacterial interaction with asialo-GM1 (GgO4Cer) and asialo-GM2 (GgO3Cer) was strongly inhibited only by disaccharide GalNAcβ1-4Galβ linked to bovine serum albumin. We observed no binding to globotetraosylceramide or Forssman antigen (Gb5Cer) glycosphingolipids or to sialic-acid-containing gangliosides. It was demonstrated that the presence of a GalCer or GlcCer residue alone is not sufficient for optimal binding, and additional carbohydrate residues are required for high-affinity adherence. Indeed, the binding efficiency of F1C fimbriated recombinant bacteria increased by 19-fold when disaccharide sequence GalNAcβ1-4Galβ is linked to glucosylceramide as in asialo-GM2 (GgO3Cer). Thus, it is suggested that the disaccharide sequence GalNAcβ1-4Galβ of asialo-GM2 (GgO3Cer) which is positioned internally in asialo-GM1 (GgO4Cer) is the high-affinity binding epitope for the F1C fimbriae of uropathogenic E. coli. PMID:10816509

Effect of thermal cycling. Final report, April 1985-January 1987

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

Jacobs, S.F.

The objective of this effort is to evaluate the stability of low expansion Zerodur, developmental Zerodur, ULE, and Cer-Vit as possible substrate materials for high energy laser mirrors. This effort will determine whether there is instability in developmental Zerodur, ULE and Cer-Vit over operating temperatures and coating temperatures (300-475K). Zerodur has already been shown to exhibit instability. Thermal cycling will be investigated as a possible approach to eliminate or reduce hysteresis. The effect of polishing on hysteresis will also be investigated.

Effect of thermal cycling

NASA Astrophysics Data System (ADS)

Jacobs, Stephen F.

1988-05-01

The objective of this effort is to evaluate the stability of low expansion Zerodur, developmental Zerodur, ULE, and Cer-Vit as possible substrate materials for high energy laser mirrors. This effort will determine whether there is instability in developmental Zerodur, ULE and Cer-Vit over operating temperatures and coating temperatures (300 to 475 K). Zerodur has already been shown to exhibit instability. Thermal cycling will be investigated as a possible approach to eliminate or reduce hysteresis. The effect of polishing on hysteresis will also be investigated.

Cost effectiveness of response-guided therapy with peginterferon in the treatment of chronic hepatitis B.

PubMed

Lo, Angeline Oi-Shan; Wong, Vincent Wai-Sun; Wong, Grace Lai-Hung; Chan, Henry Lik-Yuen; Dan, Yock-Young

2015-02-01

The high prevalence of chronic hepatitis B in Asian countries produces a substantial economic burden. Peginterferon has immunomodulatory effects and a finite course for treatment of hepatitis B, but also a high cost and side effects. The recent introduction of a 12-week stopping rule (stopping treatment after 12 weeks) has increased its appeal as a first-line treatment for hepatitis B. We aimed to determine the cost effectiveness of the 12-week stopping rule for peginterferon in hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients. We used Markov modeling, with data from the Hong Kong population, to compare the cost effectiveness of peginterferon therapy with a 12-week stopping rule vs conventional therapy (48 weeks) and with other antiviral agents. For HBeAg-positive patients, stopping peginterferon therapy after 12 weeks had the lowest cost-effectiveness ratio (CER), of $9501/quality-adjusted life-year (QALY), compared with no treatment, making it the most cost-effective option. Conventional (48-week) peginterferon treatment had a CER of $9664/QALY. For HBeAg-negative patients, entecavir had the lowest CER ($34,310/QALY). Entecavir was more cost effective than either peginterferon strategies (CERs of $37,423/QALY for 12 weeks of peginterferon and $38,474/QALY for 48 weeks of treatment). The 12-week stopping rule increases the cost effectiveness of peginterferon therapy, and is the most cost-effective treatment for HBeAg-positive patients. The need for long-term antiviral therapy for HBeAg-negative patients makes entecavir the most cost-effective strategy. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

Stress, chemical defense agents, and cholinergic receptors. Midterm report, 1 November 1987-31 July 1989

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

Lane, J.D.

1989-11-30

This project is assessing the affects of exposure to a chemical defense agent on anxiety and stress, by using rat models of anxiety (conditioned emotional response (CER); conditioned suppression) and unconditioned non-specific stres (exposure to footshock). The specific experiments determined the plasticity of muscarinic cholinergic binding sites in the central nervous system. The neuroanatomical locus and neuropharmacological profile of changes in binding sites were assessed in brain areas enriched in cholinergic markers. Acetylcholine turnover was measured to determine if the receptor response is compensatory or independent. The effects of acute exposure to doses of a chemical defense agent (soman--XGD) onmore » lethality and behaviors were examined. The experiments involved training and conditioning adult rats to CER using standard operant/respondent techniques. The binding of radiolabelled ligand was studied in vitro using brain membranes and tissue sections (autoradiography). The major findings are that CER produces increases in acetylcholine turnover in brain areas involved in anxiety, and that primarily post-synaptic M1 receptors compensatorly decrease in response. These neurochemical phenomena are directly correlated with several behaviors, including onset and extinction of CER and non-specific stress. Followup experiments have been designed to test the interaction of CER, XGD and neurochemistry.« less

Up-regulation of tumor suppressor genes by exogenous dhC16-Cer contributes to its anti-cancer activity in primary effusion lymphoma

PubMed Central

Lin, Zhen; Zabaleta, Jovanny; Dai, Lu; Qin, Zhiqiang

2017-01-01

Primary effusion lymphoma (PEL) is a rare and highly aggressive B-cell malignancy with Kaposi's sarcoma-associated herpesvirus (KSHV) infection, while lack of effective therapies. Our recent data indicated that targeting the sphingolipid metabolism by either sphingosine kinase inhibitor or exogenous ceramide species induces PEL cell apoptosis and suppresses tumor progression in vivo. However, the underlying mechanisms for these exogenous ceramides “killing” PEL cells remain largely unknown. Based on the microarray analysis, we found that exogenous dhC16-Cer treatment affected the expression of many cellular genes with important functions within PEL cells such as regulation of cell cycle, cell survival/proliferation, and apoptosis/anti-apoptosis. Interestingly, we found that a subset of tumor suppressor genes (TSGs) was up-regulated from dhC16-Cer treated PEL cells. One of these elevated TSGs, Thrombospondin-1 (THBS1) was required for dhC16-Cer induced PEL cell cycle arrest. Moreover, dhC16-Cer up-regulation of THBS1 was through the suppression of multiple KSHV microRNAs expression. Our data demonstrate that exogenous ceramides display anti-cancer activities for PEL through regulation of both host and oncogenic virus factors. PMID:28146424

New Insights on Non-Enzymatic Oxidation of Ganglioside GM1 Using Mass Spectrometry

NASA Astrophysics Data System (ADS)

Couto, Daniela; Melo, Tânia; Maciel, Elisabete; Campos, Ana; Alves, Eliana; Guedes, Sofia; Domingues, M. Rosário M.; Domingues, Pedro

2016-12-01

Gangliosides are acidic glycosphingolipids that are present in cell membranes and lipid raft domains, being particularly abundant in central nervous systems. They participate in modulating cell membrane properties, cell-cell recognition, cell regulation, and signaling. Disturbance in ganglioside metabolism has been correlated with the development of diseases, such as neurodegenerative diseases, and in inflammation. Both conditions are associated with an increased production of reactive oxidation species (ROS) that can induce changes in the structure of biomolecules, including lipids, leading to the loss or modification of their function. Oxidized phospholipids are usually involved in chronic diseases and inflammation. However, knowledge regarding oxidation of gangliosides is scarce. In order to evaluate the effect of ROS in gangliosides, an in vitro biomimetic model system was used to study the susceptibility of GM1 (Neu5Ac α2-3(Gal β1-3GalNAc β1-4)Gal β1-4Glc β1Cer) to undergo oxidative modifications. Oxidation of GM1 under Fenton reaction conditions was monitored using high resolution electrospray ionization-mass spectrometry (ESI-MS) and tandem mass spectrometry (ESI-MS/MS). Upon oxidation, GM1 underwent oxidative cleavages in the carbohydrate chain, leading to the formation of other gangliosides GM2 (GalNAcβ1-4Gal(Neu5Acα2-3)1-4Glcβ1Cer), GM3 (Neu5Acα2-3Galβ1-4Glcβ1Cer), asialo-GM1 (Gal β1-3GalNAc β1-4Gal β1-4Glc β1Cer), asialo-GM2 (GalNAc β1-4Gal β1-4Glc β1Cer), of the small glycolipids lactosylceramide (LacCer), glucosylceramide (GlcCer), and of ceramide (Cer). In addition, oxygenated GM1 and GM2 (as keto and hydroxy derivatives), glycans, oxidized glycans, and oxidized ceramides were also identified. Nonenzymatic oxidation of GM1 under oxidative stress contributes to the generation of other gangliosides that may participate in the imbalance of gangliosides metabolism in vivo, through uncontrolled enzymatic pathways and, consequently, play some role in neurodegenerative processes.

Wolbachia infections and superinfections in cytoplasmically incompatible populations of the European cherry fruit fly Rhagoletis cerasi (Diptera, Tephritidae).

PubMed

Riegler, Markus; Stauffer, Christian

2002-11-01

Wolbachia is an obligately intracellular, maternally inherited bacterium which has been detected in many arthropods. Wolbachia infections disperse in host populations by mechanisms such as cytoplasmic incompatibility (CI). CI leads to embryonic mortality which occurs when infected males mate with uninfected females or females with a different Wolbachia strain. Populations of the European cherry fruit fly Rhagoletis cerasi (Diptera, Tephritidae) were found to be infected by two different Wolbachia strains, wCer1 and wCer2. Superinfections with both strains occurred throughout southern and central Europe and infections with wCer1 were found in northern, western and eastern Europe. Strong unidirectional CI between European populations of R. cerasi were first reported in the 1970s. From the conformity in the recent geographical distribution of the Wolbachia infections and the CI expression patterns found 25 years ago it was deduced that wCer2 potentially causes CI in R. cerasi. The comparison of the geographical distributions indicated that wCer1 + 2 must have spread into wCer1-infected populations in some areas. In other regions, a spread of wCer1 + 2 was probably prevented by dispersal barriers. There, a sharp transition from infected to superinfected populations suggested regional isolation between wCer1 and wCer1 + 2-infected populations.

Evidence for Fumonisin inhibition of ceramide synthase in humans: validation in follow-up studies in Guatemala

USDA-ARS?s Scientific Manuscript database

Fumonisins (FB) are mycotoxins found in corn. FB1 is the most common FB. It is the cause of farm animal diseases and is carcinogenic in rodents. The mode of action is the inhibition of ceramide synthase (CerS). Inhibition of CerS in mice causes a dose-dependent accumulation of sphinganine 1-phosphat...

Ceramide synthase inhibition causes accumulation of 1-deoxysphinganine: biosynthesis of a novel category of bioactive sphingoid bases in diverse mammalian cell linesa and mice

USDA-ARS?s Scientific Manuscript database

Fumonisins (FB) are mycotoxins that inhibit ceramide synthases (CerS) and cause animal and plant disease. Inhibition of CerS results in a rapid increases in sphinganine (Sa), an intermediate of de novo sphingolipid biosynthesis, sphinganine 1-phosphate, and a previously unidentified metabolite tha...

Host CD40 Is Essential for DCG Treatment Against Metastatic Lung Cancer.

PubMed

Yamashita, Kimihiro; Hasegawa, Hiroshi; Fujita, Mitsugu; Nishi, Masayasu; Tanaka, Tomoko; Arimoto, Akira; Suzuki, Satoshi; Kamigaki, Takashi; Kakeji, Yoshihiro

2016-07-01

For the application of invariant natural killer T (iNKT) cells in cancer therapy, the CD40-CD40L interaction is indispensable in administering alpha-galactosylceramide (αGalCer). We hypothesized that CD40 plays an important role in dendritic cells (DC) pulsed with αGalCer (DCGs) in the treatment of lung metastases. Wild-type (WT) and CD40(-/-) mice were treated with DCGs isolated from WT or CD40(-/-) mice in a B16F10 lung metastases model and NK and NKT cell activity in lungs and the spleen were examined. DCG treatment improved WT mice survival but CD40(-/-) hosts received no survival benefit. Conversely, attenuation of a therapeutic effect in mice treated with CD40(-/-) DCGs was not observed. The functional activities of NK and NKT cells in DCG-treated CD40(-/-) mice were partially suppressed. Host CD40 is essential for DCG treatment to have a therapeutic effect on B16F10 lung metastases. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Inhibitors of dihydroceramide desaturase 1: Therapeutic agents and pharmacological tools to decipher the role of dihydroceramides in cell biology.

PubMed

Casasampere, Mireia; Ordoñez, Yadira F; Pou, Ana; Casas, Josefina

2016-05-01

Dihydroceramide desaturase (Des1) is the last enzyme in the de novo synthesis of ceramides (Cer). It catalyzes the insertion of a double bond into dihydroceramides (dhCer) to convert them to Cer, both of which are further metabolized to more complex (dihydro) sphingolipids. For many years dhCer have received poor attention, mainly due to their supposed lack of biological activity. It was not until about ten years ago that the concept that dhCer might have regulatory roles in biology emerged for the first time. Since then, multiple publications have established that dhCer are implicated in a wide spectrum of biological processes. Physiological and pathophysiological functions of dhCer have been recently reviewed. In this review we will focus on the biochemical features of Des1 and on its inhibition by different compounds with presumably different modes of action. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Stimulation of a shorter duration in the state of anergy by an invariant natural killer T cell agonist enhances its efficiency of protection from type 1 diabetes

PubMed Central

Tohn, R; Blumenfeld, H; Haeryfar, S M M; Veerapen, N; Besra, G S; Porcelli, S A; Delovitch, T L

2011-01-01

We have reported previously that treatment of non-obese diabetic (NOD) mice with the invariant natural killer T (iNK T) cell agonist α-galactosylceramide C26:0 (α-GalCer) or its T helper type 2 (Th2)-biasing derivative α-GalCer C20:2 (C20:2) protects against type 1 diabetes (T1D), with C20:2 yielding greater protection. After an initial response to α-GalCer, iNK T cells become anergic upon restimulation. While such anergic iNK T cells can induce tolerogenic dendritic cells (DCs) that mediate protection from T1D, chronic administration of α-GalCer also results in long-lasting anergy accompanied by significantly reduced iNK T cell frequencies, which raises concerns about its long-term therapeutic use. In this study, our objective was to understand more clearly the roles of anergy and induction of tolerogenic DCs in iNK T cell-mediated protection from T1D and to circumvent potential complications associated with α-GalCer. We demonstrate that NOD iNK T cells activated during multi-dose (MD) treatment in vivo with C20:2 enter into and exit from anergy more rapidly than after activation by α-GalCer. Importantly, this shorter duration of iNK T cells in the anergic state promotes the more rapid induction of tolerogenic DCs and reduced iNK T cell death, and enables C20:2 stimulated iNK T cells to elicit enhanced protection from T1D. Our findings further that suggest C20:2 is a more effective therapeutic drug than α-GalCer for protection from T1D. Moreover, the characteristics of C20:2 provide a basis of selection of next-generation iNK T cell agonists for the prevention of T1D. PMID:21361909

Health economic impacts and cost-effectiveness of aflatoxin-reduction strategies in Africa: case studies in biocontrol and post-harvest interventions.

PubMed

Wu, F; Khlangwiset, P

2010-04-01

Advances in health economics have proven useful in evaluating the cost-effectiveness of interventions, where the benefit usually takes the form of improved health outcomes rather than market outcomes. The paper performs health-based cost-effectiveness analyses of two potential aflatoxin control strategies in Africa: (1) pre-harvest biocontrol, using atoxigenic strains of Aspergillus flavus competitively to exclude toxigenic strains from colonizing maize in Nigeria; and (2) post-harvest interventions in a package to reduce aflatoxin accumulation in groundnuts in Guinea. It is described how health benefits gained from each intervention, in terms of fewer aflatoxin-induced hepatocellular carcinoma cases, can be compared with the costs of implementing the interventions. It is found that both interventions would be extremely cost-effective if applied widely in African agriculture. That is, the monetized value of lives saved and quality of life gained by reducing aflatoxin-induced hepatocellular carcinoma far exceeds the cost of either biocontrol or the post-harvest intervention package to achieve those health benefits. The estimated cost-effectiveness ratio (CER; gross domestic product multiplied by disability-adjusted life years saved per unit cost) for biocontrol in Nigerian maize ranged from 5.10 to 24.8; while the estimated CER for the post-harvest intervention package in Guinean groundnuts ranged from 0.21 to 2.08. Any intervention with a CER > 1 is considered by the World Health Organization (WHO) to be 'very cost-effective', while an intervention with a CER > 0.33 is considered 'cost-effective'. Aside from cost-effectiveness, public health interventions must be readily accepted by the public, and must have financial and infrastructural support to be feasible in the parts of the world where they are most needed.

Economic Analysis of Children’s Surgical Care in Low- and Middle-Income Countries: A Systematic Review and Analysis

PubMed Central

Poenaru, Dan; Ozgediz, Doruk; Ameh, Emmanuel A.; Farmer, Diana; Smith, Emily R.; Rice, Henry E.

2016-01-01

Background Understanding the economic value of health interventions is essential for policy makers to make informed resource allocation decisions. The objective of this systematic review was to summarize available information on the economic impact of children’s surgical care in low- and middle-income countries (LMICs). Methods We searched MEDLINE (Pubmed), Embase, and Web of Science for relevant articles published between Jan. 1996 and Jan. 2015. We summarized reported cost information for individual interventions by country, including all costs, disability weights, health outcome measurements (most commonly disability-adjusted life years [DALYs] averted) and cost-effectiveness ratios (CERs). We calculated median CER as well as societal economic benefits (using a human capital approach) by procedure group across all studies. The methodological quality of each article was assessed using the Drummond checklist and the overall quality of evidence was summarized using a scale adapted from the Agency for Healthcare Research and Quality. Findings We identified 86 articles that met inclusion criteria, spanning 36 groups of surgical interventions. The procedure group with the lowest median CER was inguinal hernia repair ($15/DALY). The procedure group with the highest median societal economic benefit was neurosurgical procedures ($58,977). We found a wide range of study quality, with only 35% of studies having a Drummond score ≥ 7. Interpretation Our findings show that many areas of children’s surgical care are extremely cost-effective in LMICs, provide substantial societal benefits, and are an appropriate target for enhanced investment. Several areas, including inguinal hernia repair, trichiasis surgery, cleft lip and palate repair, circumcision, congenital heart surgery and orthopedic procedures, should be considered “Essential Pediatric Surgical Procedures” as they offer considerable economic value. However, there are major gaps in existing research quality and methodology which limit our current understanding of the economic value of surgical care. PMID:27792792

Detecting changes in tree health and productivity in silver fir-beech forests of Slovenia

Treesearch

N. Torelli; W.C. Shortle; K. Cufar; F. Ferlin; K.T. Smith

1999-01-01

Cambial electrical resistance (CER) was used as an objective measure of vitality of silver fir (Abies alba) in the forests of Slovenia. Trees were rated during the growing season by CER and a subjective crown status index (CSI). Both CER and CSI were inversely correlated to annual ring width increment. Using both CER and CSI, fir were assigned to...

Latent Inhibition as a Function of US Intensity in a Two-Stage CER Procedure

ERIC Educational Resources Information Center

Rodriguez, Gabriel; Alonso, Gumersinda

2004-01-01

An experiment is reported in which the effect of unconditioned stimulus (US) intensity on latent inhibition (LI) was examined, using a two-stage conditioned emotional response (CER) procedure in rats. A tone was used as the pre-exposed and conditioned stimulus (CS), and a foot-shock of either a low (0.3 mA) or high (0.7 mA) intensity was used as…

Characterization and evaluation of stabilized particulate formulations as therapeutic oral vaccines for allergy.

PubMed

Kaneko, Kan; McDowell, Arlene; Ishii, Yasuyuki; Hook, Sarah

2017-09-05

Allergic conditions affect more than a quarter of the population in developed countries, but currently available treatments focus more on symptom relief than treating the underlying atopic condition. α-Galactosylceramide (α-GalCer) is a potent immunomodulating compound that has been shown to have a regulatory effect when delivered systemically in nanoparticles. Parenteral delivery is not preferred for chronic conditions, such as allergy, and therefore, the aim of this study was to determine whether a regulatory response could be induced through oral administration in a model of atopy through incorporation of α-GalCer into stable particulate formulations (cationic liposomes, polymerized liposomes and poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs)). The formulations showed only minor changes in particle size, polydispersity index and retention of the model antigen ovalbumin (OVA) during incubation in simulated gastrointestinal (GI) conditions. Oral delivery of α-GalCer in cationic liposomes could induce immunostimulating effects systemically, as seen through increases in serum IgG antibody levels, whereas delivery of α-GalCer in polymerized liposomes and PLGA NPs induced local cytokine changes in the mesenteric lymph nodes (MLNs). The generated responses did not exhibit tolerogenic traits which could be useful for immunoregulation, but the responses generated varied between formulations and suggests that further characterization and optimization could lead to the desired immune response.

Probing the role of ceramide hydroxylation in skin barrier lipid models by 2H solid-state NMR spectroscopy and X-ray powder diffraction.

PubMed

Kováčik, Andrej; Vogel, Alexander; Adler, Juliane; Pullmannová, Petra; Vávrová, Kateřina; Huster, Daniel

2018-05-01

In this work, we studied model stratum corneum lipid mixtures composed of the hydroxylated skin ceramides N-lignoceroyl 6-hydroxysphingosine (Cer[NH]) and α-hydroxylignoceroyl phytosphingosine (Cer[AP]). Two model skin lipid mixtures of the composition Cer[NH] or Cer[AP], N-lignoceroyl sphingosine (Cer[NS]), lignoceric acid (C24:0) and cholesterol in a 0.5:0.5:1:1 molar ratio were compared. Model membranes were investigated by differential scanning calorimetry and 2 H solid-state NMR spectroscopy at temperatures from 25 °C to 80 °C. Each component of the model mixture was specifically deuterated for selective detection by 2 H NMR. Thus, the exact phase composition of the mixture at varying temperatures could be quantified. Moreover, using X-ray powder diffraction we investigated the lamellar phase formation. From the solid-state NMR and DSC studies, we found that both hydroxylated Cer[NH] and Cer[AP] exhibit a similar phase behavior. At physiological skin temperature of 32 °C, the lipids form a crystalline (orthorhombic) phase. With increasing temperature, most of the lipids become fluid and form a liquid-crystalline phase, which converts to the isotropic phase at higher temperatures (65-80 °C). Interestingly, lignoceric acid in the Cer[NH]-containing mixture has a tendency to form two types of fluid phases at 65 °C. This tendency was also observed in Cer[AP]-containing membranes at 80 °C. While Cer[AP]-containing lipid models formed a short periodicity phase featuring a repeat spacing of d = 5.4 nm, in the Cer[NH]-based model skin lipid membranes, the formation of unusual long periodicity phase with a repeat spacing of d = 10.7 nm was observed. Copyright © 2018 Elsevier B.V. All rights reserved.

Enhancing Comparative Effectiveness Research With Automated Pediatric Pneumonia Detection in a Multi-Institutional Clinical Repository: A PHIS+ Pilot Study.

PubMed

Meystre, Stephane; Gouripeddi, Ramkiran; Tieder, Joel; Simmons, Jeffrey; Srivastava, Rajendu; Shah, Samir

2017-05-15

Community-acquired pneumonia is a leading cause of pediatric morbidity. Administrative data are often used to conduct comparative effectiveness research (CER) with sufficient sample sizes to enhance detection of important outcomes. However, such studies are prone to misclassification errors because of the variable accuracy of discharge diagnosis codes. The aim of this study was to develop an automated, scalable, and accurate method to determine the presence or absence of pneumonia in children using chest imaging reports. The multi-institutional PHIS+ clinical repository was developed to support pediatric CER by expanding an administrative database of children's hospitals with detailed clinical data. To develop a scalable approach to find patients with bacterial pneumonia more accurately, we developed a Natural Language Processing (NLP) application to extract relevant information from chest diagnostic imaging reports. Domain experts established a reference standard by manually annotating 282 reports to train and then test the NLP application. Findings of pleural effusion, pulmonary infiltrate, and pneumonia were automatically extracted from the reports and then used to automatically classify whether a report was consistent with bacterial pneumonia. Compared with the annotated diagnostic imaging reports reference standard, the most accurate implementation of machine learning algorithms in our NLP application allowed extracting relevant findings with a sensitivity of .939 and a positive predictive value of .925. It allowed classifying reports with a sensitivity of .71, a positive predictive value of .86, and a specificity of .962. When compared with each of the domain experts manually annotating these reports, the NLP application allowed for significantly higher sensitivity (.71 vs .527) and similar positive predictive value and specificity . NLP-based pneumonia information extraction of pediatric diagnostic imaging reports performed better than domain experts in this pilot study. NLP is an efficient method to extract information from a large collection of imaging reports to facilitate CER. ©Stephane Meystre, Ramkiran Gouripeddi, Joel Tieder, Jeffrey Simmons, Rajendu Srivastava, Samir Shah. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 15.05.2017.

Accumulation of 1-Deoxysphinganine in mammalian cells and tissues following fumonisin inhibition of ceramide synthase: a novel category of bioactive sphingoid bases and 1-Deoxydihydroceramides

USDA-ARS?s Scientific Manuscript database

Fumonisin B1(FB) is a mycotoxin that inhibits ceramide synthases (CerS) and causes kidney and liver toxicity and other disease. CerS inhibition increases sphinganine (Sa), Sa 1-phosphate and a novel sphingoid base, 1-deoxysphinganine (1-deoxySa). The purpose of this study was to i) determine the cyt...

Activation of iNKT cells by a distinct constituent of the endogenous glucosylceramide fraction

PubMed Central

Brennan, Patrick J.; Tatituri, Raju V. V.; Heiss, Christian; Watts, Gerald F. M.; Hsu, Fong-Fu; Veerapen, Natacha; Cox, Liam R.; Azadi, Parastoo; Besra, Gurdyal S.; Brenner, Michael B.

2014-01-01

Invariant natural killer T (iNKT) cells are a specialized T-cell subset that recognizes lipids as antigens, contributing to immune responses in diverse disease processes. Experimental data suggests that iNKT cells can recognize both microbial and endogenous lipid antigens. Several candidate endogenous lipid antigens have been proposed, although the contextual role of specific antigens during immune responses remains largely unknown. We have previously reported that mammalian glucosylceramides (GlcCers) activate iNKT cells. GlcCers are found in most mammalian tissues, and exist in variable molecular forms that differ mainly in N-acyl fatty acid chain use. In this report, we purified, characterized, and tested the GlcCer fractions from multiple animal species. Although activity was broadly identified in these GlcCer fractions from mammalian sources, we also found activity properties that could not be reconciled by differences in fatty acid chain use. Enzymatic digestion of β-GlcCer and a chromatographic separation method demonstrated that the activity in the GlcCer fraction was limited to a rare component of this fraction, and was not contained within the bulk of β-GlcCer molecular species. Our data suggest that a minor lipid species that copurifies with β-GlcCer in mammals functions as a lipid self antigen for iNKT cells. PMID:25197085

Impairment of ceramide synthesis causes a novel progressive myoclonus epilepsy.

PubMed

Vanni, Nicola; Fruscione, Floriana; Ferlazzo, Edoardo; Striano, Pasquale; Robbiano, Angela; Traverso, Monica; Sander, Thomas; Falace, Antonio; Gazzerro, Elisabetta; Bramanti, Placido; Bielawski, Jacek; Fassio, Anna; Minetti, Carlo; Genton, Pierre; Zara, Federico

2014-08-01

Alterations of sphingolipid metabolism are implicated in the pathogenesis of many neurodegenerative disorders. We identified a homozygous nonsynonymous mutation in CERS1, the gene encoding ceramide synthase 1, in 4 siblings affected by a progressive disorder with myoclonic epilepsy and dementia. CerS1, a transmembrane protein of the endoplasmic reticulum (ER), catalyzes the biosynthesis of C18-ceramides. We demonstrated that the mutation decreases C18-ceramide levels. In addition, we showed that downregulation of CerS1 in a neuroblastoma cell line triggers ER stress response and induces proapoptotic pathways. This study demonstrates that impairment of ceramide biosynthesis underlies neurodegeneration in humans. © 2014 American Neurological Association.

Values and Objectives in Computing Education Research

ERIC Educational Resources Information Center

Pears, Arnold; Malmi, Lauri

2009-01-01

What is Computing Education Research (CER), why are we doing this type of research, and what should the community achieve? As associate editors to this special edition we provide our perspectives and discuss how they have influenced the evolution of the Koli Calling International Conference on Computing Education Research over the last nine years.…

Association between Plasma Ceramides and Phosphatidylcholines and Hippocampal Brain Volume in Late Onset Alzheimer’s Disease

PubMed Central

Kim, Min; Nevado-Holgado, Alejo; Whiley, Luke; Snowden, Stuart G.; Soininen, Hilkka; Kloszewska, Iwona; Mecocci, Patrizia; Tsolaki, Magda; Vellas, Bruno; Thambisetty, Madhav; Dobson, Richard J.B.; Powell, John F.; Lupton, Michelle K.; Simmons, Andy; Velayudhan, Latha; Lovestone, Simon; Proitsi, Petroula; Legido-Quigley, Cristina

2016-01-01

Lipids such as ceramides and phosphatidylcholines (PC) have been found altered in the plasma of Alzheimer’s disease (AD) patients in a number of discovery studies. For this reason, the levels of 6 ceramides and 3 PCs, with different fatty acid length and saturation levels, were measured in the plasma from 412 participants (AD n = 205, Control n = 207) using mass spectrometry coupled with ultra-performance liquid chromatography. After this, associations with AD status, brain atrophy, and age-related effects were studied. In the plasma of AD participants, cross-sectional analysis revealed elevated levels of three ceramides (Cer16:0 p < 0.01, Cer18:0 p < 0.01, Cer24:1 p < 0.05). In addition, two PCs in AD plasma (PC36:5 p < 0.05, PC38:6 p < 0.05) were found to be depleted compared to the control group, with PC36:5 also associating with hippocampal atrophy (p < 0.01). Age-specific analysis further revealed that levels of Cer16:0, Cer18:0, and Cer20:0 were associated with hippocampal atrophy only in younger participants (age < 75, p < 0.05), while all 3 PCs did so in the older participants (age > 75, p < 0.05). PC36:5 was associated with AD status in the younger group (p < 0.01), while PC38:6 and 40:6 did so in the older group (p < 0.05). In this study, elevated ceramides and depleted PCs were found in the plasma from 205 AD volunteers. Our findings also suggest that dysregulation in PC and ceramide metabolism could be occurring in different stages of AD progression. PMID:27911300

Characterization of Scedosporium apiospermum Glucosylceramides and Their Involvement in Fungal Development and Macrophage Functions

PubMed Central

Rollin-Pinheiro, Rodrigo; Liporagi-Lopes, Livia Cristina; de Meirelles, Jardel Vieira; de Souza, Lauro M.; Barreto-Bergter, Eliana

2014-01-01

Scedosporium apiospermum is an emerging fungal pathogen that causes both localized and disseminated infections in immunocompromised patients. Glucosylceramides (CMH, GlcCer) are the main neutral glycosphingolipids expressed in fungal cells. In this study, glucosylceramides (GlcCer) were extracted and purified in several chromatographic steps. Using high-performance thin layer chromatography (HPTLC) and electrospray ionization mass spectrometry (ESI-MS), N-2′-hydroxyhexadecanoyl-1-β-D-glucopyranosyl-9-methyl-4,8-sphingadienine was identified as the main GlcCer in S. apiospermum. A monoclonal antibody (Mab) against this molecule was used for indirect immunofluorescence experiments, which revealed that this CMH is present on the surface of the mycelial and conidial forms of S. apiospermum. Treatment of S. apiospermum conidia with the Mab significantly reduced fungal growth. In addition, the Mab also enhanced the phagocytosis and killing of S. apiospermum by murine cells. In vitro assays were performed to evaluate the CMHs for their cytotoxic activities against the mammalian cell lines L.929 and RAW, and an inhibitory effect on cell proliferation was observed. Synergistic in vitro interactions were observed between the Mab against GlcCer and both amphotericin B (AmB) and itraconazole. Because Scedosporium species develop drug resistance, the number of available antifungal drugs is limited; our data indicate that combining immunotherapy with the available drugs might be a viable treatment option. These results suggest that in S. apiospermum, GlcCer are most likely cell wall components that are targeted by antifungal antibodies, which directly inhibit fungal development and enhance macrophage function; furthermore, these results suggest the combined use of monoclonal antibodies against GlcCer and antifungal drugs for antifungal immunotherapy. PMID:24878570

Characterization of Scedosporium apiospermum glucosylceramides and their involvement in fungal development and macrophage functions.

PubMed

Rollin-Pinheiro, Rodrigo; Liporagi-Lopes, Livia Cristina; de Meirelles, Jardel Vieira; Souza, Lauro M de; Barreto-Bergter, Eliana

2014-01-01

Scedosporium apiospermum is an emerging fungal pathogen that causes both localized and disseminated infections in immunocompromised patients. Glucosylceramides (CMH, GlcCer) are the main neutral glycosphingolipids expressed in fungal cells. In this study, glucosylceramides (GlcCer) were extracted and purified in several chromatographic steps. Using high-performance thin layer chromatography (HPTLC) and electrospray ionization mass spectrometry (ESI-MS), N-2'-hydroxyhexadecanoyl-1-β-D-glucopyranosyl-9-methyl-4,8-sphingadienine was identified as the main GlcCer in S. apiospermum. A monoclonal antibody (Mab) against this molecule was used for indirect immunofluorescence experiments, which revealed that this CMH is present on the surface of the mycelial and conidial forms of S. apiospermum. Treatment of S. apiospermum conidia with the Mab significantly reduced fungal growth. In addition, the Mab also enhanced the phagocytosis and killing of S. apiospermum by murine cells. In vitro assays were performed to evaluate the CMHs for their cytotoxic activities against the mammalian cell lines L.929 and RAW, and an inhibitory effect on cell proliferation was observed. Synergistic in vitro interactions were observed between the Mab against GlcCer and both amphotericin B (AmB) and itraconazole. Because Scedosporium species develop drug resistance, the number of available antifungal drugs is limited; our data indicate that combining immunotherapy with the available drugs might be a viable treatment option. These results suggest that in S. apiospermum, GlcCer are most likely cell wall components that are targeted by antifungal antibodies, which directly inhibit fungal development and enhance macrophage function; furthermore, these results suggest the combined use of monoclonal antibodies against GlcCer and antifungal drugs for antifungal immunotherapy.

Flavocoxid, a dual inhibitor of cyclooxygenase-2 and 5-lipoxygenase, reduces pancreatic damage in an experimental model of acute pancreatitis

PubMed Central

Polito, F; Bitto, A; Irrera, N; Squadrito, F; Fazzari, C; Minutoli, L; Altavilla, D

2010-01-01

BACKGROUND AND PURPOSE Acute pancreatitis is an autodigestive process resulting in acute inflammation of the pancreas. Accumulating evidence indicates the essential contribution of cyclooxygenase (COX)-2 and 5-lipoxygenase (5-LOX) to acute pancreatitis. We studied the effects of flavocoxid, a plant-derived dual inhibitor of COX-2 and 5-LOX, in a model of caerulein (CER)-induced acute pancreatitis. EXPERIMENTAL APPROACH Rats were given CER (80 µg·kg−1 for each of four injections at hourly intervals) or vehicle (Sham-CER). Animals were then randomized to receive flavocoxid (20 mg·kg−1 i.p.) or vehicle, 30 min after the first CER injection. Two hours after the last CER injection, we evaluated damage to the pancreas by histological methods; serum levels of amylase, lipase, leukotriene (LT)B4 and prostaglandin (PG)E2; pancreatic expression of COX-2 and 5-LOX and tumour necrosis factor-α (TNF-α) gene expression by real-time polymerase chain reaction. KEY RESULTS Caerulein induced inflammatory changes in the pancreas and raised values of the other variables measured. In CER-treated animals, but not in those given saline, flavocoxid inhibited COX-2 and 5-LOX expression, reduced serum levels of lipase and amylase and the degree of pancreatic oedema. Treatment with flavocoxid blunted the increased pancreatic TNF-α mRNA expression, serum leukotriene B4 and prostaglandin E2 levels, and protected against histological damage in terms of vacuolization and leukocyte infiltration. CONCLUSIONS AND IMPLICATIONS Our results confirm the key role of both COX-2 and 5-LOX in the inflammatory response to acute pancreatitis. Flavocoxid may provide a potential therapeutic approach to the treatment of patients at high risk of developing this life-threatening condition. PMID:20977452

Flavocoxid, a dual inhibitor of cyclooxygenase-2 and 5-lipoxygenase, reduces pancreatic damage in an experimental model of acute pancreatitis.

PubMed

Polito, F; Bitto, A; Irrera, N; Squadrito, F; Fazzari, C; Minutoli, L; Altavilla, D

2010-11-01

Acute pancreatitis is an autodigestive process resulting in acute inflammation of the pancreas. Accumulating evidence indicates the essential contribution of cyclooxygenase (COX)-2 and 5-lipoxygenase (5-LOX) to acute pancreatitis. We studied the effects of flavocoxid, a plant-derived dual inhibitor of COX-2 and 5-LOX, in a model of caerulein (CER)-induced acute pancreatitis. Rats were given CER (80 µg·kg⁻¹ for each of four injections at hourly intervals) or vehicle (Sham-CER). Animals were then randomized to receive flavocoxid (20 mg·kg⁻¹ i.p.) or vehicle, 30 min after the first CER injection. Two hours after the last CER injection, we evaluated damage to the pancreas by histological methods; serum levels of amylase, lipase, leukotriene (LT)B₄ and prostaglandin (PG)E₂ ; pancreatic expression of COX-2 and 5-LOX and tumour necrosis factor-α (TNF-α) gene expression by real-time polymerase chain reaction. Caerulein induced inflammatory changes in the pancreas and raised values of the other variables measured. In CER-treated animals, but not in those given saline, flavocoxid inhibited COX-2 and 5-LOX expression, reduced serum levels of lipase and amylase and the degree of pancreatic oedema. Treatment with flavocoxid blunted the increased pancreatic TNF-α mRNA expression, serum leukotriene B₄ and prostaglandin E₂ levels, and protected against histological damage in terms of vacuolization and leukocyte infiltration. Our results confirm the key role of both COX-2 and 5-LOX in the inflammatory response to acute pancreatitis. Flavocoxid may provide a potential therapeutic approach to the treatment of patients at high risk of developing this life-threatening condition. © 2010 The Authors. British Journal of Pharmacology © 2010 The British Pharmacological Society.

Involving Latina/o parents in patient-centered outcomes research: Contributions to research study design, implementation and outcomes.

PubMed

Pérez Jolles, Mónica; Martinez, Maria; Garcia, San Juanita; Stein, Gabriela L; Thomas, Kathleen C

2017-10-01

Comparative effectiveness research (CER) is supported by policymakers as a way to provide service providers and patients with evidence-based information to make better health-care decisions and ultimately improve services for patients. However, Latina/o patients are rarely involved as study advisors, and there is a lack of documentation on how their voices contribute to the research process when they are included as collaborators. The purpose of this article was to contribute to the literature by presenting concrete contributions of Latina/o parent involvement to study design, implementation and outcomes in the context of a CER study called Padres Efectivos (Parent Activation). Researchers facilitated a collaborative relationship with parents by establishing a mentor parent group. The contributions of parent involvement in the following stages of the research process are described: (i) proposal development, (ii) implementation of protocols, (iii) analysis plan and (iv) dissemination of results. Mentor parents' contributions helped tailor the content of the intervention to their needs during proposal, increased recruitment, validated the main outcome measure and added two important outcome measures, emphasized the importance of controlling for novice treatment status and developed innovative dissemination strategies. Mentor parents' guidance to the researchers has contributed to reaching recruitment goals, strengthened the study protocol, expanded findings, supported broad ownership of study implications and enriched the overall study data collection efforts. These findings can inform future research efforts seeking an active Latino parent collaboration and the timely incorporation of parent voices in each phase of the research process. © 2017 The Authors Health Expectations Published by John Wiley & Sons Ltd.

Neutrino nuclear responses for double beta decays and astro neutrinos by charge exchange reactions

NASA Astrophysics Data System (ADS)

Ejiri, Hiroyasu

2014-09-01

Neutrino nuclear responses are crucial for neutrino studies in nuclei. Charge exchange reactions (CER) are shown to be used to study charged current neutrino nuclear responses associated with double beta decays(DBD)and astro neutrino interactions. CERs to be used are high energy-resolution (He3 ,t) reactions at RCNP, photonuclear reactions via IAR at NewSUBARU and muon capture reactions at MUSIC RCNP and MLF J-PARC. The Gamow Teller (GT) strengths studied by CERs reproduce the observed 2 neutrino DBD matrix elements. The GT and spin dipole (SD) matrix elements are found to be reduced much due to the nucleon spin isospin correlations and the non-nucleonic (delta isobar) nuclear medium effects. Impacts of the reductions on the DBD matrix elements and astro neutrino interactions are discussed.

Preparing Electronic Clinical Data for Quality Improvement and Comparative Effectiveness Research: The SCOAP CERTAIN Automation and Validation Project

PubMed Central

Devine, Emily Beth; Capurro, Daniel; van Eaton, Erik; Alfonso-Cristancho, Rafael; Devlin, Allison; Yanez, N. David; Yetisgen-Yildiz, Meliha; Flum, David R.; Tarczy-Hornoch, Peter

2013-01-01

Background: The field of clinical research informatics includes creation of clinical data repositories (CDRs) used to conduct quality improvement (QI) activities and comparative effectiveness research (CER). Ideally, CDR data are accurately and directly abstracted from disparate electronic health records (EHRs), across diverse health-systems. Objective: Investigators from Washington State’s Surgical Care Outcomes and Assessment Program (SCOAP) Comparative Effectiveness Research Translation Network (CERTAIN) are creating such a CDR. This manuscript describes the automation and validation methods used to create this digital infrastructure. Methods: SCOAP is a QI benchmarking initiative. Data are manually abstracted from EHRs and entered into a data management system. CERTAIN investigators are now deploying Caradigm’s Amalga™ tool to facilitate automated abstraction of data from multiple, disparate EHRs. Concordance is calculated to compare data automatically to manually abstracted. Performance measures are calculated between Amalga and each parent EHR. Validation takes place in repeated loops, with improvements made over time. When automated abstraction reaches the current benchmark for abstraction accuracy - 95% - itwill ‘go-live’ at each site. Progress to Date: A technical analysis was completed at 14 sites. Five sites are contributing; the remaining sites prioritized meeting Meaningful Use criteria. Participating sites are contributing 15–18 unique data feeds, totaling 13 surgical registry use cases. Common feeds are registration, laboratory, transcription/dictation, radiology, and medications. Approximately 50% of 1,320 designated data elements are being automatically abstracted—25% from structured data; 25% from text mining. Conclusion: In semi-automating data abstraction and conducting a rigorous validation, CERTAIN investigators will semi-automate data collection to conduct QI and CER, while advancing the Learning Healthcare System. PMID:25848565

Two invaders instead of one: the true identity of species under the name Ceracis cucullatus (Coleoptera: Ciidae).

PubMed

Antunes-Carvalho, Caio; Lopes-Andrade, Cristiano

2013-01-01

The Neotropical obligate fungivorous beetle Ceracis cucullatus (Mellié) has attracted attention of coleopterists due to the increasing number of records of populations in Africa. Although its disjunct populations have been interpreted as a cohesive taxonomic unity, previous comparisons between African and Neotropical specimens revealed differences in their external morphology, causing uncertainty about the true unity of the species. Here, we compare the external morphology of specimens named Cer. cucullatus from several localities of the Neotropical, Palearctic, Afrotropical, Afrotemperate and Oriental regions. As results, we reverse three previous junior synonymies of Cer. cucullatus, proposing Cer. lamellatus (Pic) and Cer. tabellifer (Mellié), both reinstated status and new combinations, as separate species. We also propose Enn. bilamellatum Pic as a new synonym of Cer. tabellifer. In face of these taxonomic changes, we identify Cer. tabellifer as the actual invasive species on African lands, instead of Cer. cucullatus as was previously accepted. Then, through historical records gathered from scientific collections and literature, and through examination of recently collected specimens from South Africa and Brazil, we provide data on host fungi and geographic distribution of Cer. tabellifer. Based on these data, we discuss possible explanations to the successful invasion of Cer. tabellifer in Africa and elsewhere and its potential threat to native faunas of ciids. This study helps to fulfil an old gap in the literature on biological invasions, with considerably more studies on predatory species, disease vectors or potential pests of agricultural crops, than on non-pest fungivorous organisms.

Renal Allograft Function Is a Risk Factor of Left Ventricular Remodeling After Kidney Transplantation.

PubMed

Koo, T Y; Ahn, C; Yang, J

2017-06-01

Cardiovascular disease is the leading cause of morbidity and mortality in kidney transplantation (KT) patients. The prevalence of left ventricular hypertrophy increases with the progression of renal insufficiency. We investigated the association between the progression of renal insufficiency and left ventricular hypertrophy after KT. We reviewed KT patients at Seoul National University Hospital from January 1973 to December 2009. The creatinine elevation ratio (CER, the percentage change in the creatinine level from 1 month to 5 years after transplant) was calculated as follows: (creatinine level at 5 years minus creatinine level at 1 month)/creatinine level at 1 month × 100. The study population was classified into a high-CER group (CER ≥25%) and low-CER group (CER <25%). Mean left ventricular mass index (LVMI) values were 135.7 and 134.7 g/m 2 before KT and 101.7 and 123.7 g/m 2 at 5 years after KT in the low-CER and high-CER groups, respectively. The LVMI before or 1 year after KT was not different between the 2 groups, but the LVMI at 5 years post-transplant was higher in the high-CER group than in the low-CER group. The LVMI increased after its initial decrease in the high-CER group, whereas its reduction was maintained in the low-CER group during the 5 years after KT (P = .009, repeated-measures analysis of variance). These data suggest that deterioration of renal allograft function is associated with left ventricular remodeling after KT. Copyright © 2017 Elsevier Inc. All rights reserved.

Two Invaders Instead of One: The True Identity of Species under the Name Ceracis cucullatus (Coleoptera: Ciidae)

PubMed Central

Antunes-Carvalho, Caio; Lopes-Andrade, Cristiano

2013-01-01

The Neotropical obligate fungivorous beetle Ceracis cucullatus (Mellié) has attracted attention of coleopterists due to the increasing number of records of populations in Africa. Although its disjunct populations have been interpreted as a cohesive taxonomic unity, previous comparisons between African and Neotropical specimens revealed differences in their external morphology, causing uncertainty about the true unity of the species. Here, we compare the external morphology of specimens named Cer. cucullatus from several localities of the Neotropical, Palearctic, Afrotropical, Afrotemperate and Oriental regions. As results, we reverse three previous junior synonymies of Cer. cucullatus, proposing Cer. lamellatus (Pic) and Cer. tabellifer (Mellié), both reinstated status and new combinations, as separate species. We also propose Enn. bilamellatum Pic as a new synonym of Cer. tabellifer. In face of these taxonomic changes, we identify Cer. tabellifer as the actual invasive species on African lands, instead of Cer. cucullatus as was previously accepted. Then, through historical records gathered from scientific collections and literature, and through examination of recently collected specimens from South Africa and Brazil, we provide data on host fungi and geographic distribution of Cer. tabellifer. Based on these data, we discuss possible explanations to the successful invasion of Cer. tabellifer in Africa and elsewhere and its potential threat to native faunas of ciids. This study helps to fulfil an old gap in the literature on biological invasions, with considerably more studies on predatory species, disease vectors or potential pests of agricultural crops, than on non-pest fungivorous organisms. PMID:24015233

Spark Plasma Sintering of Load-Bearing Iron-Carbon Nanotube-Tricalcium Phosphate CerMets for Orthopaedic Applications

NASA Astrophysics Data System (ADS)

Montufar, Edgar B.; Horynová, Miroslava; Casas-Luna, Mariano; Diaz-de-la-Torre, Sebastián; Celko, Ladislav; Klakurková, Lenka; Spotz, Zdenek; Diéguez-Trejo, Guillermo; Fohlerová, Zdenka; Dvorak, Karel; Zikmund, Tomáš; Kaiser, Jozef

2016-04-01

Recently, ceramic-metallic composite materials (CerMets) have been investigated for orthopaedic applications with promising results. This first generation of bio-CerMets combine the bioactivity of hydroxyapatite with the mechanical stability of titanium to fabricate bioactive, tough and biomechanically more biocompatible osteosynthetic devices. Nonetheless, these first CerMets are not biodegradable materials and a second surgery is required to remove the implant after bone healing. The present work aims to develop the next generation bio-CerMets, which are potential biodegradable materials. The process to produce the new biodegradable CerMet consisted of mixing powder of soluble and osteoconductive alpha tricalcium phosphate with biocompatible and biodegradable iron with consolidation through spark plasma sintering (SPS). The microstructure, composition and mechanical strength of the new CerMet were studied by metallography, x-ray diffraction and diametral tensile strength tests, respectively. The results show that SPS produces CerMet with higher mechanical performance (120 MPa) than the ceramic component alone (29 MPa) and similar mechanical strength to the pure metallic component (129 MPa). Nonetheless, although a short sintering time (10 min) was used, partial transformation of the alpha tricalcium phosphate into its allotropic and slightly less soluble beta phase was observed. Cell adhesion tests show that osteoblasts are able to attach to the CerMet surface, presenting spread morphology regardless of the component of the material with which they are in contact. However, the degradation process restricted to the small volume of the cell culture well quickly reduces the osteoblast viability.

Cost-effectiveness of surgery and its policy implications for global health: a systematic review and analysis.

PubMed

Chao, Tiffany E; Sharma, Ketan; Mandigo, Morgan; Hagander, Lars; Resch, Stephen C; Weiser, Thomas G; Meara, John G

2014-06-01

The perception of surgery as expensive and complex might be a barrier to its widespread acceptance in global health efforts. We did a systematic review and analysis of cost-effectiveness studies that assess surgical interventions in low-income and middle-income countries to help quantify the potential value of surgery. We searched Medline for all relevant articles published between Jan 1, 1996 and Jan 31, 2013, and searched the reference lists of retrieved articles. We converted all results to 2012 US$. We extracted cost-effectiveness ratios (CERs) and appraised economic assessments for their methodological quality using the 10-point Drummond checklist. Of the 584 identified studies, 26 met full inclusion criteria. Together, these studies gave 121 independent CERs in seven categories of surgical interventions. The median CER of circumcision ($13·78 per disability-adjusted life year [DALY]) was similar to that of standard vaccinations ($12·96-25·93 per DALY) and bednets for malaria prevention ($6·48-22·04 per DALY). Median CERs of cleft lip or palate repair ($47·74 per DALY), general surgery ($82·32 per DALY), hydrocephalus surgery ($108·74 per DALY), and ophthalmic surgery ($136 per DALY) were similar to that of the BCG vaccine ($51·86-220·39 per DALY). Median CERs of caesarean sections ($315·12 per DALY) and orthopaedic surgery ($381·15 per DALY) are more favourable than those of medical treatment for ischaemic heart disease ($500·41-706·54 per DALY) and HIV treatment with multidrug antiretroviral therapy ($453·74-648·20 per DALY). Our findings suggest that many essential surgical interventions are cost-effective or very cost-effective in resource-poor countries. Quantification of the economic value of surgery provides a strong argument for the expansion of global surgery's role in the global health movement. However, economic value should not be the only argument for resource allocation--other organisational, ethical, and political arguments can also be made for its inclusion. Copyright © 2014 Chao et al. Open Access article distributed under the terms of CC BY. Published by .. All rights reserved.

5-HT6 receptor agonists and antagonists enhance learning and memory in a conditioned emotion response paradigm by modulation of cholinergic and glutamatergic mechanisms

PubMed Central

Woods, S; Clarke, NN; Layfield, R; Fone, KCF

2012-01-01

BACKGROUND AND PURPOSE 5-HT6 receptors are abundant in the hippocampus, nucleus accumbens and striatum, supporting their role in learning and memory. Selective 5-HT6 receptor antagonists produce pro-cognitive effects in several learning and memory paradigms while 5-HT6 receptor agonists have been found to enhance and impair memory. EXPERIMENTAL APPROACH The conditioned emotion response (CER) paradigm was validated in rats. Then we examined the effect of the 5-HT6 receptor antagonist, EMD 386088 (10 mg·kg−1, i.p.), and agonists, E-6801 (2.5 mg·kg−1, i.p.) and EMD 386088 (5 mg·kg−1, i.p.) on CER-induced behaviour either alone or after induction of memory impairment by the muscarinic receptor antagonist, scopolamine (0.3 mg·kg−1, i.p) or the NMDA receptor antagonist, MK-801 (0.1 mg·kg−1, i.p). KEY RESULTS Pairing unavoidable foot shocks with a light and tone cue during CER training induced a robust freezing response, providing a quantitative index of contextual memory when the rat was returned to the shock chamber 24 h later. Pretreatment (−20 min pre-training) with scopolamine or MK-801 reduced contextual freezing 24 h after CER training, showing production of memory impairment. Immediate post-training administration of 5-HT6 receptor antagonist, SB-270146, and agonists, EMD 386088 and E-6801, had little effect on CER freezing when given alone, but all significantly reversed scopolamine- and MK-801-induced reduction in freezing. CONCLUSION AND IMPLICATIONS Both the 5-HT6 receptor agonists and antagonist reversed cholinergic- and glutamatergic-induced deficits in associative learning. These findings support the therapeutic potential of 5-HT6 receptor compounds in the treatment of cognitive dysfunction, such as seen in Alzheimer's disease and schizophrenia. PMID:22568655

Adjuvant effects of invariant NKT cell ligand potentiates the innate and adaptive immunity to an inactivated H1N1 swine influenza virus vaccine in pigs.

PubMed

Dwivedi, Varun; Manickam, Cordelia; Dhakal, Santosh; Binjawadagi, Basavaraj; Ouyang, Kang; Hiremath, Jagadish; Khatri, Mahesh; Hague, Jacquelyn Gervay; Lee, Chang Won; Renukaradhya, Gourapura J

2016-04-15

Pigs are considered as the source of some of the emerging human flu viruses. Inactivated swine influenza virus (SwIV) vaccine has been in use in the US swine herds, but it failed to control the flu outbreaks. The main reason has been attributed to lack of induction of strong local mucosal immunity in the respiratory tract. Invariant natural killer T (iNKT) cell is a unique T cell subset, and activation of iNKT cell using its ligand α-Galactosylceramide (α-GalCer) has been shown to potentiate the cross-protective immunity to inactivated influenza virus vaccine candidates in mice. Recently, we discovered iNKT cell in pig and demonstrated its activation using α-GalCer. In this study, we evaluated the efficacy of an inactivated H1N1 SwIV coadministered with α-GalCer intranasally against a homologous viral challenge. Our results demonstrated the potent adjuvant effects of α-GalCer in potentiating both innate and adaptive immune responses to SwIV Ags in the lungs of pigs, which resulted in reduction in the lung viral load by 3 logs compared to without adjuvant. Immunologically, in the lungs of pigs vaccinated with α-GalCer an increased virus specific IgA response, IFN-α secretion and NK cell-cytotoxicity was observed. In addition, iNKT cell-stimulation enhanced the secretion of Th1 cytokines (IFN-γ and IL-12) and reduced the production of immunosuppressive cytokines (IL-10 and TGF-β) in the lungs of pigs⋅ In conclusion, we demonstrated for the first time iNKT cell adjuvant effects in pigs to SwIV Ags through augmenting the innate and adaptive immune responses in the respiratory tract. Copyright © 2016 Elsevier B.V. All rights reserved.

Strategies to Improve Management of Acute Watery Diarrhea during a Military Deployment: A Cost Effectiveness Analysis.

PubMed

Schrader, Andrew J; Tribble, David R; Riddle, Mark S

2017-12-01

To inform policy and decision makers, a cost-effectiveness model was developed to predict the cost-effectiveness of implementing two hypothetical management strategies separately and concurrently on the mitigation of deployment-associated travelers' diarrhea (TD) burden. The first management strategy aimed to increase the likelihood that a deployed service member with TD will seek medical care earlier in the disease course compared with current patterns; the second strategy aimed to optimize provider treatment practices through the implementation of a Department of Defense Clinical Practice Guideline. Outcome measures selected to compare management strategies were duty days lost averted (DDL-averted) and a cost effectiveness ratio (CER) of cost per DDL-averted (USD/DDL-averted). Increasing health care and by seeking it more often and earlier in the disease course as a stand-alone management strategy produced more DDL (worse) than the base case (up to 8,898 DDL-gained per year) at an increased cost to the Department of Defense (CER $193). Increasing provider use of an optimal evidence-based treatment algorithm through Clinical Practice Guidelines prevented 5,299 DDL per year with overall cost savings (CER -$74). A combination of both strategies produced the greatest gain in DDL-averted (6,887) with a modest cost increase (CER $118). The application of this model demonstrates that changes in TD management during deployment can be implemented to reduce DDL with likely favorable impacts on mission capability and individual health readiness. The hypothetical combination strategy evaluated prevents the most DDL compared with current practice and is associated with a modest cost increase.

The Role of Inflation and Price Escalation Adjustments in Properly Estimating Program Costs: F-35 Case Study

DTIC Science & Technology

2016-04-30

costs of new defense systems. An inappropriate price index can introduce errors in both development of cost estimating relationships ( CERs ) and in...indexes derived from CERs . These indexes isolate changes in price due to factors other than changes in quality over time. We develop a “Baseline” CER ...The hedonic index application has commonalities with cost estimating relationships ( CERs ), which also model system costs as a function of quality

Ceramide synthase inhibition by fumonisin B1 causes accumulation of 1-deoxy-sphinganine: a novel category of bioactive 1-deoxy-sphingoid bases and 1-deoxy-dihydroceramides biosynthesized by mammalian cell lines and animals

USDA-ARS?s Scientific Manuscript database

Fumonisin B1 (FB1) is a mycotoxin that inhibits ceramide synthases (CerS) and causes kidney and liver toxicity and other disease. Inhibition of CerS by FB1 increases sphinganine (Sa), Sa 1-phosphate and a previously unidentified metabolite. Analysis of the latter by quadrupole-time-of-flight mass ...

Perfectionism and negative/positive affect associations: the role of cognitive emotion regulation and perceived distress/coping.

PubMed

Castro, Juliana; Soares, Maria João; Pereira, Ana T; Macedo, António

2017-01-01

To explore 1) if perfectionism, perceived distress/coping, and cognitive emotion regulation (CER) are associated with and predictive of negative/positive affect (NA/PA); and 2) if CER and perceived distress/coping are associated with perfectionism and if they mediate the perfectionism-NA/PA associations. There is a distinction between maladaptive and adaptive perfectionism in its association with NA/PA. CER and perceived distress/coping may mediate the maladaptive/adaptive perfectionism and NA/PA associations. 344 students (68.4% girls) completed the Hewitt & Flett and the Frost Multidimensional Perfectionism Scales, the Composite Multidimensional Perfectionism Scale, the Profile of Mood States, the Perceived Stress Scale, and the Cognitive Emotion Regulation Questionnaire. NA predictors were maladaptive/adaptive perfectionism, maladaptive CER and perceived distress (positively), positive reappraisal and planning, and perceived coping (negatively). PA predictors were maladaptive/adaptive perfectionism and perceived distress (negatively), positive reappraisal and planning, positive refocusing and perceived coping (positively). The association between maladaptive perfectionism and NA was mediated by maladaptive CER/low adaptive CER, perceived distress/low coping. Maladaptive perfectionism and low PA association was mediated by perceived distress. High PA was determined by low maladaptive perfectionism and this association was mediated by adaptive REC and coping. Adaptive perfectionism and NA association was mediated by maladaptive CER and perceived distress. CER and perceived distress/coping are associated and mediate the perfectionism-NA/PA associations.

Low-latitude variability of ice cloud properties and cloud thermodynamic phase observed by the Atmospheric Infrared Sounder (AIRS)

NASA Astrophysics Data System (ADS)

Kahn, B. H.; Yue, Q.; Davis, S. M.; Fetzer, E. J.; Schreier, M. M.; Tian, B.; Wong, S.

2016-12-01

We will quantify the time and space dependence of ice cloud effective radius (CER), optical thickness (COT), cloud top temperature (CTT), effective cloud fraction (ECF), and cloud thermodynamic phase (ice, liquid, or unknown) with the Version 6 Atmospheric Infrared Sounder (AIRS) satellite observational data set from September 2002 until present. We show that cloud frequency, CTT, COT, and ECF have substantially different responses to ENSO variations. Large-scale changes in ice CER are also observed with a several micron tropics-wide increase during the 2015-2016 El Niño and similar decreases during the La Niña phase. We show that the ice CER variations reflect fundamental changes in the spatial distributions and relative frequencies of different ice cloud types. Lastly, the high spatial and temporal resolution variability of the cloud fields are explored and we show that these data capture a multitude of convectively coupled tropical waves such as Kelvin, westward and eastward intertio-gravity, equatorial Rossby, and mixed Rossby-gravity waves.

Regulating Anger under Stress via Cognitive Reappraisal and Sadness.

PubMed

Zhan, Jun; Wu, Xiaofei; Fan, Jin; Guo, Jianyou; Zhou, Jianshe; Ren, Jun; Liu, Chang; Luo, Jing

2017-01-01

Previous studies have reported the failure of cognitive emotion regulation (CER), especially in regulating unpleasant emotions under stress. The underlying reason for this failure was the application of CER depends heavily on the executive function of the prefrontal cortex (PFC), but this function can be impaired by stress-related neuroendocrine hormones. This observation highlights the necessity of developing self-regulatory strategies that require less top-down cognitive control. Based on traditional Chinese philosophy and medicine, which examine how different types of emotions promote or counteract one another, we have developed a novel emotion regulation strategy whereby one emotion is used to alter another. For example, our previous experiment showed that sadness induction (after watching a sad film) could reduce aggressive behavior associated with anger [i.e., "sadness counteracts anger" (SCA)] (Zhan et al., 2015). Relative to the CER strategy requiring someone to think about certain cognitive reappraisals to reinterpret the meaning of an unpleasant situation, watching a film or listening to music and experiencing the emotion contained therein seemingly requires less cognitive effort and control; therefore, this SCA strategy may be an alternative strategy that compensates for the limitations of cognitive regulation strategies, especially in stressful situations. The present study was designed to directly compare the effects of the CER and SCA strategy in regulating anger and anger-related aggression in stressful and non-stressful conditions. Participants' subjective feeling of anger, anger-related aggressive behavior, skin conductance, and salivary cortisol and alpha-amylase levels were measured. Our findings revealed that acute stress impaired one's ability to use CR to control angry responses provoked by others, whereas stress did not influence the efficiency of the SCA strategy. Compared with sadness or neutral emotion induction, CER induction was found to reduce the level of subjective anger more, but this difference only existed in non-stressful conditions. By contrast, irrespective of stress, the levels of aggressive behavior and related skin conductance after sadness induction were both significantly lower than those after CER induction or neutral emotion induction, thus suggesting the immunity of the regulatory effect of SCA strategy to the stress factor.

Regulating Anger under Stress via Cognitive Reappraisal and Sadness

PubMed Central

Zhan, Jun; Wu, Xiaofei; Fan, Jin; Guo, Jianyou; Zhou, Jianshe; Ren, Jun; Liu, Chang; Luo, Jing

2017-01-01

Previous studies have reported the failure of cognitive emotion regulation (CER), especially in regulating unpleasant emotions under stress. The underlying reason for this failure was the application of CER depends heavily on the executive function of the prefrontal cortex (PFC), but this function can be impaired by stress-related neuroendocrine hormones. This observation highlights the necessity of developing self-regulatory strategies that require less top-down cognitive control. Based on traditional Chinese philosophy and medicine, which examine how different types of emotions promote or counteract one another, we have developed a novel emotion regulation strategy whereby one emotion is used to alter another. For example, our previous experiment showed that sadness induction (after watching a sad film) could reduce aggressive behavior associated with anger [i.e., “sadness counteracts anger” (SCA)] (Zhan et al., 2015). Relative to the CER strategy requiring someone to think about certain cognitive reappraisals to reinterpret the meaning of an unpleasant situation, watching a film or listening to music and experiencing the emotion contained therein seemingly requires less cognitive effort and control; therefore, this SCA strategy may be an alternative strategy that compensates for the limitations of cognitive regulation strategies, especially in stressful situations. The present study was designed to directly compare the effects of the CER and SCA strategy in regulating anger and anger-related aggression in stressful and non-stressful conditions. Participants’ subjective feeling of anger, anger-related aggressive behavior, skin conductance, and salivary cortisol and alpha-amylase levels were measured. Our findings revealed that acute stress impaired one’s ability to use CR to control angry responses provoked by others, whereas stress did not influence the efficiency of the SCA strategy. Compared with sadness or neutral emotion induction, CER induction was found to reduce the level of subjective anger more, but this difference only existed in non-stressful conditions. By contrast, irrespective of stress, the levels of aggressive behavior and related skin conductance after sadness induction were both significantly lower than those after CER induction or neutral emotion induction, thus suggesting the immunity of the regulatory effect of SCA strategy to the stress factor. PMID:28855881

Regulation of the sphingosine-recycling pathway for ceramide generation by oxidative stress, and its role in controlling c-Myc/Max function

PubMed Central

Sultan, Iyad; Senkal, Can E.; Ponnusamy, Suriyan; Bielawski, Jacek; Szulc, Zdzislaw; Bielawska, Alicja; Hannun, Yusuf A.; Ogretmen, Besim

2005-01-01

In the present study, the regulation of the sphingosine-recycling pathway in A549 human lung adenocarcinoma cells by oxidative stress was investigated. The generation of endogenous long-chain ceramide in response to exogenous C6-cer (C6-ceramide), which is FB1 (fumonisin B1)-sensitive, was employed to probe the sphingosine-recycling pathway. The data showed that ceramide formation via this pathway was significantly blocked by GSH and NAC (N-acetylcysteine) whereas it was enhanced by H2O2, as detected by both palmitate labelling and HPLC/MS. Similar data were also obtained using a novel approach that measures the incorporation of 17Sph (sphingosine containing 17 carbons) of 17C6-cer (C6-cer containing a 17Sph backbone) into long-chain 17C16-cer in cells by HPLC/MS, which was significantly decreased and increased in response to GSH and H2O2 respectively. TNF (tumour necrosis factor)-α, which decreases the levels of endogenous GSH, increased the generation of C16-cer in response to C6-cer, and this was blocked by exogenous GSH or NAC, or by the overexpression of TPx I (thioredoxin peroxidase I), an enzyme that reduces the generation of intracellular ROS (reactive oxygen species). Additional data showed that ROS regulated both the deacylation and reacylation steps of C6-cer. At a functional level, C6-cer inhibited the DNA-binding function of the c-Myc/Max oncogene. Inhibition of the generation of longchain ceramide in response to C6-cer by FB1 or NAC significantly blocked the modulation of the c-Myc/Max function. These data demonstrate that the sphingosine-recycling pathway for the generation of endogenous long-chain ceramide in response to exogenous C6-cer is regulated by ROS, and plays an important biological role in controlling c-Myc function. PMID:16201965

CER-001, a HDL-mimetic, stimulates the reverse lipid transport and atherosclerosis regression in high cholesterol diet-fed LDL-receptor deficient mice.

PubMed

Tardy, Claudine; Goffinet, Marine; Boubekeur, Nadia; Ackermann, Rose; Sy, Gavin; Bluteau, Alice; Cholez, Guy; Keyserling, Constance; Lalwani, Narendra; Paolini, John F; Dasseux, Jean-Louis; Barbaras, Ronald; Baron, Rudi

2014-01-01

CER-001 is a novel engineered HDL-mimetic comprised of recombinant human apoA-I and phospholipids that was designed to mimic the beneficial properties of nascent pre-β HDL. In this study, we have evaluated the capacity of CER-001 to perform reverse lipid transport in single dose studies as well as to regress atherosclerosis in LDLr(-/-) mice after short-term multiple-dose infusions. CER-001 induced cholesterol efflux from macrophages and exhibited anti-inflammatory response similar to natural HDL. Studies with HUVEC demonstrated CER-001 at a concentration of 500 μg/mL completely suppressed the secretion of cytokines IL-6, IL-8, GM-CSF and MCP-1. Following infusion of CER-001 (10mg/kg) in C57Bl/6J mice, we observed a transient increase in the mobilization of unesterified cholesterol in HDL particles containing recombinant human apoA-I. Finally we show that cholesterol elimination was stimulated in CER-001 treated animals as demonstrated by the increased cholesterol concentration in liver and feces. In a familial hypercholesterolemia mouse model (LDL-receptor deficient mice), the infusion of CER-001 caused 17% and 32% reductions in plaque size, 17% and 23% reductions in lipid content after 5 and 10 doses given every 2 days, respectively. Also, there was an 80% reduction in macrophage content in the plaque following 5 doses, and decreased VCAM-1 expression by 16% and 22% in the plaque following 5 and 10 intravenous doses of CER-001, respectively. These data demonstrate that CER-001 rapidly enhances reverse lipid transport in the mouse, reducing vascular inflammation and promoting regression of diet-induced atherosclerosis in LDLr(-/-) mice upon a short-term multiple dose treatment. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Chronic Ethanol Consumption Profoundly Alters Regional Brain Ceramide and Sphingomyelin Content in Rodents

PubMed Central

2015-01-01

Ceramides (CER) are involved in alcohol-induced neuroinflammation. In a mouse model of chronic alcohol exposure, 16 CER and 18 sphingomyelin (SM) concentrations from whole brain lipid extracts were measured using electrospray mass spectrometry. All 18 CER concentrations in alcohol exposed adults increased significantly (range: 25–607%); in juveniles, 6 CER decreased (range: −9 to −37%). In contrast, only three SM decreased in adult and one increased significantly in juvenile. Next, regional identification at 50 μm spatial resolution from coronal sections was obtained with matrix implanted laser desorption/ionization mass spectrometry imaging (MILDI-MSI) by implanting silver nanoparticulate matrices followed by focused laser desorption. Most of the CER and SM quantified in whole brain extracts were detected in MILDI images. Coronal sections from three brain levels show qualitative regional changes in CER-SM ion intensities, as a function of group and brain region, in cortex, striatum, accumbens, habenula, and hippocampus. Highly correlated changes in certain white matter CER-SM pairs occur in regions across all groups, including the hippocampus and the lateral (but not medial) cerebellar cortex of adult mice. Our data provide the first microscale MS evidence of regional lipid intensity variations induced by alcohol. PMID:25387107

Thermodynamic Insights and Conceptual Design of Skin-Sensitive Chitosan Coated Ceramide/PLGA Nanodrug for Regeneration of Stratum Corneum on Atopic Dermatitis

PubMed Central

Jung, Sang-Myung; Yoon, Gwang Heum; Lee, Hoo Chul; Jung, Moon Hee; Yu, Sun Il; Yeon, Seung Ju; Min, Seul Ki; Kwon, Yeo Seon; Hwang, Jin Ha; Shin, Hwa Sung

2015-01-01

Atopic dermatitis (AD) is a complex skin disease primarily characterized by psoriasis of the stratum corneum. AD drugs have usually been used in acidic and hydrophilic solvents to supply moisture and prevent lipid defects. Ceramide is a typical treatment agent to regenerate the stratum corneum and relieve symptoms of AD. However, ceramide has limitation on direct use for skin because of its low dispersion properties in hydrophilic phase and side effects at excessive treatment. In this study, ceramide imbedded PLGA nanoparticles were developed with chitosan coating (Chi-PLGA/Cer) to overcome this problem. The chitosan coating enhanced initial adherence to the skin and prevented the initial burst of ceramide, but was degraded by the weakly acidic nature of skin, resulting in controlled release of ceramide with additional driving force of the squeezed PLGA nanoparticles. Additionally, the coating kinetics of chitosan were controlled by manipulating the reaction conditions and then mathematically modeled. The Chi-PLGA/Cer was not found to be cytotoxic and ceramide release was controlled by pH, temperature, and chitosan coating. Finally, Chi-PLGA/Cer was demonstrated to be effective at stratum corneum regeneration in a rat AD model. Overall, the results presented herein indicated that Chi-PLGA/Cer is a novel nanodrug for treatment of AD. PMID:26666701

Comparative effectiveness regulations and pharmaceutical innovation.

PubMed

Vernon, John A; Golec, Joseph H; Stevens, J Stedman

2010-01-01

As healthcare reform evolves and takes shape, comparative effectiveness research (CER) appears to be one of the central topics on the national healthcare agenda. Over the past couple of years, comparative effectiveness has been explicitly incorporated in more than ten bills. For example, the passage of the American Recovery and Reinvestment Act of 2009 authorized $US1.1 billion for CER. Comparative effectiveness, when costs are formally considered, offers the hope of efficient resource allocation within US healthcare markets. However, the future operationalization and implementation of comparative effectiveness is uncertain, and there exist potentially negative, and unintended, consequences under certain scenarios. One example, and the focus of this article, is pharmaceutical innovation. Incentives for pharmaceutical R&D could be affected if drug development costs increase as a result of firms having to bear, directly or indirectly, the costs of running larger, randomized, head-to-head comparative effectiveness trials. While this may or may not be the case with current and future comparative effectiveness legislation and its subsequent implementation, the potential consequences for pharmaceutical innovation warrant recognition. This is the purpose of the article. To achieve this goal, we develop several models of clinical trial design, drug development costs and R&D investment. By example, we shed light on the causal links between the models and the ways in which industry R&D investment can be affected.

Is photography-based taxonomy really inadequate, unnecessary, and potentially harmful for biological sciences? A reply to Ceríaco et al. (2016).

PubMed

Thorpe, Stephen E

2017-01-26

An opinion piece was recently published in this journal which, remarkably, is less than one page in length, but has 493 authors (signatories) and has gained over 15 thousand reads on ResearchGate in a very short time. Ceríaco et al. (2016) argue for a blanket ban to be imposed on the uncommon practice of basing new species descriptions in zoology on photographic evidence only of the animal. I herein aim to show that their argument is a non sequitur, i.e. their stated reasons do not support their desired conclusion.

The hitchhiker's guide to Europe: the infection dynamics of an ongoing Wolbachia invasion and mitochondrial selective sweep in Rhagoletis cerasi.

PubMed

Schuler, Hannes; Köppler, Kirsten; Daxböck-Horvath, Sabine; Rasool, Bilal; Krumböck, Susanne; Schwarz, Dietmar; Hoffmeister, Thomas S; Schlick-Steiner, Birgit C; Steiner, Florian M; Telschow, Arndt; Stauffer, Christian; Arthofer, Wolfgang; Riegler, Markus

2016-04-01

Wolbachia is a maternally inherited and ubiquitous endosymbiont of insects. It can hijack host reproduction by manipulations such as cytoplasmic incompatibility (CI) to enhance vertical transmission. Horizontal transmission of Wolbachia can also result in the colonization of new mitochondrial lineages. In this study, we present a 15-year-long survey of Wolbachia in the cherry fruit fly Rhagoletis cerasi across Europe and the spatiotemporal distribution of two prevalent strains, wCer1 and wCer2, and associated mitochondrial haplotypes in Germany. Across most of Europe, populations consisted of either 100% singly (wCer1) infected individuals with haplotype HT1, or 100% doubly (wCer1&2) infected individuals with haplotype HT2, differentiated only by a single nucleotide polymorphism. In central Germany, singly infected populations were surrounded by transitional populations, consisting of both singly and doubly infected individuals, sandwiched between populations fixed for wCer1&2. Populations with fixed infection status showed perfect association of infection and mitochondria, suggesting a recent CI-driven selective sweep of wCer2 linked with HT2. Spatial analysis revealed a range expansion for wCer2 and a large transition zone in which wCer2 splashes appeared to coalesce into doubly infected populations. Unexpectedly, the transition zone contained a large proportion (22%) of wCer1&2 individuals with HT1, suggesting frequent intraspecific horizontal transmission. However, this horizontal transmission did not break the strict association between infection types and haplotypes in populations outside the transition zone, suggesting that this horizontally acquired Wolbachia infection may be transient. Our study provides new insights into the rarely studied Wolbachia invasion dynamics in field populations. © 2016 The Authors. Molecular Ecology Published by John Wiley & Sons Ltd.

Cubic crystalline erbium oxide growth on GaN(0001) by atomic layer deposition

NASA Astrophysics Data System (ADS)

Chen, Pei-Yu; Posadas, Agham B.; Kwon, Sunah; Wang, Qingxiao; Kim, Moon J.; Demkov, Alexander A.; Ekerdt, John G.

2017-12-01

Growth of crystalline Er2O3, a rare earth sesquioxide, on GaN(0001) is described. Ex situ HCl and NH4OH solutions and an in situ N2 plasma are used to remove impurities on the GaN surface and result in a Ga/N stoichiometry of 1.02. Using atomic layer deposition with erbium tris(isopropylcyclopentadienyl) [Er(iPrCp)3] and water, crystalline cubic Er2O3 (C-Er2O3) is grown on GaN at 250 °C. The orientation relationships between the C-Er2O3 film and the GaN substrate are C-Er2O3(222) ǁ GaN(0001), C-Er2O3⟨-440⟩ ǁ GaN ⟨11-20⟩, and C-Er2O3⟨-211⟩ ǁ GaN ⟨1-100⟩. Scanning transmission electron microscopy and electron energy loss spectroscopy are used to examine the microstructure of C-Er2O3 and its interface with GaN. With post-deposition annealing at 600 °C, a thicker interfacial layer is observed, and two transition layers, crystalline GaNwOz and crystalline GaErxOy, are found between GaN and C-Er2O3. The tensile strain in the C-Er2O3 film is studied with x-ray diffraction by changes in both out-of-plane and in-plane d-spacing. Fully relaxed C-Er2O3 films on GaN are obtained when the film thickness is around 13 nm. Additionally, a valence band offset of 0.7 eV and a conduction band offset of 1.2 eV are obtained using x-ray photoelectron spectroscopy.

Proteomic identification of proteins translocated to membrane microdomains upon treatment of fibroblasts with the glycosphingolipid, C8-beta-D-lactosylceramide.

PubMed

Kim, Seong-Youl; Wang, Teng-ke; Singh, Raman Deep; Wheatley, Christine L; Marks, David L; Pagano, Richard E

2009-09-01

Plasma membrane (PM) microdomains, including caveolae and other cholesterol-enriched subcompartments, are involved in the regulation of many cellular processes, including endocytosis, attachment and signaling. We recently reported that brief incubation of human skin fibroblasts with the synthetic glycosphingolipid, D-erythro-octanoyl-lactosylceramide (C8-D-e-LacCer), stimulates endocytosis via caveolae and induces the appearance of micron-size microdomains on the PM. To further understand the effects of C8-D-e-LacCer treatment on PM microdomains, we used a detergent-free method to isolate microdomain-enriched membranes from fibroblasts treated +/-C8-D-e-LacCer, and performed 2-DE and mass spectrophotometry to identify proteins that were altered in their distribution in microdomains. Several proteins were identified in the microdomain-enriched fractions, including lipid transfer proteins and proteins related to the functions of small GTPases. One protein, Rho-associated protein kinase 2 (ROCK2), was verified by Western blotting to occur in microdomain fractions and to increase in these fractions after D-e-LacCer treatment. Immunofluorescence revealed that ROCK2 exhibited an increased localization at or near the PM in C8-D-e-LacCer-treated cells. In contrast, ROCK2 distribution in microdomains was decreased by treatment of cells with C8-L-threo-lactosylceramide, a glycosphingolipid with non-natural stereochemistry. This study identifies new microdomain-associated proteins and provides evidence that microdomains play a role in the regulation of the Rho/ROCK signaling pathway.

Statins: cost analysis in Indian scenario from eight major clinical trials.

PubMed

Sanmukhani, J; Shah, V

2010-01-01

Coronary heart disease (CHD) is the leading cause of death in India resulting in loss of young Indians. Statins have proved to reduce the CHD mortality in various clinical trials. The aim of the study is to find the cost-effectiveness ratio (CER) for each major coronary event averted and a coronary death avoided by use of statins in different clinical settings based on the data from the major clinical trials on statins. Using electronic database and as per our inclusion and exclusion criteria we selected the West of Scotland Coronary Prevention Study (WOSCOPS), the Air Force Coronary Atherosclerosis Prevention Study (AFCAPS) and the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA) study for primary prevention; the Cholesterol and Recurrent Events Trial (CARE), the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Study and the Scandinavian Simvastatin Survival Study (4S) for secondary prevention and two studies, the Heart Protection Study (HPS) and the Pravastatin in elderly individuals at risk of vascular disease (PROSPER) study for high-risk patients. The results of these studies were used for cost-effectiveness analysis of statins in different patient groups. Absolute risk reduction, Number Needed to Benefit (NNTB), NNTB/year for total sample and in subgroups of males, females and age >65 was derived. CER for branded and generic versions was calculated by using the prices of statins listed in Indian Drug Review Triple i. Cost-effectiveness ratio (CER) in primary prevention studies i.e., the WOSCOPS, the AFCAPS and the ASCOT-LLA was Rs. 25.8 lacs, Rs. 23.8 lacs and Rs. 7.9 lacs per major coronary event averted respectively. CER in secondary prevention studies i.e., the CARE and the LIPID was approximately Rs. 20 lacs per major coronary event averted while it was Rs. 52.4 lacs and Rs. 37 lacs per coronary heart disease (CHD) death avoided. CER from the 4S was Rs. 6.9 lacs per major coronary event and Rs. 16.9 lacs per CHD death averted. CER in the HPS and the PROSPER study was Rs. 17.9 lacs and Rs. 27.1 lacs per major coronary event avoided in high-risk patients. Cost associated with the use of statins is higher in primary prevention as compared to secondary prevention. More studies are needed to confirm the cost-effectiveness of statins to make any decision for health policy.

STED Imaging of Golgi Dynamics with Cer-SiR: A Two-Component, Photostable, High-Density Lipid Probe for Live Cells.

PubMed

Erdmann, Roman S; Toomre, Derek; Schepartz, Alanna

2017-01-01

Long time-lapse super-resolution imaging in live cells requires a labeling strategy that combines a bright, photostable fluorophore with a high-density localization probe. Lipids are ideal high-density localization probes, as they are >100 times more abundant than most membrane-bound proteins and simultaneously demark the boundaries of cellular organelles. Here, we describe Cer-SiR, a two-component, high-density lipid probe that is exceptionally photostable. Cer-SiR is generated in cells via a bioorthogonal reaction of two components: a ceramide lipid tagged with trans-cyclooctene (Cer-TCO) and a reactive, photostable Si-rhodamine dye (SiR-Tz). These components assemble within the Golgi apparatus of live cells to form Cer-SiR. Cer-SiR is benign to cellular function, localizes within the Golgi at a high density, and is sufficiently photostable to enable visualization of Golgi structure and dynamics by 3D confocal or long time-lapse STED microscopy.

Carbon partitioning patterns of mycorrhizal versus non-mycorrhizal plants: real-time dynamic measurements using 11 CO2.

PubMed

Wang, G M; Coleman, D C; Freckman, D W; Dyer, M I; McNAUGHTON, S J; Agra, M A; Goeschl, J D

1989-08-01

Gas exchange and carbon allocation patterns were studied in two populations of Panicum coloratum, an Africa C-4 grass. The plants were grown in split-root pots, containing partially sterilized soil, with one side either inoculated (I) or not inoculated (NI) with a vesicular arbuscular (VA) mycorrhizal Fungus, Gigaspora margarita. Net carbon exchange rates (CER) and stomatal conductances were measured with conventional gas exchange apparatus, and carbon assimilation, translocation, and allocation were measured using photosynthetically-fixed 11 CO 2 . Mycorrhizal infection on one half of the split-root system caused a 20%, increase in CER. The effect on CER was less in tillers on the opposite side of the plants from the infected half of the roots. The rate at which photosynthates were stored in the leaves was 45% higher. Sink activity (concentration of labelled photosynthates in stem phloem tissue) more than doubled in 1 versus NI plants. CER and stomatal conductances, along with most of the carbon allocation patterns, were nearly identical between the NI (control) high grazing and low grazing ecotypes. However, VA mycorrhizal fungi caused a greater storage of photosynthates in the low grazing ecotype.

Non-clinical development of CER-001.

PubMed

Barbaras, Ronald

2015-01-01

Cardiovascular disease remains the most pressing healthcare issue for the developed world and is becoming so for developing countries. There are no currently approved therapies that can rapidly reduce the burden of unstable, inflamed plaque in the overall coronary vascular bed. High-density lipoprotein (HDL) has multiple actions that could lead to plaque stabilization, such as rapid removal of large quantities of cholesterol from the vasculature through the process of reverse lipid transport, improvement in endothelial function, protection against oxidative damage, and reduction in inflammation. Short-term infusion of HDL-mimetics in animal models as well as in humans has shown promising effects on the plaque size and morphology. Cerenis Therapeutics has developed CER-001, a negatively charged lipoprotein complex consisting of phospholipid and recombinant human apoA-I that mimics the structure and function of natural HDL. Three clinical trials using CER-001 infusions have demonstrated improvements in the carotid wall thickness of patients with familial hypercholesterolaemia and in patients with hypo-alphalipoproteinaemia, as well as an impact on coronary plaque burden measured by intravascular ultrasonography at the lowest tested dose (3 mg/kg) in post-ACS patients. Here, we reviewed the non-clinical data leading to the demonstration that CER-001 is a full HDL mimetic.

75 FR 7577 - Combined Notice of Filings # 1

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-22

... following exempt wholesale generator filings: Docket Numbers: EG10-18-000. Applicants: CER Generation, LLC. Description: Notice of Self-Certification of Exempt Wholesale Generator Status of CER Generation, LLC. Filed...Energy, Inc., Nine Mile Point Nuclear Station, LLC, CER Generation II, LLC, Handsome Lake Energy, LLC...

75 FR 66106 - Government-Owned Inventions; Availability for Licensing

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-27

... in order to rapidly elicit an immune response. [alpha]- galactosylceramide ([alpha]-GalCer) is a... why the human clinical trials of [alpha]-GalCer or KRN7000 were not very successful. Investigators at the National Cancer Institute have found that [beta]-mannosylceramide ([beta]-ManCer) promotes...

75 FR 58348 - Revision of the Shoshone National Forest Land and Resource Management Plan

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-24

... process: 1. Comprehensive Evaluation Report (CER) (April 2009)--Much of the background material in this report will be carried forward in the Analysis of the Management Situation or draft EIS. The CER..., and ecological conditions and trends that contribute to sustainability. The CER identifies factors...

Contactless electroreflectance studies of free exciton binding energy in Zn1-xMgxO epilayers

NASA Astrophysics Data System (ADS)

Wełna, M.; Kudrawiec, R.; Kaminska, A.; Kozanecki, A.; Laumer, B.; Eickhoff, M.; Misiewicz, J.

2013-12-01

Contactless electroreflectance (CER) has been applied to study optical transitions in Zn1-xMgxO layers with magnesium concentration ≤44%. CER resonances related to free exciton and band-to-band transitions were clearly observed at room temperature. For ZnO the two transitions are separated by the energy of ˜65 meV, which is attributed to the free exciton binding energy in ZnO. Due to magnesium incorporation, the CER resonances broaden and shift to blue. The energy separation between excitonic and band-to-band transitions increases up to ˜100 meV when the magnesium concentration reaches 22%. For larger magnesium concentrations, CER resonances are significantly broadened and the excitonic transition is no longer resolved in the CER spectrum.

Lecithin-based microemulsions for targeted delivery of ceramide AP into the stratum corneum: formulation, characterizations, and in vitro release and penetration studies.

PubMed

Sahle, Fitsum F; Metz, Hendrik; Wohlrab, Johannes; Neubert, Reinhard H H

2013-02-01

To improve the solubility and penetration of Ceramide AP (CER [AP]) into the stratum corneum that potentially restores the barrier function of aged and affected skin. CER [AP] microemulsions (MEs) were formulated using lecithin, Miglyol® 812 (miglyol) and water-1,2 pentandiol (PeG) mixture as amphiphilic, oily and hydrophilic components, respectively. The nanostructure of the MEs was revealed using electrical conductivity, differential scanning calorimeter (DSC) and electron paramagnetic resonance (EPR) techniques. Photon correlation spectroscopy (PCS) was used to measure the sizes and shape of ME droplets. The release and penetration of the CER into the stratum corneum was investigated in vitro using a multi-layer membrane model. The MEs exhibited excellent thermodynamic stability (>2 years) and loading capacity (0.5% CER [AP]). The pseudo-ternary phase diagrams of the MEs were obtained and PCS results showed that the droplets are spherical in shape and bigger in size. In vitro investigations showed that the MEs exhibited excellent rate and extent of release and penetration. Stable lecithin-based CER [AP] MEs that significantly enhance the solubility and penetration of CER [AP] into the stratum corneum were developed. The MEs also have better properties than the previously reported polyglycerol fatty acid surfactant-based CER [AP] MEs.

RDR1 and SGS3, components of RNA-mediated gene silencing, are required for the regulation of cuticular wax biosynthesis in developing inflorescence stems of Arabidopsis.

PubMed

Lam, Patricia; Zhao, Lifang; McFarlane, Heather E; Aiga, Mytyl; Lam, Vivian; Hooker, Tanya S; Kunst, Ljerka

2012-08-01

The cuticle is a protective layer that coats the primary aerial surfaces of land plants and mediates plant interactions with the environment. It is synthesized by epidermal cells and is composed of a cutin polyester matrix that is embedded and covered with cuticular waxes. Recently, we have discovered a novel regulatory mechanism of cuticular wax biosynthesis that involves the ECERIFERUM7 (CER7) ribonuclease, a core subunit of the exosome. We hypothesized that at the onset of wax production, the CER7 ribonuclease degrades an mRNA specifying a repressor of CER3, a wax biosynthetic gene whose protein product is required for wax formation via the decarbonylation pathway. In the absence of this repressor, CER3 is expressed, leading to wax production. To identify the putative repressor of CER3 and to unravel the mechanism of CER7-mediated regulation of wax production, we performed a screen for suppressors of the cer7 mutant. Our screen resulted in the isolation of components of the RNA-silencing machinery, RNA-DEPENDENT RNA POLYMERASE1 and SUPPRESSOR OF GENE SILENCING3, implicating RNA silencing in the control of cuticular wax deposition during inflorescence stem development in Arabidopsis (Arabidopsis thaliana).

The β-Ketoacyl-CoA Synthase HvKCS1, Encoded by Cer-zh, Plays a Key Role in Synthesis of Barley Leaf Wax and Germination of Barley Powdery Mildew.

PubMed

Li, Chao; Haslam, Tegan M; Krüger, Anna; Schneider, Lizette M; Mishina, Kohei; Samuels, Lacey; Yang, Hongxing; Kunst, Ljerka; Schaffrath, Ulrich; Nawrath, Christiane; Chen, Guoxiong; Komatsuda, Takao; von Wettstein-Knowles, Penny

2018-04-01

The cuticle coats the primary aerial surfaces of land plants. It consists of cutin and waxes, which provide protection against desiccation, pathogens and herbivores. Acyl cuticular waxes are synthesized via elongase complexes that extend fatty acyl precursors up to 38 carbons for downstream modification pathways. The leaves of 21 barley eceriferum (cer) mutants appear to have less or no epicuticular wax crystals, making these mutants excellent tools for identifying elongase and modification pathway biosynthetic genes. Positional cloning of the gene mutated in cer-zh identified an elongase component, β-ketoacyl-CoA synthase (CER-ZH/HvKCS1) that is one of 34 homologous KCSs encoded by the barley genome. The biochemical function of CER-ZH was deduced from wax and cutin analyses and by heterologous expression in yeast. Combined, these experiments revealed that CER-ZH/HvKCS1 has a substrate specificity for C16-C20, especially unsaturated, acyl chains, thus playing a major role in total acyl chain elongation for wax biosynthesis. The contribution of CER-ZH to water barrier properties of the cuticle and its influence on the germination of barley powdery mildew fungus were also assessed.

First surface-based estimation of the aerosol indirect effect over a site in southeastern China

NASA Astrophysics Data System (ADS)

Liu, Jianjun; Li, Zhanqing

2018-02-01

The deployment of the U.S. Atmospheric Radiation Measurement mobile facility in Shouxian from May to December 2008 amassed the most comprehensive set of measurements of atmospheric, surface, aerosol, and cloud variables in China. This deployment provided a unique opportunity to investigate the aerosol-cloud interactions, which are most challenging and, to date, have not been examined to any great degree in China. The relationship between cloud droplet effective radius (CER) and aerosol index (AI) is very weak in summer because the cloud droplet growth is least affected by the competition for water vapor. Mean cloud liquid water path (LWP) and cloud optical depth (COD) significantly increase with increasing AI in fall. The sensitivities of CER and LWP to aerosol loading increases are not significantly different under different air mass conditions. There is a significant correlation between the changes in hourly mean AI and the changes in hourly mean CER, LWP, and COD. The aerosol first indirect effect (FIE) is estimated in terms of relative changes in both CER (FIECER) and COD (FIECOD) with changes in AI for different seasons and air masses. FIECOD and FIECER are similar in magnitude and close to the typical FIE value of ˜ 0.23, and do not change much between summer and fall or between the two different air mass conditions. Similar analyses were done using spaceborne Moderate Resolution Imaging Spectroradiometer data. The satellite-derived FIE is contrary to the FIE estimated from surface retrievals and may have large uncertainties due to some inherent limitations.

Directed Research Program in Reading, Early Childhood, Vocational Education, School Organization and Administration, FY 72 - FY 76.

ERIC Educational Resources Information Center

National Center for Educational Research and Development (DHEW/OE), Washington, DC.

In 1970 the National Center for Educational Research and Development (CER) reviewed United States Office of Education (USOE) Bureau of Research policies over the previous 15 years, and as a result of this review, initiated the Directed Research Program. This program will concentrate funds in four areas of high educational significance and will be…

Super learning to hedge against incorrect inference from arbitrary parametric assumptions in marginal structural modeling.

PubMed

Neugebauer, Romain; Fireman, Bruce; Roy, Jason A; Raebel, Marsha A; Nichols, Gregory A; O'Connor, Patrick J

2013-08-01

Clinical trials are unlikely to ever be launched for many comparative effectiveness research (CER) questions. Inferences from hypothetical randomized trials may however be emulated with marginal structural modeling (MSM) using observational data, but success in adjusting for time-dependent confounding and selection bias typically relies on parametric modeling assumptions. If these assumptions are violated, inferences from MSM may be inaccurate. In this article, we motivate the application of a data-adaptive estimation approach called super learning (SL) to avoid reliance on arbitrary parametric assumptions in CER. Using the electronic health records data from adults with new-onset type 2 diabetes, we implemented MSM with inverse probability weighting (IPW) estimation to evaluate the effect of three oral antidiabetic therapies on the worsening of glomerular filtration rate. Inferences from IPW estimation were noticeably sensitive to the parametric assumptions about the associations between both the exposure and censoring processes and the main suspected source of confounding, that is, time-dependent measurements of hemoglobin A1c. SL was successfully implemented to harness flexible confounding and selection bias adjustment from existing machine learning algorithms. Erroneous IPW inference about clinical effectiveness because of arbitrary and incorrect modeling decisions may be avoided with SL. Copyright © 2013 Elsevier Inc. All rights reserved.

Lipid functions in skin: Differential effects of n-3 polyunsaturated fatty acids on cutaneous ceramides, in a human skin organ culture model.

PubMed

Kendall, Alexandra C; Kiezel-Tsugunova, Magdalena; Brownbridge, Luke C; Harwood, John L; Nicolaou, Anna

2017-09-01

Ceramides are important for skin health, with a multitude of species found in both dermis and epidermis. The epidermis contains linoleic acid-Ester-linked Omega-hydroxylated ceramides of 6-Hydroxy-sphingosine, Sphingosine and Phytosphingosine bases (CER[EOH], CER[EOS] and CER[EOP], respectively), that are crucial for the formation of the epidermal barrier, conferring protection from environmental factors and preventing trans-epidermal water loss. Furthermore, a large number of ceramides, derivatives of the same sphingoid bases and various fatty acids, are produced by dermal and epidermal cells and perform signalling roles in cell functions ranging from differentiation to apoptosis. Supplementation with the n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have shown promise as therapeutic agents in a number of inflammatory skin conditions, altering the lipid profile of the skin and production of bioactive lipids such as the eicosanoids, docosanoids and endocannabinoids. In this study we wished to investigate whether EPA and DHA could also affect the ceramide profile in epidermis and dermis, and, in this way, contribute to formation of a robust lipid barrier and ceramide-mediated regulation of skin functions. Ex vivo skin explants were cultured for 6days, and supplemented with EPA or DHA (50μM). Liquid chromatography coupled to tandem mass spectrometry with electrospray ionisation was used to assess the prevalence of 321 individual ceramide species, and a number of sphingoid bases, phosphorylated sphingoid bases, and phosphorylated ceramides, within the dermis and epidermis. EPA augmented dermal production of members of the ceramide families containing Non-hydroxy fatty acids and Sphingosine or Dihydrosphingosine bases (CER[NS] and CER[NDS], respectively), while epidermal CER[EOH], CER[EOS] and CER[EOP] ceramides were not affected. DHA did not significantly affect ceramide production. Ceramide-1-phosphate levels in the epidermis, but not the dermis, increased in response to EPA, but not DHA. This ex vivo study shows that dietary supplementation with EPA has the potential to alter the ceramide profile of the skin, and this may contribute to its anti-inflammatory profile. This has implications for formation of the epidermal lipid barrier, and signalling pathways within the skin mediated by ceramides and other sphingolipid species. This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escribá. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Adjusting for geographic variation in observational comparative effectiveness studies: a case study of antipsychotics using state Medicaid data.

PubMed

Root, Elisabeth Dowling; Thomas, Deborah S K; Campagna, Elizabeth J; Morrato, Elaine H

2014-08-27

Area-level variation in treatment and outcomes may be a potential source of confounding bias in observational comparative effectiveness studies. This paper demonstrates how to use exploratory spatial data analysis (ESDA) and spatial statistical methods to investigate and control for these potential biases. The case presented compares the effectiveness of two antipsychotic treatment strategies: oral second-generation antipsychotics (SGAs) vs. long-acting paliperiodone palmitate (PP). A new-start cohort study was conducted analyzing patient-level administrative claims data (8/1/2008-4/30/2011) from Missouri Medicaid. ESDA techniques were used to examine spatial patterns of antipsychotic prescriptions and outcomes (hospitalization and emergency department (ED) visits). Likelihood of mental health-related outcomes were compared between patients starting PP (N = 295) and oral SGAs (N = 8,626) using multilevel logistic regression models adjusting for patient composition (demographic and clinical factors) and geographic region. ESDA indicated significant spatial variation in antipsychotic prescription patterns and moderate variation in hospitalization and ED visits thereby indicating possible confounding by geography. In the multilevel models for this antipsychotic case example, patient composition represented a stronger source of confounding than geographic context. Because geographic variation in health care delivery is ubiquitous, it could be a comparative effectiveness research (CER) best practice to test for possible geographic confounding in observational data. Though the magnitude of the area-level geography effects were small in this case, they were still statistically significant and should therefore be examined as part of this observational CER study. More research is needed to better estimate the range of confounding due to geography across different types of observational comparative effectiveness studies and healthcare utilization outcomes.

75 FR 21221 - Plan Revision for Kaibab National Forest; Coconino, Yavapai, and Mojave Counties; AZ

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-23

... available at: http://fs.usda.gov/goto/kaibab/plan_rev_docs . The Comprehensive Evaluation Report (CER) that... the existing Forest Plan and the proposed action for the plan revision. The CER supplementary document, which supplemented the CER with additional information to conform to the Analysis of Management...

78 FR 32385 - Exelon Generation Company, LLC; CER Generation II, LLC; Constellation Mystic Power, LLC...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-30

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. EL13-64-000] Exelon Generation Company, LLC; CER Generation II, LLC; Constellation Mystic Power, LLC; Constellation NewEnergy...) Rules of Practice and Procedure, 18 CFR 385.207, Exelon Generation Company, LLC, CER Generation II, LLC...

Non‐glycosidic compounds can stimulate both human and mouse iNKT cells

PubMed Central

Jukes, John‐Paul; Gileadi, Uzi; Ghadbane, Hemza; Yu, Ting‐Fong; Shepherd, Dawn; Cox, Liam R.; Besra, Gurdyal S.

2016-01-01

Invariant natural killer T (iNKT) cells recognize CD1d/glycolipid complexes and upon activation with synthetic agonists display immunostimulatory properties. We have previously described that the non‐glycosidic CD1d‐binding lipid, threitolceramide (ThrCer) activates murine and human iNKT cells. Here, we show that incorporating the headgroup of ThrCer into a conformationally more restricted 6‐ or 7‐membered ring results in significantly more potent non‐glycosidic analogs. In particular, ThrCer 6 was found to promote strong anti‐tumor responses and to induce a more prolonged stimulation of iNKT cells than does the canonical α‐galactosylceramide (α‐GalCer), achieving an enhanced T‐cell response at lower concentrations compared with α‐GalCer both in vitro, using human iNKT‐cell lines and in vivo, using C57BL/6 mice. Collectively, these studies describe novel non‐glycosidic ThrCer‐based analogs that have improved potency in iNKT‐cell activation compared with that of α‐GalCer, and are clinically relevant iNKT‐cell agonists. PMID:26873393

Parvovirus B19 VLP recognizes globoside in supported lipid bilayers.

PubMed

Nasir, Waqas; Nilsson, Jonas; Olofsson, Sigvard; Bally, Marta; Rydell, Gustaf E

2014-05-01

Studies have suggested that the glycosphingolipid globoside (Gb4Cer) is a receptor for human parvovirus B19. Virus-like particles bind to Gb4Cer on thin-layer chromatograms, but a direct interaction between the virus and lipid membrane-associated Gb4Cer has been debated. Here, we characterized the binding of parvovirus B19 VP1/VP2 virus-like particles to glycosphingolipids (i) on thin-layer chromatograms (TLCs) and (ii) incorporated into supported lipid bilayers (SLBs) acting as cell-membrane mimics. The binding specificities of parvovirus B19 determined in the two systems were in good agreement; the VLP recognized both Gb4Cer and the Forssman glycosphingolipid on TLCs and in SLBs compatible with the role of Gb4Cer as a receptor for this virus. Copyright © 2014 Elsevier Inc. All rights reserved.

Increase in cognitive eating restraint predicts weight loss and change in other anthropometric measurements in overweight/obese premenopausal women.

PubMed

Urbanek, J Kalina; Metzgar, Catherine J; Hsiao, Pao Ying; Piehowski, Kathryn E; Nickols-Richardson, Sharon M

2015-04-01

In modern societies characterized by food abundance, dietary restraint may serve as a factor in the successful control of weight or facilitation of weight loss. This secondary analysis of data examined whether changes in cognitive eating restraint (CER) and disinhibition predicted weight loss in a sample of 60 overweight/obese premenopausal women [mean ± SD, age = 35.9 ± 5.8 y; weight = 84.4 ± 13.1 kg; body mass index (BMI) = 31.0 ± 4.3 kg/m(2)]. Changes in weight, BMI, waist circumference, hip circumference, waist-to-hip ratio and body fat percentage (BF%) were examined in relation to changes in CER, disinhibition and hunger as measured by the Eating Inventory questionnaire at baseline and week 18 of an 18-week dietary intervention. Multivariate linear regression analysis was used to identify predictors of weight loss and changes in other anthropometric variables from baseline to study completion. Increase in CER was found to be the most robust predictor of reduction in weight (P < 0.0001), BMI (P < 0.0001), waist circumference (P < 0.001), hip circumference (P < 0.0001) and BF% (P < 0.0001). Effect of increase in CER on change in BMI, hip circumference and BF% was moderated by increase in disinhibition (all P < 0.05). Results suggest that strategies that target CER and disinhibition should be emphasized in programs proposed to treat and prevent obesity. Copyright © 2014 Elsevier Ltd. All rights reserved.

Analysis of sphingolipids in human corneal fibroblasts from normal and keratoconus patients[S

PubMed Central

Qi, Hui; Priyadarsini, Shrestha; Nicholas, Sarah E.; Sarker-Nag, Akhee; Allegood, Jeremy; Chalfant, Charles E.; Mandal, Nawajes A.; Karamichos, Dimitrios

2017-01-01

The pathophysiology of human keratoconus (KC), a bilateral progressive corneal disease leading to protrusion of the cornea, stromal thinning, and scarring, is not well-understood. In this study, we investigated a novel sphingolipid (SPL) signaling pathway through which KC may be regulated. Using human corneal fibroblasts (HCFs) and human KC cells (HKCs), we examined the SPL pathway modulation. Both cell types were stimulated by the three transforming growth factor (TGF)-β isoforms: TGF-β1 (T1), TGF-β2 (T2), and TGF-β3 (T3). All samples were analyzed using lipidomics and real-time PCR. Our data showed that HKCs have increased levels of signaling SPLs, ceramide (Cer), and sphingosine 1-phosphate (S1P). Treatment with T1 reversed the increase in Cer in HKCs and treatment with T3 reversed the increase in S1P. S1P3 receptor mRNA levels were also significantly upregulated in HKCs, but were reduced to normal levels following T3 treatment. Furthermore, stimulation with Cer and S1P led to significant upregulation of fibrotic markers in HCFs, but not in HKCs. Additionally, stimulation with a Cer synthesis inhibitor (FTY720) led to significant downregulation of specific fibrotic markers in HKCs (TGF-β1, collagen type III, and α smooth muscle actin) without an effect on healthy HCFs, suggesting a causative role of Cer and S1P in fibrogenesis. Overall, this study suggests an association of the SPL signaling pathway in KC disease and its relation with the TGF-β pathway. PMID:28188148

Augmented trophoblast cell death in preeclampsia can proceed via ceramide-mediated necroptosis

PubMed Central

Bailey, Liane Jennifer; Alahari, Sruthi; Tagliaferro, Andrea; Post, Martin; Caniggia, Isabella

2017-01-01

Preeclampsia, a serious hypertensive disorder of pregnancy, is characterized by elevated ceramide (CER) content that is responsible for heightened trophoblast cell death rates via apoptosis and autophagy. Whether trophoblast cells undergo necroptosis, a newly characterized form of regulated necrosis, and the potential role of CER in this process remain to be established. Herein, we report that exposure of both JEG3 cells and primary isolated cytotrophoblasts to C16:0 CER in conjunction with a caspase-8 inhibitor (Q-VD-OPh) promoted necroptotic cell death, as evidenced by increased expression and association of receptor-interacting protein kinases RIP1 and RIP3, as well as phosphorylation of mixed lineage kinase domain-like (MLKL) protein. MLKL activation and oligomerization could be abrogated by pretreatment with the necroptosis inhibitor necrostatin-1 (Nec-1). CER+Q-VD-OPH-treated primary trophoblasts displayed striking necrotic morphology along with disrupted fusion processes as evidenced by maintenance of E-cadherin-stained membrane boundaries and reduced glial cell missing-1 expression, but these events were effectively reversed using Nec-1. Of clinical relevance, we established an increased susceptibility to necroptotic cell death in preeclamptic placentae relative to normotensive controls. In preeclampsia, increased necrosome (RIP1/RIP3) protein levels, as well as MLKL activation and oligomerization associated with necrotic cytotrophoblast morphology. In addition, caspase-8 activity was reduced in severe early-onset preeclampsia cases. This study is the first to report that trophoblast cells undergo CER-induced necroptotic cell death, thereby contributing to the increased placental dysfunction and cell death found in preeclampsia. PMID:28151467

The effect of cost construction based on either DRG or ICD-9 codes or risk group stratification on the resulting cost-effectiveness ratios.

PubMed

Chumney, Elinor C G; Biddle, Andrea K; Simpson, Kit N; Weinberger, Morris; Magruder, Kathryn M; Zelman, William N

2004-01-01

As cost-effectiveness analyses (CEAs) are increasingly used to inform policy decisions, there is a need for more information on how different cost determination methods affect cost estimates and the degree to which the resulting cost-effectiveness ratios (CERs) may be affected. The lack of specificity of diagnosis-related groups (DRGs) could mean that they are ill-suited for costing applications in CEAs. Yet, the implications of using International Classification of Diseases-9th edition (ICD-9) codes or a form of disease-specific risk group stratification instead of DRGs has yet to be clearly documented. To demonstrate the implications of different disease coding mechanisms on costs and the magnitude of error that could be introduced in head-to-head comparisons of resulting CERs. We based our analyses on a previously published Markov model for HIV/AIDS therapies. We used the Healthcare Cost and Utilisation Project Nationwide Inpatient Sample (HCUP-NIS) data release 6, which contains all-payer data on hospital inpatient stays from selected states. We added costs for the mean number of hospitalisations, derived from analyses based on either DRG or ICD-9 codes or risk group stratification cost weights, to the standard outpatient and prescription drug costs to yield an estimate of total charges for each AIDS-defining illness (ADI). Finally, we estimated the Markov model three times with the appropriate ADI cost weights to obtain CERs specific to the use of either DRG or ICD-9 codes or risk group. Contrary to expectations, we found that the choice of coding/grouping assumptions that are disease-specific by either DRG codes, ICD-9 codes or risk group resulted in very similar CER estimates for highly active antiretroviral therapy. The large variations in the specific ADI cost weights across the three different coding approaches was especially interesting. However, because no one approach produced consistently higher estimates than the others, the Markov model's weighted cost per event and resulting CERs were remarkably close in value to one another. Although DRG codes are based on broader categories and contain less information than ICD-9 codes, in practice the choice of whether to use DRGs or ICD-9 codes may have little effect on the CEA results in heterogeneous conditions such as HIV/AIDS.

Structure-guided design of an invariant natural killer T cell agonist for optimum protection from type 1 diabetes in non-obese diabetic mice

PubMed Central

Blumenfeld, H J; Tohn, R; Haeryfar, S M M; Liu, Y; Savage, P B; Delovitch, T L

2011-01-01

Because invariant natural killer T (iNK T) cells link innate and adaptive immunity, the structure-dependent design of iNK T cell agonists may have therapeutic value as vaccines for many indications, including autoimmune disease. Previously, we showed that treatment of non-obese diabetic (NOD) mice with the iNK T cell activating prototypic glycolipid α-galactosylceramide (α-GalCer) protects them from type 1 diabetes (T1D). However, α-GalCer is a strong agonist that can hyperactivate iNK T cells, elicit several side effects and has shown only limited success in clinical trials. Here, we used a structure-guided design approach to identify an iNK T cell agonist that optimally protects from T1D with minimal side effects. Analyses of the kinetics and function of a panel of synthetic α-GalCer fatty acyl chain derivatives (C8:0-C16:0) were performed in NOD mice. C16:0 elicited the highest protection from insulitis and T1D, which was associated with a higher frequency and survival of iNK T cells and enhanced activity of tolerogenic dendritic cells (DCs) in draining pancreatic lymph nodes (PLN), inability to transactivate NK cells and a more rapid kinetics of induction and recovery of iNK T cells from anergy. We conclude that the length and structure of the acyl chain of α-GalCer regulates the level of protection against T1D in mice, and propose that the extent of this protection depends on the relative capacity of the acyl chain to accommodate an endogenous spacer lipid of appropriate length and structure. Thus, our findings with the α-GalCer C16:0 derivative suggest strongly that it be considered as a lead glycolipid candidate in clinical trials of T1D. PMID:21910729

Development of GK-2A cloud optical and microphysical properties retrieval algorithm

NASA Astrophysics Data System (ADS)

Yang, Y.; Yum, S. S.; Um, J.

2017-12-01

Cloud and aerosol radiative forcing is known to be one of the the largest uncertainties in climate change prediction. To reduce this uncertainty, remote sensing observation of cloud radiative and microphysical properties have been used since 1970s and the corresponding remote sensing techniques and instruments have been developed. As a part of such effort, Geo-KOMPSAT-2A (Geostationary Korea Multi-Purpose Satellite-2A, GK-2A) will be launched in 2018. On the GK-2A, the Advanced Meteorological Imager (AMI) is primary instrument which have 3 visible, 3 near-infrared, and 10 infrared channels. To retrieve optical and microphysical properties of clouds using AMI measurements, the preliminary version of new cloud retrieval algorithm for GK-2A was developed and several validation tests were conducted. This algorithm retrieves cloud optical thickness (COT), cloud effective radius (CER), liquid water path (LWP), and ice water path (IWP), so we named this algorithm as Daytime Cloud Optical thickness, Effective radius and liquid and ice Water path (DCOEW). The DCOEW uses cloud reflectance at visible and near-infrared channels as input data. An optimal estimation (OE) approach that requires appropriate a-priori values and measurement error information is used to retrieve COT and CER. LWP and IWP are calculated using empirical relationships between COT/CER and cloud water path that were determined previously. To validate retrieved cloud properties, we compared DCOEW output data with other operational satellite data. For COT and CER validation, we used two different data sets. To compare algorithms that use cloud reflectance at visible and near-IR channels as input data, MODIS MYD06 cloud product was selected. For the validation with cloud products that are based on microwave measurements, COT(2B-TAU)/CER(2C-ICE) data retrieved from CloudSat cloud profiling radar (W-band, 94 GHz) was used. For cloud water path validation, AMSR-2 Level-3 Cloud liquid water data was used. Detailed results will be shown at the conference.

Co-localization of a CD1d-binding glycolipid with an adenovirus-based malaria vaccine for a potent adjuvant effect.

PubMed

Li, Xiangming; Huang, Jing; Kawamura, Akira; Funakoshi, Ryota; Porcelli, Steven A; Tsuji, Moriya

2017-05-31

A CD1d-binding, invariant (i) natural killer T (NKT)-cell stimulatory glycolipid, α-Galactosylceramide (αGalCer), has been shown to act as an adjuvant. We previously identified a fluorinated phenyl ring-modified αGalCer analog, 7DW8-5, displaying a higher binding affinity for CD1d molecule and more potent adjuvant activity than αGalCer. In the present study, 7DW8-5 co-administered intramuscularly (i.m.) with a recombinant adenovirus expressing a Plasmodium yoelii circumsporozoite protein (PyCSP), AdPyCS, has led to a co-localization of 7DW8-5 and a PyCSP in draining lymph nodes (dLNs), particularly in dendritic cells (DCs). This occurrence initiates a cascade of events, such as the recruitment of DCs to dLNs and their activation and maturation, and the enhancement of the ability of DCs to prime CD8+ T cells induced by AdPyCS and ultimately leading to a potent adjuvant effect and protection against malaria. Copyright © 2017 Elsevier Ltd. All rights reserved.

Glucosylceramide Administration as a Vaccination Strategy in Mouse Models of Cryptococcosis.

PubMed

Mor, Visesato; Farnoud, Amir M; Singh, Ashutosh; Rella, Antonella; Tanno, Hiromasa; Ishii, Keiko; Kawakami, Kazuyoshi; Sato, Toshiya; Del Poeta, Maurizio

2016-01-01

Cryptococcus neoformans is an opportunistic fungal pathogen and the causative agent of the disease cryptococcosis. Cryptococcosis is initiated as a pulmonary infection and in conditions of immune deficiency disseminates to the blood stream and central nervous system, resulting in life-threatening meningoencephalitis. A number of studies have focused on the development of a vaccine against Cryptococcus, primarily utilizing protein-conjugated components of the Cryptococcus polysaccharide capsule as antigen. However, there is currently no vaccine against Cryptococcus in the clinic. Previous studies have shown that the glycosphingolipid, glucosylceramide (GlcCer), is a virulence factor in C. neoformans and antibodies against this lipid inhibit fungal growth and cell division. In the present study, we have investigated the possibility of using GlcCer as a therapeutic agent against C. neoformans infections in mouse models of cryptococcosis. GlcCer purified from a non-pathogenic fungus, Candida utilis, was administered intraperitoneally, prior to infecting mice with a lethal dose of C. neoformans. GlcCer administration prevented the dissemination of C. neoformans from the lungs to the brain and led to 60% mouse survival. GlcCer administration did not cause hepatic injury and elicited an anti-GlcCer antibody response, which was observed independent of the route of administration and the strains of mouse. Taken together, our results suggest that fungal GlcCer can protect mice against lethal doses of C. neoformans infection and can provide a viable vaccination strategy against Cryptococcus.

Sphingomyelinase-Induced Domain Shape Relaxation Driven by Out-of-Equilibrium Changes of Composition

PubMed Central

Fanani, Maria Laura; De Tullio, Luisina; Hartel, Steffen; Jara, Jorge; Maggio, Bruno

2009-01-01

Abstract Sphingomyelinase (SMase)-induced ceramide (Cer)-enriched domains in a lipid monolayer are shown to result from an out-of-equilibrium situation. This is induced by a change of composition caused by the enzymatic production of Cer in a sphingomyelin (SM) monolayer that leads to a fast SM/Cer demixing into a liquid-condensed (LC), Cer-enriched and a liquid-expanded, SM-enriched phases. The morphological evolution and kinetic dependence of Cer-enriched domains is studied under continuous observation by epifluorescence microscopy. Domain shape annealing is observed from branched to rounded shapes after SMase activity quenching by EDTA, with a decay halftime of ∼10 min. An out-of-equilibrium fast domain growth is not the determinant factor for domain morphology. Domain shape rearrangement in nearly equilibrium conditions result from the counteraction of intradomain dipolar repulsion and line tension, according to McConnell's shape transition theory. Phase separation causes a transient compositional overshoot within the LC phase that implies an increased out-of-equilibrium enrichment of Cer into the LC domains. As a consequence, higher intradomain repulsion leads to transient branched structures that relax to rounded shapes by lowering the proportion of Cer in the domain to equilibrium values. The fast action of SMase can be taken as a compositional perturbation that brings about important consequences for the surface organization. PMID:18849413

Glucosylceramide Contained in Koji Mold-Cultured Cereal Confers Membrane and Flavor Modification and Stress Tolerance to Saccharomyces cerevisiae during Coculture Fermentation.

PubMed

Sawada, Kazutaka; Sato, Tomoya; Hamajima, Hiroshi; Jayakody, Lahiru Niroshan; Hirata, Miyo; Yamashiro, Mikako; Tajima, Marie; Mitsutake, Susumu; Nagao, Koji; Tsuge, Keisuke; Abe, Fumiyoshi; Hanada, Kentaro; Kitagaki, Hiroshi

2015-06-01

In nature, different microorganisms create communities through their physiochemical and metabolic interactions. Many fermenting microbes, such as yeasts, lactic acid bacteria, and acetic acid bacteria, secrete acidic substances and grow faster at acidic pH values. However, on the surface of cereals, the pH is neutral to alkaline. Therefore, in order to grow on cereals, microbes must adapt to the alkaline environment at the initial stage of colonization; such adaptations are also crucial for industrial fermentation. Here, we show that the yeast Saccharomyces cerevisiae, which is incapable of synthesizing glucosylceramide (GlcCer), adapted to alkaline conditions after exposure to GlcCer from koji cereal cultured with Aspergillus kawachii. We also show that various species of GlcCer derived from different plants and fungi similarly conferred alkali tolerance to yeast. Although exogenous ceramide also enhanced the alkali tolerance of yeast, no discernible degradation of GlcCer to ceramide was observed in the yeast culture, suggesting that exogenous GlcCer itself exerted the activity. Exogenous GlcCer also increased ethanol tolerance and modified the flavor profile of the yeast cells by altering the membrane properties. These results indicate that GlcCer from A. kawachii modifies the physiology of the yeast S. cerevisiae and demonstrate a new mechanism for cooperation between microbes in food fermentation. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Glucosylceramide Contained in Koji Mold-Cultured Cereal Confers Membrane and Flavor Modification and Stress Tolerance to Saccharomyces cerevisiae during Coculture Fermentation

PubMed Central

Sawada, Kazutaka; Sato, Tomoya; Hamajima, Hiroshi; Jayakody, Lahiru Niroshan; Hirata, Miyo; Yamashiro, Mikako; Tajima, Marie; Mitsutake, Susumu; Nagao, Koji; Tsuge, Keisuke; Abe, Fumiyoshi; Hanada, Kentaro

2015-01-01

In nature, different microorganisms create communities through their physiochemical and metabolic interactions. Many fermenting microbes, such as yeasts, lactic acid bacteria, and acetic acid bacteria, secrete acidic substances and grow faster at acidic pH values. However, on the surface of cereals, the pH is neutral to alkaline. Therefore, in order to grow on cereals, microbes must adapt to the alkaline environment at the initial stage of colonization; such adaptations are also crucial for industrial fermentation. Here, we show that the yeast Saccharomyces cerevisiae, which is incapable of synthesizing glucosylceramide (GlcCer), adapted to alkaline conditions after exposure to GlcCer from koji cereal cultured with Aspergillus kawachii. We also show that various species of GlcCer derived from different plants and fungi similarly conferred alkali tolerance to yeast. Although exogenous ceramide also enhanced the alkali tolerance of yeast, no discernible degradation of GlcCer to ceramide was observed in the yeast culture, suggesting that exogenous GlcCer itself exerted the activity. Exogenous GlcCer also increased ethanol tolerance and modified the flavor profile of the yeast cells by altering the membrane properties. These results indicate that GlcCer from A. kawachii modifies the physiology of the yeast S. cerevisiae and demonstrate a new mechanism for cooperation between microbes in food fermentation. PMID:25795678

Effects of the high-density lipoprotein mimetic agent CER-001 on coronary atherosclerosis in patients with acute coronary syndromes: a randomized trial.

PubMed

Tardif, Jean-Claude; Ballantyne, Christie M; Barter, Philip; Dasseux, Jean-Louis; Fayad, Zahi A; Guertin, Marie-Claude; Kastelein, John J P; Keyserling, Constance; Klepp, Heather; Koenig, Wolfgang; L'Allier, Philippe L; Lespérance, Jacques; Lüscher, Thomas F; Paolini, John F; Tawakol, Ahmed; Waters, David D

2014-12-07

High-density lipoproteins (HDLs) have several potentially protective vascular effects. Most clinical studies of therapies targeting HDL have failed to show benefits vs. placebo. To investigate the effects of an HDL-mimetic agent on atherosclerosis by intravascular ultrasonography (IVUS) and quantitative coronary angiography (QCA). A prospective, double-blinded, randomized trial was conducted at 51 centres in the USA, the Netherlands, Canada, and France. Intravascular ultrasonography and QCA were performed to assess coronary atherosclerosis at baseline and 3 (2-5) weeks after the last study infusion. Five hundred and seven patients were randomized; 417 and 461 had paired IVUS and QCA measurements, respectively. Patients were randomized to receive 6 weekly infusions of placebo, 3 mg/kg, 6 mg/kg, or 12 mg/kg CER-001. The primary efficacy parameter was the nominal change in the total atheroma volume. Nominal changes in per cent atheroma volume on IVUS and coronary scores on QCA were also pre-specified endpoints. The nominal change in the total atheroma volume (adjusted means) was -2.71, -3.13, -1.50, and -3.05 mm(3) with placebo, CER-001 3 mg/kg, 6 mg/kg, and 12 mg/kg, respectively (primary analysis of 12 mg/kg vs. placebo: P = 0.81). There was also no difference among groups for the nominal change in per cent atheroma volume (0.02, -0.02, 0.01, and 0.19%; nominal P = 0.53 for 12 mg/kg vs. placebo). Change in the coronary artery score was -0.022, -0.036, -0.022, and -0.015 mm (nominal P = 0.25, 0.99, 0.55), and change in the cumulative coronary stenosis score was -0.51, 2.65, 0.71, and -0.77% (compared with placebo, nominal P = 0.85 for 12 mg/kg and nominal P = 0.01 for 3 mg/kg). The number of patients with major cardiovascular events was 10 (8.3%), 16 (13.3%), 17 (13.7%), and 12 (9.8%) in the four groups. CER-001 infusions did not reduce coronary atherosclerosis on IVUS and QCA when compared with placebo. Whether CER-001 administered in other regimens or to other populations could favourably affect atherosclerosis must await further study. Name of the trial registry: Clinicaltrials.gov; Registry's URL: http://clinicaltrials.gov/ct2/show/NCT01201837?term=cer-001&rank=2; NCT01201837. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.

75 FR 11105 - Kootenai (KNF) and Idaho Panhandle National Forests (IPNF); Montana, Idaho and Washington...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-10

... plan revision. The Comprehensive Evaluation Report (CER) provided for public review and comment in 2006, built upon the AMS and documents the evaluation of the 1987 Forest Plans and proposed changes. The CER.... The CER, under the 2005 and 2008 Planning Rules, served as the principle document that supported the...

Foreign Language Analysis and Recognition (FLARe)

DTIC Science & Technology

2016-10-08

10 7 Chinese CER ...Rates ( CERs ) were obtained with each feature set: (1) 19.2%, (2) 17.3%, and (3) 15.3%. Based on these results, a GMM-HMM speech recognition system...These systems were evaluated on the HUB4 and HKUST test partitions. Table 7 shows the CER obtained on each test set. Whereas including the HKUST data

Intermittent v. continuous energy restriction: differential effects on postprandial glucose and lipid metabolism following matched weight loss in overweight/obese participants.

PubMed

Antoni, Rona; Johnston, Kelly L; Collins, Adam L; Robertson, M Denise

2018-03-01

The intermittent energy restriction (IER) approach to weight loss involves short periods of substantial (>70 %) energy restriction (ER) interspersed with normal eating. Studies to date comparing IER to continuous energy restriction (CER) have predominantly measured fasting indices of cardiometabolic risk. This study aimed to compare the effects of IER and CER on postprandial glucose and lipid metabolism following matched weight loss. In all, twenty-seven (thirteen male) overweight/obese participants (46 (sem 3) years, 30·1 (sem 1·0) kg/m2) who were randomised to either an IER intervention (2638 kJ for 2 d/week with an overall ER of 22 (sem 0·3) %, n 15) or a CER intervention (2510 kJ below requirements with overall ER of 23 (sem 0·8) %) completed the study. Postprandial responses to a test meal (over 360 min) and changes in anthropometry (fat mass, fat-free mass, circumferences) were assessed at baseline and upon attainment of 5 % weight loss, following a 7-d period of weight stabilisation. The study found no statistically significant difference in the time to attain a 5 % weight loss between groups (median 59 d (interquartile range (IQR) 41-80) and 73 d (IQR 48-128), respectively, P=0·246), or in body composition (P≥0·437). For postprandial measures, neither diet significantly altered glycaemia (P=0·266), whereas insulinaemia was reduced comparatively (P=0·903). The reduction in C-peptide tended (P=0·057) to be greater following IER (309 128 (sem23 268) to 247781 (sem20 709) pmol×360 min/l) v. CER (297 204 (sem25 112) to 301 655 (sem32 714) pmol×360 min/l). The relative reduction in TAG responses was greater (P=0·045) following IER (106 (sem30) to 68 (sem 15) mmol×360 min/l) compared with CER (117 (sem 43) to 130 (sem 31) mmol×360 min/l). In conclusion, these preliminary findings highlight underlying differences between IER and CER, including a superiority of IER in reducing postprandial lipaemia, which now warrant targeted mechanistic evaluation within larger study cohorts.

Analyses of barley spike mutant waxes identify alkenes, cyclopropanes and internally branched alkanes with dominating isomers at carbon 9.

PubMed

von Wettstein-Knowles, Penny

2007-01-01

About 15% of the epidermal wax on Hordeum vulgare cv. Bonus barley spikes is n-alkanes. Longer homologues are greatly reduced in the eceriferum mutants, cer-a(6), cer-e(8), cer-n(26), cer-n(53), cer-n(985), cer-x(60), cer-yc(135) and cer-yl(187). Simultaneously hydrocarbons accounting for only traces in the wild-type become prominent in the mutants, although their chain-length distributions remain unchanged. Accordingly several new hydrocarbon series were identified. The two major ones were C(23)-C(35)cis monoenoic alkenes (the major 9-ene isomer was part of a homologous series including 11, 13 and 15-enes), and the novel C(27)-C(31) cyclopropanes (the ring carbons of major isomers were 9,10 and 11,12 with lesser amounts of 13,14). Three minor series included 2- and 3-methylalkanes plus C(25)-C(33) internally branched alkanes (methyls on carbons 9, 11, 13, 15 or 17; shorter homologues dominated by the 9 isomer, longer homologues by 11, 13 or 15 isomers). Acyl chains destined for spike waxes are synthesized via acyl and polyketide elongase systems plus associated reductive and decarbonylative/decarboxylative enzyme systems. Both elongation systems are defective in synthesizing C(32) acyl chains in all nine mutants. The similarities in the position of the chemical groups (primarily on carbon 9, secondarily on carbon 11) of the alkenes, cyclopropanes and internally branched methyl alkanes imply an origin from a common, hitherto unrecognized associated pathway in barley, designated the enoic pathway. The elongation system leading to the enoic derived hydrocarbons differs from the known elongation systems by inclusion of a mechanism for introducing a double bond.

Self-recognition of high-mannose type glycans mediating adhesion of embryonal fibroblasts.

PubMed

Yoon, Seon-Joo; Utkina, Natalia; Sadilek, Martin; Yagi, Hirokazu; Kato, Koichi; Hakomori, Sen-itiroh

2013-07-01

High-mannose type N-linked glycan with 6 mannosyl residues, termed "M6Gn2", displayed clear binding to the same M6Gn2, conjugated with ceramide mimetic (cer-m) and incorporated in liposome, or coated on polystyrene plates. However, the conjugate of M6Gn2-cer-m did not interact with complex-type N-linked glycan with various structures having multiple GlcNAc termini, conjugated with cer-m. The following observations indicate that hamster embryonic fibroblast NIL-2 K cells display homotypic autoadhesion, mediated through the self-recognition capability of high-mannose type glycans expressed on these cells: (i) NIL-2 K cells display clear binding to lectins capable of binding to high-mannose type glycans (e.g., ConA), but not to other lectins capable of binding to other carbohydrates (e.g. GS-II). (ii) NIL-2 K cells adhere strongly to plates coated with M6Gn2-cer-m, but not to plates coated with complex-type N-linked glycans having multiple GlcNAc termini, conjugated with cer-m; (iii) degree of NIL-2 K cell adhesion to plates coated with M6Gn2-cer-m showed a clear dose-dependence on the amount of M6Gn2-cer-m; and (iv) the degree of NIL-2 K adhesion to plates coated with M6Gn2-cer-m was inhibited in a dose-dependent manner by α1,4-L-mannonolactone, the specific inhibitor in high-mannose type glycans addition. These data indicate that adhesion of NIL-2 K is mediated by self-aggregation of high mannose type glycan. Further studies are to be addressed on auto-adhesion of other types of cells based on self interaction of high mannose type glycans.

Non-clinical development of CER-001

PubMed Central

Barbaras, Ronald

2015-01-01

Cardiovascular disease remains the most pressing healthcare issue for the developed world and is becoming so for developing countries. There are no currently approved therapies that can rapidly reduce the burden of unstable, inflamed plaque in the overall coronary vascular bed. High-density lipoprotein (HDL) has multiple actions that could lead to plaque stabilization, such as rapid removal of large quantities of cholesterol from the vasculature through the process of reverse lipid transport, improvement in endothelial function, protection against oxidative damage, and reduction in inflammation. Short-term infusion of HDL-mimetics in animal models as well as in humans has shown promising effects on the plaque size and morphology. Cerenis Therapeutics has developed CER-001, a negatively charged lipoprotein complex consisting of phospholipid and recombinant human apoA-I that mimics the structure and function of natural HDL. Three clinical trials using CER-001 infusions have demonstrated improvements in the carotid wall thickness of patients with familial hypercholesterolaemia and in patients with hypo-alphalipoproteinaemia, as well as an impact on coronary plaque burden measured by intravascular ultrasonography at the lowest tested dose (3 mg/kg) in post-ACS patients. Here, we reviewed the non-clinical data leading to the demonstration that CER-001 is a full HDL mimetic. PMID:26500552

Direct observation of current-induced conductive path in colossal-electroresistance manganite thin films

NASA Astrophysics Data System (ADS)

Wei, Wengang; Zhu, Yinyan; Bai, Yu; Liu, Hao; Du, Kai; Zhang, Kai; Kou, Yunfang; Shao, Jian; Wang, Wenbin; Hou, Denglu; Dong, Shuai; Yin, Lifeng; Shen, Jian

2016-01-01

Manganites are known to often show colossal electroresistance (CER) in addition to colossal magnetoresistance. The (La1-yP ry) 1 -xC axMn O3 (LPCMO) system has a peculiar CER behavior in that little change of magnetization occurs. We use a magnetic force microscope to uncover the CER mechanism in the LPCMO system. In contrast to the previous belief that current reshapes the ferromagnetic metallic (FMM) domains, we show that the shape of the FMM domains remain virtually unchanged after passing electric current. Instead, it is the appearance of a tiny fraction of FMM "bridges" that is responsible for the CER behavior.

Assessment of Confounders in Comparative Effectiveness Studies From Secondary Databases.

PubMed

Franklin, Jessica M; Schneeweiss, Sebastian; Solomon, Daniel H

2017-03-15

Secondary clinical databases are an important and growing source of data for comparative effectiveness research (CER) studies. However, measurement of confounders, such as biomarker values or patient-reported health status, in secondary clinical databases may not align with the initiation of a new treatment. In many published CER analyses of registry data, investigators assessed confounders based on the first questionnaire in which the new exposure was recorded. However, it is known that adjustment for confounders measured after the start of exposure can lead to biased treatment effect estimates. In the present study, we conducted simulations to compare assessment strategies for a dynamic clinical confounder in a registry-based comparative effectiveness study of 2 therapies. As expected, we found that adjustment for the confounder value at the time of the first questionnaire after the start of exposure creates a biased estimate the total effect of exposure choice on outcome when the confounder mediates part of the effect. However, adjustment for the prior value can also be badly biased when measured long before exposure initiation. Thus, investigators should carefully consider the timing of confounder measurements relative to exposure initiation and the rate of change in the confounder in order to choose the most relevant measure for each patient. © The Author 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Overexpression of ceramide synthase 1 increases C18-ceramide and leads to lethal autophagy in human glioma

PubMed Central

Wang, Zheng; Wen, Lijun; Zhu, Fei; Wang, Yanping; Xie, Qing; Chen, Zijun; Li, Yunsen

2017-01-01

Ceramide synthase 1 (CERS1) is the most highly expressed CERS in the central nervous system, and ceramide with an 18-carbon–containing fatty acid chain (C18-ceramide) in the brain plays important roles in signaling and sphingolipid development. However, the roles of CERS1 and C18-ceramide in glioma are largely unknown. In the present study, measured by electrospray ionization linear ion trap mass spectrometry, C18-ceramide was significantly lower in glioma tumor tissues compared with controls (P < 0.001), indicating that C18-ceramide might have a role in glioma. These roles were examined by reconstitution of C18-ceramide in U251 and A172 glioma cells via addition of exogenous C18-ceramide or overexpression of CERS1, which has been shown to specifically induce the generation of C18-ceramide. Overexpression of CERS1 or adding exogenous C18-ceramide inhibited cell viability and induced cell death by activating endoplasmic reticulum stress, which induced lethal autophagy and inhibited PI3K/AKT signal pathway in U251 and A172 glioma cells. Moreover, overexpression of CERS1 or adding exogenous C18-ceramide increased the sensitivity of U251 and A172 glioma cells to teniposide (VM-26). Thus, the combined therapy of CERS1/C18-ceramide and VM-26 may be a novel therapeutic strategy for the treatment of human glioma. PMID:29262618

Glucosylceramide Administration as a Vaccination Strategy in Mouse Models of Cryptococcosis

PubMed Central

Mor, Visesato; Farnoud, Amir M.; Singh, Ashutosh; Rella, Antonella; Tanno, Hiromasa; Ishii, Keiko; Kawakami, Kazuyoshi; Sato, Toshiya; Del Poeta, Maurizio

2016-01-01

Cryptococcus neoformans is an opportunistic fungal pathogen and the causative agent of the disease cryptococcosis. Cryptococcosis is initiated as a pulmonary infection and in conditions of immune deficiency disseminates to the blood stream and central nervous system, resulting in life-threatening meningoencephalitis. A number of studies have focused on the development of a vaccine against Cryptococcus, primarily utilizing protein-conjugated components of the Cryptococcus polysaccharide capsule as antigen. However, there is currently no vaccine against Cryptococcus in the clinic. Previous studies have shown that the glycosphingolipid, glucosylceramide (GlcCer), is a virulence factor in C. neoformans and antibodies against this lipid inhibit fungal growth and cell division. In the present study, we have investigated the possibility of using GlcCer as a therapeutic agent against C. neoformans infections in mouse models of cryptococcosis. GlcCer purified from a non-pathogenic fungus, Candida utilis, was administered intraperitoneally, prior to infecting mice with a lethal dose of C. neoformans. GlcCer administration prevented the dissemination of C. neoformans from the lungs to the brain and led to 60% mouse survival. GlcCer administration did not cause hepatic injury and elicited an anti-GlcCer antibody response, which was observed independent of the route of administration and the strains of mouse. Taken together, our results suggest that fungal GlcCer can protect mice against lethal doses of C. neoformans infection and can provide a viable vaccination strategy against Cryptococcus. PMID:27082428

Performance analysis of Rogowski coils and the measurement of the total toroidal current in the ITER machine

NASA Astrophysics Data System (ADS)

Quercia, A.; Albanese, R.; Fresa, R.; Minucci, S.; Arshad, S.; Vayakis, G.

2017-12-01

The paper carries out a comprehensive study of the performances of Rogowski coils. It describes methodologies that were developed in order to assess the capabilities of the Continuous External Rogowski (CER), which measures the total toroidal current in the ITER machine. Even though the paper mainly considers the CER, the contents are general and relevant to any Rogowski sensor. The CER consists of two concentric helical coils which are wound along a complex closed path. Modelling and computational activities were performed to quantify the measurement errors, taking detailed account of the ITER environment. The geometrical complexity of the sensor is accurately accounted for and the standard model which provides the classical expression to compute the flux linkage of Rogowski sensors is quantitatively validated. Then, in order to take into account the non-ideality of the winding, a generalized expression, formally analogue to the classical one, is presented. Models to determine the worst case and the statistical measurement accuracies are hence provided. The following sources of error are considered: effect of the joints, disturbances due to external sources of field (the currents flowing in the poloidal field coils and the ferromagnetic inserts of ITER), deviations from ideal geometry, toroidal field variations, calibration, noise and integration drift. The proposed methods are applied to the measurement error of the CER, in particular in its high and low operating ranges, as prescribed by the ITER system design description documents, and during transients, which highlight the large time constant related to the shielding of the vacuum vessel. The analyses presented in the paper show that the design of the CER diagnostic is capable of achieving the requisite performance as needed for the operation of the ITER machine.

IDA 2004 Cost Research Symposium: Investments in, Use of, and Management of Cost Research

DTIC Science & Technology

2004-09-01

Database: None Publication: Technical Report Keywords: Government, Aircraft, SD&D, Production, Integration, Data Collection, Database, CER B- 71 ... Martin Plant in Marietta , Georgia,” IDA Paper P-3590, July 2001 “Econometric Modeling of Acquisition Category I Systems at the Raytheon Plant in...NAVSEA) ............................................................ B- 71 Naval Surface Warfare Center, Dahlgren Division (NSWCDD

Test-Retest Reliability of the Adaptive Chemistry Assessment Survey for Teachers: Measurement Error and Alternatives to Correlation

ERIC Educational Resources Information Center

Harshman, Jordan; Yezierski, Ellen

2016-01-01

Determining the error of measurement is a necessity for researchers engaged in bench chemistry, chemistry education research (CER), and a multitude of other fields. Discussions regarding what constructs measurement error entails and how to best measure them have occurred, but the critiques about traditional measures have yielded few alternatives.…

What We See, What Is Missing, and What Has Fallen Away: The 2011 "Comparative Education Review" Bibliography

ERIC Educational Resources Information Center

Stambach, Amy; Cappy, Christina

2012-01-01

Each year, the "CER" publishes a free, open-access bibliography that records the previous year's published research in the field of comparative and international education. The bibliography serves as a guide for researchers, teachers, policy makers, and students who wish to track developments within the field of comparative and international…

A Novel Qualitative Method to Improve Access, Elicitation, and Sample Diversification for Enhanced Transferability Applied to Studying Chemistry Outreach

ERIC Educational Resources Information Center

Pratt, Justin M.; Yezierski, Ellen J.

2018-01-01

Conducting qualitative research in any discipline warrants two actions: accessing participants and eliciting their ideas. In chemistry education research (CER), survey techniques have been used to increase access to participants and diversify samples. Interview tasks (such as card sorting, using demonstrations, and using simulations) have been…

Sustainability considerations for health research and analytic data infrastructures.

PubMed

Wilcox, Adam; Randhawa, Gurvaneet; Embi, Peter; Cao, Hui; Kuperman, Gilad J

2014-01-01

The United States has made recent large investments in creating data infrastructures to support the important goals of patient-centered outcomes research (PCOR) and comparative effectiveness research (CER), with still more investment planned. These initial investments, while critical to the creation of the infrastructures, are not expected to sustain them much beyond the initial development. To provide the maximum benefit, the infrastructures need to be sustained through innovative financing models while providing value to PCOR and CER researchers. Based on our experience with creating flexible sustainability strategies (i.e., strategies that are adaptive to the different characteristics and opportunities of a resource or infrastructure), we define specific factors that are important considerations in developing a sustainability strategy. These factors include assets, expansion, complexity, and stakeholders. Each factor is described, with examples of how it is applied. These factors are dimensions of variation in different resources, to which a sustainability strategy should adapt. We also identify specific important considerations for maintaining an infrastructure, so that the long-term intended benefits can be realized. These observations are presented as lessons learned, to be applied to other sustainability efforts. We define the lessons learned, relating them to the defined sustainability factors as interactions between factors. Using perspectives and experiences from a diverse group of experts, we define broad characteristics of sustainability strategies and important observations, which can vary for different projects. Other descriptions of adaptive, flexible, and successful models of collaboration between stakeholders and data infrastructures can expand this framework by identifying other factors for sustainability, and give more concrete directions on how sustainability can be best achieved.

Plasma membrane domains enriched in cortical endoplasmic reticulum function as membrane protein trafficking hubs.

PubMed

Fox, Philip D; Haberkorn, Christopher J; Weigel, Aubrey V; Higgins, Jenny L; Akin, Elizabeth J; Kennedy, Matthew J; Krapf, Diego; Tamkun, Michael M

2013-09-01

In mammalian cells, the cortical endoplasmic reticulum (cER) is a network of tubules and cisterns that lie in close apposition to the plasma membrane (PM). We provide evidence that PM domains enriched in underlying cER function as trafficking hubs for insertion and removal of PM proteins in HEK 293 cells. By simultaneously visualizing cER and various transmembrane protein cargoes with total internal reflectance fluorescence microscopy, we demonstrate that the majority of exocytotic delivery events for a recycled membrane protein or for a membrane protein being delivered to the PM for the first time occur at regions enriched in cER. Likewise, we observed recurring clathrin clusters and functional endocytosis of PM proteins preferentially at the cER-enriched regions. Thus the cER network serves to organize the molecular machinery for both insertion and removal of cell surface proteins, highlighting a novel role for these unique cellular microdomains in membrane trafficking.

Plasma membrane domains enriched in cortical endoplasmic reticulum function as membrane protein trafficking hubs

PubMed Central

Fox, Philip D.; Haberkorn, Christopher J.; Weigel, Aubrey V.; Higgins, Jenny L.; Akin, Elizabeth J.; Kennedy, Matthew J.; Krapf, Diego; Tamkun, Michael M.

2013-01-01

In mammalian cells, the cortical endoplasmic reticulum (cER) is a network of tubules and cisterns that lie in close apposition to the plasma membrane (PM). We provide evidence that PM domains enriched in underlying cER function as trafficking hubs for insertion and removal of PM proteins in HEK 293 cells. By simultaneously visualizing cER and various transmembrane protein cargoes with total internal reflectance fluorescence microscopy, we demonstrate that the majority of exocytotic delivery events for a recycled membrane protein or for a membrane protein being delivered to the PM for the first time occur at regions enriched in cER. Likewise, we observed recurring clathrin clusters and functional endocytosis of PM proteins preferentially at the cER-enriched regions. Thus the cER network serves to organize the molecular machinery for both insertion and removal of cell surface proteins, highlighting a novel role for these unique cellular microdomains in membrane trafficking. PMID:23864710

Statistical Power of Alternative Structural Models for Comparative Effectiveness Research: Advantages of Modeling Unreliability.

PubMed

Coman, Emil N; Iordache, Eugen; Dierker, Lisa; Fifield, Judith; Schensul, Jean J; Suggs, Suzanne; Barbour, Russell

2014-05-01

The advantages of modeling the unreliability of outcomes when evaluating the comparative effectiveness of health interventions is illustrated. Adding an action-research intervention component to a regular summer job program for youth was expected to help in preventing risk behaviors. A series of simple two-group alternative structural equation models are compared to test the effect of the intervention on one key attitudinal outcome in terms of model fit and statistical power with Monte Carlo simulations. Some models presuming parameters equal across the intervention and comparison groups were underpowered to detect the intervention effect, yet modeling the unreliability of the outcome measure increased their statistical power and helped in the detection of the hypothesized effect. Comparative Effectiveness Research (CER) could benefit from flexible multi-group alternative structural models organized in decision trees, and modeling unreliability of measures can be of tremendous help for both the fit of statistical models to the data and their statistical power.

Electronic health record use to classify patients with newly diagnosed versus preexisting type 2 diabetes: infrastructure for comparative effectiveness research and population health management.

PubMed

Kudyakov, Rustam; Bowen, James; Ewen, Edward; West, Suzanne L; Daoud, Yahya; Fleming, Neil; Masica, Andrew

2012-02-01

Use of electronic health record (EHR) content for comparative effectiveness research (CER) and population health management requires significant data configuration. A retrospective cohort study was conducted using patients with diabetes followed longitudinally (N=36,353) in the EHR deployed at outpatient practice networks of 2 health care systems. A data extraction and classification algorithm targeting identification of patients with a new diagnosis of type 2 diabetes mellitus (T2DM) was applied, with the main criterion being a minimum 30-day window between the first visit documented in the EHR and the entry of T2DM on the EHR problem list. Chart reviews (N=144) validated the performance of refining this EHR classification algorithm with external administrative data. Extraction using EHR data alone designated 3205 patients as newly diagnosed with T2DM with classification accuracy of 70.1%. Use of external administrative data on that preselected population improved classification accuracy of cases identified as new T2DM diagnosis (positive predictive value was 91.9% with that step). Laboratory and medication data did not help case classification. The final cohort using this 2-stage classification process comprised 1972 patients with a new diagnosis of T2DM. Data use from current EHR systems for CER and disease management mandates substantial tailoring. Quality between EHR clinical data generated in daily care and that required for population health research varies. As evidenced by this process for classification of newly diagnosed T2DM cases, validation of EHR data with external sources can be a valuable step.

Biological effects of polyacrylic acid-coated and non-coated superparamagnetic iron oxide nanoparticles in in vitro and in vivo experimental models

NASA Astrophysics Data System (ADS)

Couto, Diana Manuel Mocho de Bastos

As piroxenas sao um vasto grupo de silicatos minerais encontrados em muitas rochas igneas e metamorficas. Na sua forma mais simples, estes silicatos sao constituidas por cadeias de SiO3 ligando grupos tetrahedricos de SiO4. A formula quimica geral das piroxenas e M2M1T2O6, onde M2 se refere a catioes geralmente em uma coordenacao octaedrica distorcida (Mg2+, Fe2+, Mn2+, Li+, Ca2+, Na+), M1 refere-se a catioes numa coordenacao octaedrica regular (Al3+, Fe3+, Ti4+, Cr3+, V3+, Ti3+, Zr4+, Sc3+, Zn2+, Mg2+, Fe2+, Mn2+), e T a catioes em coordenacao tetrahedrica (Si4+, Al3+, Fe3+). As piroxenas com estrutura monoclinica sao designadas de clinopiroxenes. A estabilidade das clinopyroxenes num espectro de composicoes quimicas amplo, em conjugacao com a possibilidade de ajustar as suas propriedades fisicas e quimicas e a durabilidade quimica, tem gerado um interesse mundial devido a suas aplicacoes em ciencia e tecnologia de materiais. Este trabalho trata do desenvolvimento de vidros e de vitro-cerâmicos baseadas de clinopiroxenas para aplicacoes funcionais. O estudo teve objectivos cientificos e tecnologicos; nomeadamente, adquirir conhecimentos fundamentais sobre a formacao de fases cristalinas e solucoes solidas em determinados sistemas vitro-cerâmicos, e avaliar a viabilidade de aplicacao dos novos materiais em diferentes areas tecnologicas, com especial enfase sobre a selagem em celulas de combustivel de oxido solido (SOFC). Com este intuito, prepararam-se varios vidros e materiais vitro-cerâmicos ao longo das juntas Enstatite (MgSiO3) - diopsidio (CaMgSi2O6) e diopsidio (CaMgSi2O6) - Ca - Tschermak (CaAlSi2O6), os quais foram caracterizados atraves de um vasto leque de tecnicas. Todos os vidros foram preparados por fusao-arrefecimento enquanto os vitro-cerâmicos foram obtidos quer por sinterizacao e cristalizacao de fritas, quer por nucleacao e cristalizacao de vidros monoliticos. Estudaram-se ainda os efeitos de varias substituicoes ionicas em composicoes de diopsidio contendo Al na estrutura, sinterizacao e no comportamento durante a cristalizacao de vidros e nas propriedades dos materiais vitro-cerâmicos, com relevância para a sua aplicacao como selantes em SOFC. Verificou-se que Foi observado que os vidros/vitro-cerâmicos a base de enstatite nao apresentavam as caracteristicas necessarias para serem usados como materiais selantes em SOFC, enquanto as melhores propriedades apresentadas pelos vitro-cerâmicos a base de diopsidio qualificaram-nos para futuros estudos neste tipo de aplicacoes. Para alem de investigar a adequacao dos vitro-cerâmicos a base de clinopyroxene como selantes, esta tese tem tambem como objetivo estudar a influencia dos agentes de nucleacao na nucleacao em volume dos vitro-cerâmicos resultantes a base de diopsidio, de modo a qualifica-los como potenciais materiais hopedeiros de residuos nucleares radioactivos.

Parametric study of helicopter aircraft systems costs and weights

NASA Technical Reports Server (NTRS)

Beltramo, M. N.

1980-01-01

Weight estimating relationships (WERs) and recurring production cost estimating relationships (CERs) were developed for helicopters at the system level. The WERs estimate system level weight based on performance or design characteristics which are available during concept formulation or the preliminary design phase. The CER (or CERs in some cases) for each system utilize weight (either actual or estimated using the appropriate WER) and production quantity as the key parameters.

Involvement of glycosphingolipid-enriched lipid rafts in inflammatory responses.

PubMed

Iwabuchi, Kazuhisa

2015-01-01

Glycosphingolipids (GSLs) are membrane components consisting of hydrophobic ceramide and hydrophilic sugar moieties. GSLs cluster with cholesterol in cell membranes to form GSL-enriched lipid rafts. Biochemical analyses have demonstrated that GSL-enriched lipid rafts contain several kinds of transducer molecules, including Src family kinases. Among the GSLs, lactosylceramide (LacCer, CDw17) can bind to various microorganisms, is highly expressed on the plasma membranes of human phagocytes, and forms lipid rafts containing the Src family tyrosine kinase Lyn. LacCer-enriched lipid rafts mediate immunological and inflammatory reactions, including superoxide generation, chemotaxis, and non-opsonic phagocytosis. Therefore, LacCer-enriched membrane microdomains are thought to function as pattern recognition receptors (PRRs), which recognize pathogen-associated molecular patterns (PAMPs) expressed on microorganisms. LacCer also serves as a signal transduction molecule for functions mediated by CD11b/CD18-integrin (αM/β2-integrin, CR3, Mac-1), as well as being associated with several key cellular processes. LacCer recruits PCKα/ε and phospholipase A2 to stimulate PECAM-1 expression in human monocytes and their adhesion to endothelial cells, as well as regulating β1-integrin clustering and endocytosis on cell surfaces. This review describes the organizational and inflammation-related functions of LacCer-enriched lipid rafts.

Natural Killer T Cell Activation Protects Mice Against Experimental Autoimmune Encephalomyelitis

PubMed Central

Singh, Avneesh K.; Wilson, Michael T.; Hong, Seokmann; Olivares-Villagómez, Danyvid; Du, Caigan; Stanic, Aleksandar K.; Joyce, Sebastian; Sriram, Subramaniam; Koezuka, Yasuhiko; Van Kaer, Luc

2001-01-01

Experimental autoimmune encephalomyelitis (EAE) serves as a prototypic model for T cell–mediated autoimmunity. Vα14 natural killer T (NKT) cells are a subset of T lymphocytes that recognize glycolipid antigens presented by the nonpolymorphic major histocompatibility complex (MHC) class I–like protein CD1d. Here, we show that activation of Vα14 NKT cells by the glycosphingolipid α-galactosylceramide (α-GalCer) protects susceptible mice against EAE. β-GalCer, which binds CD1d but is not recognized by NKT cells, failed to protect mice against EAE. Furthermore, α-GalCer was unable to protect CD1d knockout (KO) mice against EAE, indicating the requirement for an intact CD1d antigen presentation pathway. Protection of disease conferred by α-GalCer correlated with its ability to suppress myelin antigen-specific Th1 responses and/or to promote myelin antigen-specific Th2 cell responses. α-GalCer was unable to protect IL-4 KO and IL-10 KO mice against EAE, indicating a critical role for both of these cytokines. Because recognition of α-GalCer by NKT cells is phylogenetically conserved, our findings have identified NKT cells as novel target cells for treatment of inflammatory diseases of the central nervous system. PMID:11748281

Relationship between Water and Carbon Utilization under Different Straw Mulching and Plant Density of Summer Maize in North China Plain

NASA Astrophysics Data System (ADS)

Liu, Quanru; Du, Shoujian; Yin, Honglian; Wang, Juan

2018-03-01

To explore the relationship between water and carbon utilization and key factors to keep high water use efficiency (WUE), a 2-yr experiment was conduct by covering 0 and 0.6 kg m-2 straw to the surface of soil with plant densities of 1.0 × 105, 7.5 × 104, and 5.5 × 104 plants ha-1 in North China Plain during summer maize growing seasons of the 2012 and 2013. Results showed that straw mulching not only increased grain yield (GY), WUE, and carbon efficient ratio (CER) but also inhibited CO2 emission significantly. WUE positively correlated with CER, GY and negative correlated with evapotranspiration (ET) and CO2 emission. CER had the larger direct effect on WUE compared with ET and CO2 emission. The results indicate that straw mulching management in summer maize growing seasons could make sense for inhibiting CO2 emission.

Bioequivalence of cyclobenzaprine hydrochloride extended-release capsule taken intact or sprinkled over applesauce
.

PubMed

Adar, Liat; Zarycranski, William; Conner, Jill B; Dragone, Jeffrey; Janka, Lindsay; Rabinovich-Guilatt, Laura

2017-12-01

Difficulty swallowing pills can compromise pain control in painful musculoskeletal disorders. This open-label, 2-period crossover study assessed pharmacokinetics and safety of cyclobenzaprine extended-release (CER) 30-mg capsule contents sprinkled over applesauce compared with intact capsules in healthy subjects. 32 subjects were randomized to treatment sequences AB or BA (A = single CER intact capsule; B = single CER capsule contents sprinkled over applesauce (15 mL)). Treatments were separated by a ≥ 14-day washout. Pharmacokinetic assessments included maximum observed plasma drug concentration (C_max), time to C_max (t_max), time to first quantifiable plasma drug concentration (t_lag), and area under the plasma drug concentration-vs.-time curve from time 0 to the last measurable drug concentration (AUC_0-t) and extrapolated to infinity (AUC_0-∞). Bioequivalence was established if the 90% confidence intervals (CIs) of the geometric least squares (LS) means ratios of B:A of C_max, AUC_0-t, and AUC_0-∞ were 80 - 125%. Safety was also assessed. Mean plasma drug concentration-vs.-time profiles were similar for CER intact and sprinkled over applesauce. The 90% CIs of LS means ratios indicated bioequivalence: C_max 91.96 - 100.76%, AUC_0-t 96.18 - 103.50%, and AUC_0-∞ 95.70 - 103.07%. Median t_max was not significantly different (p > 0.05), and median t_lag was the same (1 hour). All adverse effects were mild and resolved during the study. No clinically meaningful changes were noted for clinical laboratory values. CER capsules intact and sprinkled over applesauce are bioequivalent. Sprinkling CER capsule contents is not expected to affect efficacy or safety and can, therefore, be an option for patients with musculoskeletal pain and difficulty swallowing capsules.
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Free fatty acids chain length distribution affects the permeability of skin lipid model membranes.

PubMed

Uchiyama, Masayuki; Oguri, Masashi; Mojumdar, Enamul H; Gooris, Gert S; Bouwstra, Joke A

2016-09-01

The lipid matrix in the stratum corneum (SC) plays an important role in the barrier function of the skin. The main lipid classes in this lipid matrix are ceramides (CERs), cholesterol (CHOL) and free fatty acids (FFAs). The aim of this study was to determine whether a variation in CER subclass composition and chain length distribution of FFAs affect the permeability of this matrix. To examine this, we make use of lipid model membranes, referred to as stratum corneum substitute (SCS). We prepared SCS containing i) single CER subclass with either a single FFA or a mixture of FFAs and CHOL, or ii) a mixture of various CER subclasses with either a single FFA or a mixture of FFAs and CHOL. In vitro permeation studies were performed using ethyl-p-aminobenzoic acid (E-PABA) as a model drug. The flux of E-PABA across the SCS containing the mixture of FFAs was higher than that across the SCS containing a single FA with a chain length of 24 C atoms (FA C24), while the E-PABA flux was not effected by the CER composition. To select the underlying factors for the changes in permeability, the SCSs were examined by Fourier transform infrared spectroscopy (FTIR) and Small angle X-ray scattering (SAXS). All lipid models demonstrated a similar phase behavior. However, when focusing on the conformational ordering of the individual FFA chains, the shorter chain FFA (with a chain length of 16, 18 or 20 C atoms forming only 11m/m% of the total FFA level) had a higher conformational disordering, while the conformational ordering of the chains of the CER and FA C24 and FA C22 hardly did not change irrespective of the composition of the SCS. In conclusion, the conformational mobility of the short chain FFAs present only at low levels in the model SC lipid membranes has a great impact on the permeability of E-PABA. Copyright © 2016 Elsevier B.V. All rights reserved.

Disrupted functional connectivity of cerebellar default network areas in attention-deficit/hyperactivity disorder

PubMed Central

Kucyi, Aaron; Hove, Michael J.; Biederman, Joseph; Van Dijk, Koene R.A.; Valera, Eve M.

2015-01-01

Attention-deficit/hyperactivity disorder (ADHD) is increasingly understood as a disorder of spontaneous brain-network interactions. The default mode network (DMN), implicated in ADHD-linked behaviors including mind-wandering and attentional fluctuations, has been shown to exhibit abnormal spontaneous functional connectivity (FC) within-network and with other networks (salience, dorsal attention and frontoparietal) in ADHD. Although the cerebellum has been implicated in the pathophysiology of ADHD, it remains unknown whether cerebellar areas of the DMN (CerDMN) exhibit altered FC with cortical networks in ADHD. Here, 23 adults with ADHD and 23 age-, IQ-, and sex-matched controls underwent resting state fMRI. The mean time series of CerDMN areas was extracted, and FC with the whole brain was calculated. Whole-brain between-group differences in FC were assessed. Additionally, relationships between inattention and individual differences in FC were assessed for between-group interactions. In ADHD, CerDMN areas showed positive FC (in contrast to average FC in the negative direction in controls) with widespread regions of salience, dorsal attention and sensorimotor networks. ADHD individuals also exhibited higher FC (more positive correlation) of CerDMN areas with frontoparietal and visual network regions. Within the control group, but not in ADHD, participants with higher inattention had higher FC between CerDMN and regions in the visual and dorsal attention networks. This work provides novel evidence of impaired CerDMN coupling with cortical networks in ADHD and highlights a role of the cerebro-cerebellar interactions in cognitive function. These data provide support for the potential targeting of CerDMN areas for therapeutic interventions in ADHD. PMID:26109476

Analysis of relations between aerosol optical depth and cloud parameters over land and offshore area of Eastern China and America

NASA Astrophysics Data System (ADS)

Chen, Yi-Lun; Fu, Yun-Fei; Yang, Yuan-Jian; Zhang, Ao-Qi

2014-11-01

As we know, China is the largest developing country and the United State (US) is one of the most developed countries of the world. Due to significant differences of the developmental levels between China and the US, different pollutants emissions may be performed. It is found that aerosol optical depth (AOD) over China is much higher than that over America. Since China and the US locate in westerly wind belts, it is feasible to examine the relationship between different AOD and cloud parameters over land and offshore area of the two countries. In this paper, cloud effective radius (CER), liquid water path (LWP) and AOD derived from the Moderate Resolution Imaging Spectroradiometer (MODIS) and circulations supplied by NCEP/NCAR reanalysis data from 2000 to 2013 are employed to explore the relationships between AOD and CER under different LWP levels. Results indicate that there is a clear negative relationship between AOD and CER in different LWP levels over the offshore area contrary to the insignificant relationship over land or the open sea. It suggests that aerosol indirect effects are more obvious over the offshore area.

Evaluation of pH-sensitive fusogenic polymer-modified liposomes co-loaded with antigen and α-galactosylceramide as an anti-tumor vaccine

PubMed Central

OKAZAKI, Seiji; IWASAKI, Tadashi; YUBA, Eiji; WATARAI, Shinobu

2017-01-01

pH-Sensitive fusogenic polymer-modified (pH-sensitive) liposomes co-loaded with tumor model antigen, ovalbumin (OVA), and adjuvant, α-galactosylceramide (α-GalCer) were fabricated and administered subcutaneously into mice. The ability of pH-sensitive liposomes containing OVA and α-GalCer to stimulate cellular and humoral immune responses in vivo was compared with OVA-encapsulating pH-sensitive liposomes as well as with OVA alone. After immunization, significant OVA-specific antibodies were detected in the serum. When sera were analyzed for isotype distribution, antigen-specific IgG1 antibody responses were noted in mice immunized with OVA alone, whereas immunization with OVA-containing pH-sensitive liposomes and with pH-sensitive liposomes containing OVA and α-GalCer resulted in the induction of OVA-specific IgG1 and IgG2b antibody responses. Moreover, more substantial production of IFN-γ and IL-4 was demonstrated in spleen cells from mice immunized with pH-sensitive liposomes having OVA and α-GalCer than OVA-containing pH-sensitive liposomes in vitro. Spleen cells from the immunized mice showed strong cytotoxic activity against E.G7-OVA tumor cells. In addition, prophylactic vaccination efficacy against tumor formation was evaluated. In all mice immunized with pH-sensitive liposomes having OVA and α-GalCer, immunization provided substantial protection from tumor formation. The therapeutic efficacy of pH-sensitive liposomes containing OVA and α-GalCer against already established E.G7-OVA tumors was also investigated. Tumor growth was reduced significantly in all mice treated with pH-sensitive liposomes having OVA and α-GalCer. The provided evidence on the advantage of antigen and α-GalCer co-encapsulation into pH-sensitive liposomes should be considered in the design of future cancer vaccines for prophylactic and therapeutic purposes. PMID:29311431

Evaluation of pH-sensitive fusogenic polymer-modified liposomes co-loaded with antigen and α-galactosylceramide as an anti-tumor vaccine.

PubMed

Okazaki, Seiji; Iwasaki, Tadashi; Yuba, Eiji; Watarai, Shinobu

2018-02-09

pH-Sensitive fusogenic polymer-modified (pH-sensitive) liposomes co-loaded with tumor model antigen, ovalbumin (OVA), and adjuvant, α-galactosylceramide (α-GalCer) were fabricated and administered subcutaneously into mice. The ability of pH-sensitive liposomes containing OVA and α-GalCer to stimulate cellular and humoral immune responses in vivo was compared with OVA-encapsulating pH-sensitive liposomes as well as with OVA alone. After immunization, significant OVA-specific antibodies were detected in the serum. When sera were analyzed for isotype distribution, antigen-specific IgG1 antibody responses were noted in mice immunized with OVA alone, whereas immunization with OVA-containing pH-sensitive liposomes and with pH-sensitive liposomes containing OVA and α-GalCer resulted in the induction of OVA-specific IgG1 and IgG2b antibody responses. Moreover, more substantial production of IFN-γ and IL-4 was demonstrated in spleen cells from mice immunized with pH-sensitive liposomes having OVA and α-GalCer than OVA-containing pH-sensitive liposomes in vitro. Spleen cells from the immunized mice showed strong cytotoxic activity against E.G7-OVA tumor cells. In addition, prophylactic vaccination efficacy against tumor formation was evaluated. In all mice immunized with pH-sensitive liposomes having OVA and α-GalCer, immunization provided substantial protection from tumor formation. The therapeutic efficacy of pH-sensitive liposomes containing OVA and α-GalCer against already established E.G7-OVA tumors was also investigated. Tumor growth was reduced significantly in all mice treated with pH-sensitive liposomes having OVA and α-GalCer. The provided evidence on the advantage of antigen and α-GalCer co-encapsulation into pH-sensitive liposomes should be considered in the design of future cancer vaccines for prophylactic and therapeutic purposes.

Structure of Ceramide-1-Phosphate at the Air-Water Solution Interface in the Absence and Presence of Ca2+

PubMed Central

Kooijman, Edgar E.; Vaknin, David; Bu, Wei; Joshi, Leela; Kang, Shin-Woong; Gericke, Arne; Mann, Elizabeth K.; Kumar, Satyendra

2009-01-01

Ceramide-1-phosphate, the phosphorylated form of ceramide, gained attention recently due to its diverse intracellular roles, in particular in inflammation mediated by cPLA2α. However, surprisingly little is known about the physical chemical properties of this lipid and its potential impact on physiological function. For example, the presence of Ca2+ is indispensable for the interaction of Cer-1-P with the C2 domain of cPLA2α. We report on the structure and morphology of Cer-1-P in monomolecular layers at the air/water solution interface in the absence and presence of Ca2+ using diverse biophysical techniques, including synchrotron x-ray reflectivity and grazing angle diffraction, to gain insight into the role and function of Cer-1-P in biomembranes. We show that relatively small changes in pH and the presence of monovalent cations dramatically affect the behavior of Cer-1-P. On pure water Cer-1-P forms a solid monolayer despite the negative charge of the phosphomonoester headgroup. In contrast, pH 7.2 buffer yields a considerably less solid-like monolayer, indicating that charge-charge repulsion becomes important at higher pH. Calcium was found to bind strongly to the headgroup of Cer-1-P even in the presence of a 100-fold larger Na+ concentration. Analysis of the x-ray reflectivity data allowed us to estimate how much Ca2+ is bound to the headgroup, ∼0.5 Ca2+ and ∼1.0 Ca2+ ions per Cer-1-P molecule for the water and buffer subphase respectively. These results can be qualitatively understood based on the molecular structure of Cer-1-P and the electrostatic/hydrogen-bond interactions of its phosphomonoester headgroup. Biological implications of our results are also discussed. PMID:19289047

Controlled penetration of ceramides into and across the stratum corneum using various types of microemulsions and formulation associated toxicity studies.

PubMed

Sahle, Fitsum F; Wohlrab, Johannes; Neubert, Reinhard H H

2014-02-01

Several skin diseases such as psoriasis and atopic dermatitis are associated with the depletion or disturbance of stratum corneum (SC) lipids such as ceramides (CERs), free fatty acids and cholesterol. Studies suggested that replenishment of these lipids might help to treat diseased, affected or aged skin. With this premises in mind, there are some formulations in the market that contain SC lipids and currently, to facilitate permeation of the lipids deep into the SC, various CERs, and other SC lipid microemulsions (MEs) were developed and characterised using lecithin or TEGO® CARE PL 4 (TCPL4) as base surfactants. However, to date, there are no reports that involve the permeability of SC lipids into and across the SC, and therefore, the penetration of CER [NP] as a model ceramide from various formulations was investigated ex vivo using Franz diffusion cell. Besides, the toxicity of the MEs was assessed using hen's egg test chorioallantoic membrane (HET-CAM). The results of the study showed that CER [NP] could not permeate into deeper layers of the SC from a conventional hydrophilic cream. Unlike the cream, CER [NP] permeated into the deeper layers of the SC from both type of MEs, where permeation of the CER was more and into deeper layers from droplet type and lecithin-based MEs than bicontinuous (BC) type and TCPL4 based MEs, respectively. The CER also permeated into deeper layers from ME gels which was, however, shallow and to a lesser extent when compared with the MEs. The results of HET-CAM showed that both MEs are safe to be used topically, with lecithin-based MEs exhibiting better safety profiles than TCPL4 based MEs. Concluding, the study showed that the MEs are safe to be used on the skin for the controlled penetration of CER [NP] deep into the SC. Copyright © 2013 Elsevier B.V. All rights reserved.

Protein Mobility within Secretory Granules

PubMed Central

Weiss, Annita Ngatchou; Bittner, Mary A.; Holz, Ronald W.; Axelrod, Daniel

2014-01-01

We investigated the basis for previous observations that fluorescent-labeled neuropeptide Y (NPY) is usually released within 200 ms after fusion, whereas labeled tissue plasminogen activator (tPA) is often discharged over many seconds. We found that tPA and NPY are endogenously expressed in small and different subpopulations of bovine chromaffin cells in culture. We measured the mobility of these proteins (tagged with fluorophore) within the lumen of individual secretory granules in living chromaffin cells, and related their mobilities to postfusion release kinetics. A method was developed that is not limited by standard optical resolution, in which a bright flash of strongly decaying evanescent field (∼64 nm exponential decay constant) produced by total internal reflection (TIR) selectively bleaches cerulean-labeled protein proximal to the glass coverslip within individual granules. Fluorescence recovery occurred as unbleached protein from distal regions within the 300 nm granule diffused into the bleached proximal regions. The fractional bleaching of tPA-cerulean (tPA-cer) was greater when subsequently probed with TIR excitation than with epifluorescence, indicating that tPA-cer mobility was low. The almost equal NPY-cer bleaching when probed with TIR and epifluorescence indicated that NPY-cer equilibrated within the 300 ms bleach pulse, and therefore had a greater mobility than tPA-cer. TIR-fluorescence recovery after photobleaching revealed a significant recovery of tPA-cer (but not NPY-cer) fluorescence within several hundred milliseconds after bleaching. Numerical simulations, which take into account bleach duration, granule diameter, and the limited number of fluorophores in a granule, are consistent with tPA-cer being 100% mobile, with a diffusion coefficient of 2 × 10−10 cm2/s (∼1/3000 of that for a protein of similar size in aqueous solution). However, the low diffusive mobility of tPA cannot alone explain its slow postfusion release. In the accompanying study, we suggest that, additionally, tPA itself stabilizes the fusion pore with dimensions that restrict its own exit. PMID:24988337

Radiation effects in materials for optical interferometric devices

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

Koumvakalis, N.; Jani, M.G.; Halliburton, L.E.

The effects of ionizing radiation have been investigated in a series of materials commonly used in optical interferometric devices. Included in the study were three glass-ceramics (Zerodur, Cer-Vit 101, and Cer-Vit 142) and one Faraday-rotator glass (SF-57). Each glass-ceramic was irradiated at room temperature with 1.5-MeV electrons from a Van De Graaff accelerator. Similar irradiations were done on the Faraday-rotator glass at room temperature and 77 K. Optical absorption and electron spin resonance measurements provided a monitor of the radiation-induced point defects in all cases. The spectral characteristics and the production and thermal annealing behavior of these defects are described,more » and their possible effect on the performance of optical devices which incorporate these materials is considered.« less

Composition and morphology characterization of exopolymeric substances produced by the PAH-degrading fungus of Mucor mucedo.

PubMed

Jia, Chunyun; Li, Xiaojun; Allinson, Graeme; Liu, Changfeng; Gong, Zongqiang

2016-05-01

To explore the role of exopolymeric substances (EPS) in the process of polycyclic aromatic hydrocarbons (PAH) biodegradation, the characteristics of EPS isolated from a PAH-degrading fungus were investigated firstly by spectrometric determination, microscopic observation, Fourier transform-infrared spectroscopy (FT-IR), and three-dimensional excitation-emission matrix fluorescence spectroscopy (3D-EEM), and then the PAH-degrading ability of isolated EPS was evaluated. The EPS compositions and morphology varied significantly with the extraction methods. EPS were mainly composed of proteins, carbohydrate, and humic-like substances, and the cation exchange resin (CER)-extracted EPS were granular while other EPS samples were all powders. Heating was the most effective treatment method, followed by the CER, centrifugation, and ultrasonication methods. However, 3D-EEM data demonstrated that heating treatment makes the mycelia lyse the most. Overall, therefore, the CER was the best EPS extraction method for Mucor mucedo (M. mucedo). The PAH degradation results indicated that 87 % of pyrene and 81 % of benzo[a]pyrene (B[a]P) were removed by M. mucedo over 12 days and 9 % more pyrene and 7 % more B[a]P were reduced after CER-extracted EPS addition of 465 mg l(-1). The investigation of EPS characterization and EPS enhancing PAH biodegradation is the premise for further in-depth exploration of the role of EPS contribution to PAH biodegradation.

The Chlamydial Inclusion Preferentially Intercepts Basolaterally Directed Sphingomyelin-Containing Exocytic Vacuoles

PubMed Central

Moore, Elizabeth R.; Fischer, Elizabeth R.; Mead, David J.; Hackstadt, Ted

2010-01-01

Chlamydiae replicate intracellularly within a unique vacuole termed the inclusion. The inclusion circumvents classical endosomal/lysosomal pathways but actively intercepts a subset of Golgi-derived exocytic vesicles containing sphingomyelin (SM) and cholesterol. To further examine this interaction, we developed a polarized epithelial cell model to study vectoral trafficking of lipids and proteins to the inclusion. We examined seven epithelial cell lines for their ability to form single monolayers of polarized cells and support chlamydial development. Of these cell lines, polarized colonic mucosal C2BBe1 cells were readily infected with Chlamydia trachomatis and remained polarized throughout infection. Trafficking of (6-((N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl) amino)hexanoyl)sphingosine) (NBD-C6-ceramide) and its metabolic derivatives, NBD-glucosylceramide (GlcCer) and NBD-SM, was analyzed. SM was retained within L2-infected cells relative to mock-infected cells, correlating with a disruption of basolateral SM trafficking. There was no net retention of GlcCer within L2-infected cells and purification of C. trachomatis elementary bodies from polarized C2BBe1 cells confirmed that bacteria retained only SM. The chlamydial inclusion thus appears to preferentially intercept basolaterally-directed SM-containing exocytic vesicles, suggesting a divergence in SM and GlcCer trafficking. The observed changes in lipid trafficking were a chlamydia-specific effect because Coxiella burnetii-infected cells revealed no changes in GlcCer or SM polarized trafficking. PMID:18778406

The dopamine D1 receptor agonist SKF81297 has dose-related effects on locomotor activity but is without effect in a CER trace conditioning procedure conducted with two versus four trials.

PubMed

Pezze, M A; Marshall, H J; Cassaday, H J

2016-08-01

In an appetitively motivated procedure, we have previously reported that systemic treatment with the dopamine (DA) D1 receptor agonist SKF81297 (0.4 and 0.8 mg/kg) depressed acquisition at a 2 s inter-stimulus-interval (ISI), suitable to detect trace conditioning impairment. However since DA is involved in reinforcement processes, the generality of effects across appetitively- and aversively-motivated trace conditioning procedures cannot be assumed. The present study tested the effects of SKF81297 (0.4 and 0.8 mg/kg) in an established conditioned emotional response (CER) procedure. Trace-dependent conditioning was clearly shown in two experiments: while conditioning was relatively strong at a 3-s ISI, it was attenuated at a 30-s ISI. This was shown after two (Experiment 1) or four (Experiment 2) conditioning trials conducted in - as far as possible - the same CER procedure. Contrary to prediction, in neither experiment was there any indication that trace conditioning was attenuated by treatment with 0.4 or 0.8 mg/kg SKF81297. In the same rats, locomotor activity was significantly enhanced at the 0.8 mg/kg dose of SKF81297. These results suggest that procedural details of the trace conditioning variant in use are an important determinant of the profile of dopaminergic modulation.

The Design of an Adaptive Attitude Control System

DTIC Science & Technology

1992-09-01

spacecraft to reorient itself by rotating about the eigenaxis will be executing an optimal maneuver . [Ref. 9: pp. 375-3761 2. Quaternion Feedback Regulator...34% The below program will simulate the CER Control System for Large "% Angle (Slewing) Motion. The Control Law is a Quaternion Feedback "% Regulator...Equipment/Retriever (CER) during autonomous attitude hold and large angle or slewing maneuvers . The CER is a proposed space robot that deploys from

The cost-effectiveness of interbody fusions versus posterolateral fusions in 137 patients with lumbar spondylolisthesis.

PubMed

Bydon, Mohamad; Macki, Mohamed; Abt, Nicholas B; Witham, Timothy F; Wolinsky, Jean-Paul; Gokaslan, Ziya L; Bydon, Ali; Sciubba, Daniel M

2015-03-01

Reimbursements for interbody fusions have declined recently because of their questionable cost-effectiveness. A Markov model was adopted to compare the cost-effectiveness of posterior lumbar interbody fusion (PLIF) or transforaminal lumbar interbody fusion (/TLIF) versus noninterbody fusion and posterolateral fusion (PLF) in patients with lumbar spondylolisthesis. Decision model analysis based on retrospective data from a single institutional series. One hundred thirty-seven patients underwent first-time instrumented lumbar fusions for degenerative or isthmic spondylolisthesis. Quality of life adjustments and expenditures were assigned to each short-term complication (durotomy, surgical site infection, and medical complication) and long-term outcome (bowel/bladder dysfunction and paraplegia, neurologic deficit, and chronic back pain). Patients were divided into a PLF cohort and a PLF plus PLIF/TLIF cohort. Anterior techniques and multilevel interbody fusions were excluded. Each short-term complication and long-term outcome was assigned a numerical quality-adjusted life-year (QALY), based on time trade-off values in the Beaver Dam Health Outcomes Study. The cost data for short-term complications were calculated from charges accrued by the institution's finance sector, and the cost data for long-term outcomes were estimated from the literature. The difference in cost of PLF plus PLIF/TLIF from the cost of PLF alone divided by the difference in QALY equals the cost-effectiveness ratio (CER). We do not report any study funding sources or any study-specific appraisal of potential conflict of interest-associated biases in this article. Of 137 first-time lumbar fusions for spondylolisthesis, 83 patients underwent PLF and 54 underwent PLIF/TLIF. The average time to reoperation was 3.5 years. The mean QALY over 3.5 years was 2.81 in the PLF cohort versus 2.66 in the PLIFo/TLIF cohort (p=.110). The mean 3.5-year costs of $54,827.05 after index interbody fusion were statistically higher than that of the $48,822.76 after PLF (p=.042). The CER of interbody fusion to PLF after the first operation was -$46,699.40 per QALY; however, of the 27 patients requiring reoperation, the incident (reoperation) rate ratio was 7.89 times higher after PLF (2.91, 26.67). The CER after the first reoperation was -$24,429.04 per QALY (relative to PLF). Two patients in the PLF cohort required a second reoperation, whereas none required a second reoperation in the PLIF/TLIF cohort. Taken collectively, the total CER for the interbody fusion is $9,883.97 per QALY. The reoperation rate was statistically higher for PLF, whereas the negative CER for the initial operation and first reoperation favors PLF. However, when second reoperations were included, the CER for the interbody fusion became $9,883.97 per QALY, suggesting moderate long-term cost savings and better functional outcomes with the interbody fusion. Copyright © 2015 Elsevier Inc. All rights reserved.

NKT Cells as an Ideal Anti-Tumor Immunotherapeutic

PubMed Central

Fujii, Shin-ichiro; Shimizu, Kanako; Okamoto, Yoshitaka; Kunii, Naoki; Nakayama, Toshinori; Motohashi, Shinichiro; Taniguchi, Masaru

2013-01-01

Human natural killer T (NKT) cells are characterized by their expression of an invariant T cell antigen receptor α chain variable region encoded by a Vα24Jα18 rearrangement. These NKT cells recognize α-galactosylceramide (α-GalCer) in conjunction with the MHC class I-like CD1d molecule and bridge the innate and acquired immune systems to mediate efficient and augmented immune responses. A prime example of one such function is adjuvant activity: NKT cells augment anti-tumor responses because they can rapidly produce large amounts of IFN-γ, which acts on NK cells to eliminate MHC negative tumors and also on CD8 cytotoxic T cells to kill MHC positive tumors. Thus, upon administration of α-GalCer-pulsed DCs, both MHC negative and positive tumor cells can be effectively eliminated, resulting in complete tumor eradication without tumor recurrence. Clinical trials have been completed in a cohort of 17 patients with advanced non-small cell lung cancers and 10 cases of head and neck tumors. Sixty percent of advanced lung cancer patients with high IFN-γ production had significantly prolonged median survival times of 29.3 months with only the primary treatment. In the case of head and neck tumors, 10 patients who completed the trial all had stable disease or partial responses 5 weeks after the combination therapy of α-GalCer-DCs and activated NKT cells. We now focus on two potential powerful treatment options for the future. One is to establish artificial adjuvant vector cells containing tumor mRNA and α-GalCer/CD1d. This stimulates host NKT cells followed by DC maturation and NK cell activation but also induces tumor-specific long-term memory CD8 killer T cell responses, suppressing tumor metastasis even 1 year after the initial single injection. The other approach is to establish induced pluripotent stem (iPS) cells that can generate unlimited numbers of NKT cells with adjuvant activity. Such iPS-derived NKT cells produce IFN-γ in vitro and in vivo upon stimulation with α-GalCer/DCs, and mediated adjuvant effects, suppressing tumor growth in vivo. PMID:24348476

The effect of an apolipoprotein A-I-containing high-density lipoprotein-mimetic particle (CER-001) on carotid artery wall thickness in patients with homozygous familial hypercholesterolemia: The Modifying Orphan Disease Evaluation (MODE) study.

PubMed

Hovingh, G Kees; Smits, Loek P; Stefanutti, Claudia; Soran, Handrean; Kwok, See; de Graaf, Jacqueline; Gaudet, Daniel; Keyserling, Constance H; Klepp, Heather; Frick, Jennifer; Paolini, John F; Dasseux, Jean-Louis; Kastelein, John J P; Stroes, Erik S

2015-05-01

Patients with homozygous familial hypercholesterolemia (HoFH) are at extremely elevated risk for early cardiovascular disease because of exposure to elevated low-density lipoprotein cholesterol (LDL-C) plasma levels from birth. Lowering LDL-C by statin therapy is the cornerstone for cardiovascular disease prevention, but the residual risk in HoFH remains high, emphasizing the need for additional therapies. In the present study, we evaluated the effect of serial infusions with CER-001, a recombinant human apolipoprotein A-I (apoA-I)-containing high-density lipoprotein-mimetic particle, on carotid artery wall dimensions in patients with HoFH. Twenty-three patients (mean age 39.4 ± 13.5 years, mean LDL-C 214.2 ± 81.5 mg/dL) with genetically confirmed homozygosity or compound heterozygosity for LDLR, APOB, PCSK9, or LDLRAP1 mutations received 12 biweekly infusions with CER-001 (8 mg/kg). Before and 1 hour after the first infusion, lipid values were measured. Magnetic resonance imaging (3-T magnetic resonance imaging) scans of the carotid arteries were acquired at baseline and after 24 weeks to assess changes in artery wall dimensions. After CER-001 infusion, apoA-I increased from 114.8 ± 20.7 mg/dL to 129.3 ± 23.0 mg/dL. After 24 weeks, mean vessel wall area (primary end point) decreased from 17.23 to 16.75 mm(2) (P = .008). A trend toward reduction of mean vessel wall thickness was observed (0.75 mm at baseline and 0.74 mm at follow-up, P = .0835). In HoFH, 12 biweekly infusions with an apoA-I-containing high-density lipoprotein-mimetic particle resulted in a significant reduction in carotid mean vessel wall area, implying that CER-001 may reverse atherogenic changes in the arterial wall on top of maximal low-density lipoprotein-lowering therapy. This finding supports further clinical evaluation of apoA-I-containing particles in patients with HoFH. Copyright © 2015 Mosby, Inc. All rights reserved.

Erythrocyte and porcine intestinal glycosphingolipids recognized by F4 fimbriae of enterotoxigenic Escherichia coli.

PubMed

Coddens, Annelies; Valis, Erik; Benktander, John; Ångström, Jonas; Breimer, Michael E; Cox, Eric; Teneberg, Susann

2011-01-01

Enterotoxigenic F4-fimbriated Escherichia coli is associated with diarrheal disease in neonatal and postweaning pigs. The F4 fimbriae mediate attachment of the bacteria to the pig intestinal epithelium, enabling an efficient delivery of diarrhea-inducing enterotoxins to the target epithelial cells. There are three variants of F4 fimbriae designated F4ab, F4ac and F4ad, respectively, having different antigenic and adhesive properties. In the present study, the binding of isolated F4ab, F4ac and F4ad fimbriae, and F4ab/ac/ad-fimbriated E. coli, to glycosphingolipids from erythrocytes and from porcine small intestinal epithelium was examined, in order to get a comprehensive view of the F4-binding glycosphingolipids involved in F4-mediated hemagglutination and adhesion to the epithelial cells of porcine intestine. Specific interactions between the F4ab, F4ac and F4ad fimbriae and both acid and non-acid glycosphingolipids were obtained, and after isolation of binding-active glycosphingolipids and characterization by mass spectrometry and proton NMR, distinct carbohydrate binding patterns were defined for each fimbrial subtype. Two novel glycosphingolipids were isolated from chicken erythrocytes, and characterized as GalNAcα3GalNAcß3Galß4Glcß1Cer and GalNAcα3GalNAcß3Galß4GlcNAcß3Galß4Glcß1Cer. These two compounds, and lactosylceramide (Galß4Glcß1Cer) with phytosphingosine and hydroxy fatty acid, were recognized by all three variants of F4 fimbriae. No binding of the F4ad fimbriae or F4ad-fimbriated E. coli to the porcine intestinal glycosphingolipids occurred. However, for F4ab and F4ac two distinct binding patterns were observed. The F4ac fimbriae and the F4ac-expressing E. coli selectively bound to galactosylceramide (Galß1Cer) with sphingosine and hydroxy 24:0 fatty acid, while the porcine intestinal glycosphingolipids recognized by F4ab fimbriae and the F4ab-fimbriated bacteria were characterized as galactosylceramide, sulfatide (SO(3)-3Galß1Cer), sulf-lactosylceramide (SO(3)-3Galß4Glcß1Cer), and globotriaosylceramide (Galα4Galß4Glcß1Cer) with phytosphingosine and hydroxy 24:0 fatty acid. Finally, the F4ad fimbriae and the F4ad-fimbriated E. coli, but not the F4ab or F4ac subtypes, bound to reference gangliotriaosylceramide (GalNAcß4Galß4Glcß1Cer), gangliotetraosylceramide (Galß3GalNAcß4Galß4Glcß1Cer), isoglobotriaosylceramide (Galα3Galß4Glcß1Cer), and neolactotetraosylceramide (Galß4GlcNAcß3Galß4Glcß1Cer).

Erythrocyte and Porcine Intestinal Glycosphingolipids Recognized by F4 Fimbriae of Enterotoxigenic Escherichia coli

PubMed Central

Coddens, Annelies; Valis, Erik; Benktander, John; Ångström, Jonas; Breimer, Michael E.; Cox, Eric; Teneberg, Susann

2011-01-01

Enterotoxigenic F4-fimbriated Escherichia coli is associated with diarrheal disease in neonatal and postweaning pigs. The F4 fimbriae mediate attachment of the bacteria to the pig intestinal epithelium, enabling an efficient delivery of diarrhea-inducing enterotoxins to the target epithelial cells. There are three variants of F4 fimbriae designated F4ab, F4ac and F4ad, respectively, having different antigenic and adhesive properties. In the present study, the binding of isolated F4ab, F4ac and F4ad fimbriae, and F4ab/ac/ad-fimbriated E. coli, to glycosphingolipids from erythrocytes and from porcine small intestinal epithelium was examined, in order to get a comprehensive view of the F4-binding glycosphingolipids involved in F4-mediated hemagglutination and adhesion to the epithelial cells of porcine intestine. Specific interactions between the F4ab, F4ac and F4ad fimbriae and both acid and non-acid glycosphingolipids were obtained, and after isolation of binding-active glycosphingolipids and characterization by mass spectrometry and proton NMR, distinct carbohydrate binding patterns were defined for each fimbrial subtype. Two novel glycosphingolipids were isolated from chicken erythrocytes, and characterized as GalNAcα3GalNAcß3Galß4Glcß1Cer and GalNAcα3GalNAcß3Galß4GlcNAcß3Galß4Glcß1Cer. These two compounds, and lactosylceramide (Galß4Glcß1Cer) with phytosphingosine and hydroxy fatty acid, were recognized by all three variants of F4 fimbriae. No binding of the F4ad fimbriae or F4ad-fimbriated E. coli to the porcine intestinal glycosphingolipids occurred. However, for F4ab and F4ac two distinct binding patterns were observed. The F4ac fimbriae and the F4ac-expressing E. coli selectively bound to galactosylceramide (Galß1Cer) with sphingosine and hydroxy 24:0 fatty acid, while the porcine intestinal glycosphingolipids recognized by F4ab fimbriae and the F4ab-fimbriated bacteria were characterized as galactosylceramide, sulfatide (SO3-3Galß1Cer), sulf-lactosylceramide (SO3-3Galß4Glcß1Cer), and globotriaosylceramide (Galα4Galß4Glcß1Cer) with phytosphingosine and hydroxy 24:0 fatty acid. Finally, the F4ad fimbriae and the F4ad-fimbriated E. coli, but not the F4ab or F4ac subtypes, bound to reference gangliotriaosylceramide (GalNAcß4Galß4Glcß1Cer), gangliotetraosylceramide (Galß3GalNAcß4Galß4Glcß1Cer), isoglobotriaosylceramide (Galα3Galß4Glcß1Cer), and neolactotetraosylceramide (Galß4GlcNAcß3Galß4Glcß1Cer). PMID:21949679

Infrastructure to support learning health systems: are we there yet? Innovative solutions and lessons learned from American Recovery and Reinvestment Act CER investments.

PubMed

Holve, Erin; Segal, Courtney

2014-11-01

The 11 big health data networks participating in the AcademyHealth Electronic Data Methods Forum represent cutting-edge efforts to harness the power of big health data for research and quality improvement. This paper is a comparative case study based on site visits conducted with a subset of these large infrastructure grants funded through the Recovery Act, in which four key issues emerge that can inform the evolution of learning health systems, including the importance of acknowledging the challenges of scaling specialized expertise needed to manage and run CER networks; the delicate balance between privacy protections and the utility of distributed networks; emerging community engagement strategies; and the complexities of developing a robust business model for multi-use networks.

Shape Transitions and Lattice Structuring of Ceramide-Enriched Domains Generated by Sphingomyelinase in Lipid Monolayers

PubMed Central

Härtel, Steffen; Fanani, María Laura; Maggio, Bruno

2005-01-01

Sphingomyelinases (SMases) hydrolyze the membrane constituent sphingomyelin (SM) to phosphocholine and ceramide (Cer). Growing evidence supports that SMase-induced SM→Cer conversion leads to the formation of lateral Cer-enriched domains which drive structural reorganization in lipid membranes. We previously provided visual evidence in real-time for the formation of Cer-enriched domains in SM monolayers through the action of the neutral Bacillus cereus SMase. In this work, we disclose a succession of discrete morphologic transitions and lateral organization of Cer-enriched domains that underlay the SMase-generated surface topography. We further reveal how these structural parameters couple to the generation of two-dimensional electrostatic fields, based upon the specific orientation of the lipid dipole moments in the Cer-enriched domains. Advanced image processing routines in combination with time-resolved epifluorescence microscopy on Langmuir monolayers revealed: 1), spontaneous nucleation and circular growth of Cer-enriched domains after injection of SMase into the subphase of the SM monolayer; 2), domain-intrinsic discrete transitions from circular to periodically undulating shapes followed by a second transition toward increasingly branched morphologies; 3), lateral superstructure organization into predominantly hexagonal domain lattices; 4), formation of super-superstructures by the hexagonal lattices; and 5), rotationally and laterally coupled domain movement before domain border contact. All patterns proved to be specific for the SMase-driven system since they could not be observed with Cer-enriched domains generated by defined mixtures of SM/Cer in enzyme-free monolayers at the same surface pressure (Π = 10 mN/m). Following the theories of lateral shape transitions, dipolar electrostatic interactions of lipid domains, and direct determinations of the monolayer dipole potential, our data show that SMase induces a domain-specific packing and orientation of the molecular dipole moments perpendicular to the air/water interface. In consequence, protein-driven generation of specific out-of-equilibrium states, an accepted concept for maintenance of transmembrane lipid asymmetry, must also be considered on the lateral level. Lateral enzyme-specific out-of-equilibrium organization of lipid domains represents a new level of signal transduction from local (nm) to long-range (μm) scales. The cross-talk between lateral domain structures and dipolar electrostatic fields adds new perspectives to the mechanisms of SMase-mediated signal transduction in biological membranes. PMID:15489298

Sphingosine-1-phosphate and ceramide are associated with health and atresia of bovine ovarian antral follicles.

PubMed

Hernández-Coronado, C G; Guzmán, A; Espinosa-Cervantes, R; Romano, M C; Verde-Calvo, J R; Rosales-Torres, A M

2015-02-01

The follicle destiny towards ovulation or atresia is multi-factorial in nature and involves outcries, paracrine and endocrine factors that promote cell proliferation and survival (development) or unchain apoptosis as part of the atresia process. In several types of cells, sphingosine-1-phospate (S1P) promotes cellular proliferation and survival, whereas ceramide (CER) triggers cell death, and the S1P/CER ratio may determine the fate of the cell. The aim of present study was to quantify S1P and CER concentrations and their ratio in bovine antral follicles of 8 to 17 mm classified as healthy and atretic antral follicles. Follicles were dissected from cow ovaries collected from a local abattoir. The theca cell layer, the granulosa cells and follicular fluid were separated, and 17β-estradiol (E2) and progesterone (P4) concentrations were measured in the follicular fluid by radioimmunoassay. Based on the E2/P4 ratio, the follicles were classified as healthy (2.2±0.3) or atretic (0.2±0.3). In both follicular compartments (granulosa and theca cell layer), sphingolipids were extracted and S1P and CER concentrations were quantified by HPLC (XTerra RP18; 5 µm, 3.0×150 mm column). Results showed that in both follicular compartments, S1P concentrations were higher in healthy antral follicles than in atretic antral follicles (P<0.05). The concentration of CER in the granulosa cells was higher in atretic antral follicles than in healthy antral follicles, but no differences were observed in the theca cell layer. The S1P/CER ratio in both follicular compartments was also higher in healthy antral follicles. Interestingly, in these follicles, there was a 45-fold greater concentration of S1P than CER in the granulosa cells (P<0.05), whereas in the theca cell layer, S1P had only a 14-fold greater concentration than CER when compared with atretic antral follicles. These results suggest that S1P plays a role in follicle health, increasing cellular proliferation and survival. In contrast, reduction of S1P and the S1P/CER in the antral follicle could trigger cellular death and atresia.

HDL mimetic CER-001 targets atherosclerotic plaques in patients.

PubMed

Zheng, Kang He; van der Valk, Fleur M; Smits, Loek P; Sandberg, Mara; Dasseux, Jean-Louis; Baron, Rudi; Barbaras, Ronald; Keyserling, Constance; Coolen, Bram F; Nederveen, Aart J; Verberne, Hein J; Nell, Thijs E; Vugts, Danielle J; Duivenvoorden, Raphaël; Fayad, Zahi A; Mulder, Willem J M; van Dongen, Guus A M S; Stroes, Erik S G

2016-08-01

Infusion of high-density lipoprotein (HDL) mimetics aimed at reducing atherosclerotic burden has led to equivocal results, which may relate in part to the inability of HDL mimetics to adequately reach atherosclerotic lesions in humans. This study evaluated delivery of recombinant human apolipoprotein A-I (apoA-I) containing HDL mimetic CER-001 in carotid plaques in patients. CER-001 was radiolabeled with the long-lived positron emitter zirconium-89 ((89)Zr) to enable positron emission tomography with computed tomography (PET/CT) imaging. Eight patients with atherosclerotic carotid artery disease (>50% stenosis) received a single infusion of unlabeled CER-001 (3 mg/kg), co-administered with 10 mg of (89)Zr-labeled CER-001 (18 MBq). Serial PET/CT imaging and contrast enhanced-magnetic resonance imaging (CE-MRI) were performed to evaluate targeted delivery of CER-001. One hour after infusion, mean plasma apoA-I levels increased by 9.9 mg/dL (p = 0.026), with a concomitant relative increase in the plasma cholesterol efflux capacity of 13.8% (p < 0.001). Using serial PET/CT imaging, we showed that arterial uptake of CER-001 expressed as target-to-background ratio (TBRmax) increased significantly 24 h after infusion, and remained increased up to 48 h (TBRmax t = 10 min: 0.98; t = 24 h: 1.14 (p = 0.001); t = 48 h: 1.12 (p = 0.007)). TBRmax was higher in plaque compared with non-plaque segments (1.18 vs. 1.05; p < 0.001). Plaque TBRmax correlated with local plaque contrast enhancement (r = 0.56; p = 0.019) as assessed by CE-MRI. Infusion of HDL mimetic CER-001 increases plasma apoA-I concentration and plasma cholesterol efflux capacity. Our data support the concept that CER-001 targets plaque regions in patients, which correlates with plaque contrast enhancement. These clinical findings may also guide future nanomedicine development using HDL particles for drug delivery in atherosclerosis. Netherlands Trial Registry - NTR5178. http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5178. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

76 FR 41783 - Combined Notice of Filings #2

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-15

... Commodities Group, Constellation Pwr Source Generation LLC, Constellation NewEnergy, Inc., CER Generation II..., CER Generation, LLC, Constellation Energy Commodities Group M, Constellation Mystic Power, LLC...

A Topographical Atlas of Shiga Toxin 2e Receptor Distribution in the Tissues of Weaned Piglets.

PubMed

Steil, Daniel; Bonse, Robert; Meisen, Iris; Pohlentz, Gottfried; Vallejo, German; Karch, Helge; Müthing, Johannes

2016-11-30

Shiga toxin (Stx) 2e of Stx-producing Escherichia coli (STEC) is the primary virulence factor in the development of pig edema disease shortly after weaning. Stx2e binds to the globo-series glycosphingolipids (GSLs) globotriaosylceramide (Gb3Cer, Galα1-4Galβ1-4Glcβ1-1Cer) and globotetraosylceramide (Gb4Cer, GalNAcβ1-3Galα1-4Galβ1-4Glcβ1-1Cer), the latter acting as the preferential Stx2e receptor. We determined Stx receptor profiles of 25 different tissues of a male and a female weaned piglet using immunochemical solid phase binding assays combined with mass spectrometry. All probed tissues harbored GSL receptors, ranging from high (category I) over moderate (category II) to low content (category III). Examples of Gb4Cer expression in category I tissues are small intestinal ileum, kidney pelvis and whole blood, followed by colon, small intestinal duodenum and jejunum belonging to category II, and kidney cortex, cerebrum and cerebellum as members of category III organs holding true for both genders. Dominant Gb3Cer and Gb4Cer lipoforms were those with ceramides carrying constant sphingosine (d18:1) and a variable C16:0, C22:0 or C24:1/C24:0 fatty acid. From the mapping data, we created a topographical atlas for Stx2e receptors in piglet tissues and organs, which might be helpful to further investigations on the molecular and cellular mechanisms that underlie infections of Stx2e-producing STEC in pigs and their zoonotic potential for humans.

A Topographical Atlas of Shiga Toxin 2e Receptor Distribution in the Tissues of Weaned Piglets

PubMed Central

Steil, Daniel; Bonse, Robert; Meisen, Iris; Pohlentz, Gottfried; Vallejo, German; Karch, Helge; Müthing, Johannes

2016-01-01

Shiga toxin (Stx) 2e of Stx-producing Escherichia coli (STEC) is the primary virulence factor in the development of pig edema disease shortly after weaning. Stx2e binds to the globo-series glycosphingolipids (GSLs) globotriaosylceramide (Gb3Cer, Galα1-4Galβ1-4Glcβ1-1Cer) and globotetraosylceramide (Gb4Cer, GalNAcβ1-3Galα1-4Galβ1-4Glcβ1-1Cer), the latter acting as the preferential Stx2e receptor. We determined Stx receptor profiles of 25 different tissues of a male and a female weaned piglet using immunochemical solid phase binding assays combined with mass spectrometry. All probed tissues harbored GSL receptors, ranging from high (category I) over moderate (category II) to low content (category III). Examples of Gb4Cer expression in category I tissues are small intestinal ileum, kidney pelvis and whole blood, followed by colon, small intestinal duodenum and jejunum belonging to category II, and kidney cortex, cerebrum and cerebellum as members of category III organs holding true for both genders. Dominant Gb3Cer and Gb4Cer lipoforms were those with ceramides carrying constant sphingosine (d18:1) and a variable C16:0, C22:0 or C24:1/C24:0 fatty acid. From the mapping data, we created a topographical atlas for Stx2e receptors in piglet tissues and organs, which might be helpful to further investigations on the molecular and cellular mechanisms that underlie infections of Stx2e-producing STEC in pigs and their zoonotic potential for humans. PMID:27916888

Disrupted functional connectivity of cerebellar default network areas in attention-deficit/hyperactivity disorder.

PubMed

Kucyi, Aaron; Hove, Michael J; Biederman, Joseph; Van Dijk, Koene R A; Valera, Eve M

2015-09-01

Attention-deficit/hyperactivity disorder (ADHD) is increasingly understood as a disorder of spontaneous brain-network interactions. The default mode network (DMN), implicated in ADHD-linked behaviors including mind-wandering and attentional fluctuations, has been shown to exhibit abnormal spontaneous functional connectivity (FC) within-network and with other networks (salience, dorsal attention and frontoparietal) in ADHD. Although the cerebellum has been implicated in the pathophysiology of ADHD, it remains unknown whether cerebellar areas of the DMN (CerDMN) exhibit altered FC with cortical networks in ADHD. Here, 23 adults with ADHD and 23 age-, IQ-, and sex-matched controls underwent resting state fMRI. The mean time series of CerDMN areas was extracted, and FC with the whole brain was calculated. Whole-brain between-group differences in FC were assessed. Additionally, relationships between inattention and individual differences in FC were assessed for between-group interactions. In ADHD, CerDMN areas showed positive FC (in contrast to average FC in the negative direction in controls) with widespread regions of salience, dorsal attention and sensorimotor networks. ADHD individuals also exhibited higher FC (more positive correlation) of CerDMN areas with frontoparietal and visual network regions. Within the control group, but not in ADHD, participants with higher inattention had higher FC between CerDMN and regions in the visual and dorsal attention networks. This work provides novel evidence of impaired CerDMN coupling with cortical networks in ADHD and highlights a role of cerebro-cerebellar interactions in cognitive function. These data provide support for the potential targeting of CerDMN areas for therapeutic interventions in ADHD. © 2015 Wiley Periodicals, Inc.

Glucosylceramide and Lysophosphatidylcholines as Potential Blood Biomarkers for Drug-Induced Hepatic Phospholipidosis

PubMed Central

Saito, Kosuke; Maekawa, Keiko; Ishikawa, Masaki; Senoo, Yuya; Urata, Masayo; Murayama, Mayumi; Nakatsu, Noriyuki; Yamada, Hiroshi; Saito, Yoshiro

2014-01-01

Drug-induced phospholipidosis is one of the major concerns in drug development and clinical treatment. The present study involved the use of a nontargeting lipidomic analysis with liquid chromatography-mass spectrometry to explore noninvasive blood biomarkers for hepatic phospholipidosis from rat plasma. We used three tricyclic antidepressants (clomipramine [CPM], imipramine [IMI], and amitriptyline [AMT]) for the model of phospholipidosis in hepatocytes and ketoconazole (KC) for the model of phospholipidosis in cholangiocytes and administered treatment for 3 and 28 days each. Total plasma lipids were extracted and measured. Lipid molecules contributing to the separation of control and drug-treated rat plasma in a multivariate orthogonal partial least squares discriminant analysis were identified. Four lysophosphatidylcholines (LPCs) (16:1, 18:1, 18:2, and 20:4) and 42:1 hexosylceramide (HexCer) were identified as molecules separating control and drug-treated rats in all models of phospholipidosis in hepatocytes. In addition, 16:1, 18:2, and 20:4 LPCs and 42:1 HexCer were identified in a model of hepatic phospholipidosis in cholangiocytes, although LPCs were identified only in the case of 3-day treatment with KC. The levels of LPCs were decreased by drug-induced phospholipidosis, whereas those of 42:1 HexCer were increased. The increase in 42:1 HexCer was much higher in the case of IMI and AMT than in the case of CPM; moreover, the increase induced by IMI was dose-dependent. Structural characterization determining long-chain base and hexose delineated that 42:1 HexCer was d18:1/24:0 glucosylceramide (GluCer). In summary, our study demonstrated that d18:1/24:0 GluCer and LPCs are potential novel biomarkers for drug-induced hepatic phospholipidosis. PMID:24980264

Simultaneously inferring above-cloud absorbing aerosol optical thickness and underlying liquid phase cloud optical and microphysical properties using MODIS

NASA Astrophysics Data System (ADS)

Meyer, Kerry; Platnick, Steven; Zhang, Zhibo

2015-06-01

The regional haze over the southeast (SE) Atlantic Ocean induced by biomass burning in southern Africa can be problematic for passive imager-based retrievals of the underlying quasi-permanent marine boundary layer (MBL) clouds and for estimates of top-of-atmosphere (TOA) aerosol direct radiative effect (DRE). Here an algorithm is introduced to simultaneously retrieve above-cloud aerosol optical thickness (AOT), the cloud optical thickness (COT), and cloud effective particle radius (CER) of the underlying MBL clouds while also providing pixel-level estimates of retrieval uncertainty. This approach utilizes reflectance measurements at six Moderate Resolution Imaging Spectroradiometer (MODIS) channels from the visible to the shortwave infrared. Retrievals are run under two aerosol model assumptions on 8 years (2006-2013) of June-October Aqua MODIS data over the SE Atlantic, from which a regional cloud and above-cloud aerosol climatology is produced. The cloud retrieval methodology is shown to yield COT and CER consistent with those from the MODIS operational cloud product (MOD06) when forcing AOT to zero, while the full COT-CER-AOT retrievals that account for the above-cloud aerosol attenuation increase regional monthly mean COT and CER by up to 9% and 2%, respectively. Retrieved AOT is roughly 3 to 5 times larger than the collocated 532 nm Cloud-Aerosol Lidar with Orthogonal Polarization (CALIOP) retrievals, though closer agreement is observed with the CALIOP 1064 nm retrievals, a result consistent with previous case study analyses. Regional cloudy-sky above-cloud aerosol DRE calculations are also performed that illustrate the importance of the aerosol model assumption and underlying cloud retrievals.

The Role of Inflation and Price Escalation Adjustments in Properly Estimating Program Costs: F-35 Case Study

DTIC Science & Technology

2016-03-01

regression models that yield hedonic price indexes is closely related to standard techniques for developing cost estimating relationships ( CERs ...October 2014). iii analysis) and derives a price index from the coefficients on variables reflecting the year of purchase. In CER development, the...index. The relevant cost metric in both cases is unit recurring flyaway (URF) costs. For the current project, we develop a “Baseline” CER model, taking

Aircraft Airframe Cost Estimation Using a Random Coefficients Model

DTIC Science & Technology

1979-12-01

approach will also be used here. 2 Model Formulation Several different types of equations could be used for the basic form of the CER, such as linear ...5) Marcotte developed several CER’s for fighter aircraft airframes using the log- linear model . A plot of the residuals from the CER for recurring...of the natural logarithm. Ordinary Least Squares The ordinary least squares procedure starts with the equation for the general linear model . The

Role for cER and Mmr1p in anchorage of mitochondria at sites of polarized surface growth in budding yeast.

PubMed

Swayne, Theresa C; Zhou, Chun; Boldogh, Istvan R; Charalel, Joseph K; McFaline-Figueroa, José Ricardo; Thoms, Sven; Yang, Christine; Leung, Galen; McInnes, Joseph; Erdmann, Ralf; Pon, Liza A

2011-12-06

Mitochondria accumulate at neuronal and immunological synapses and yeast bud tips and associate with the ER during phospholipid biosynthesis, calcium homeostasis, and mitochondrial fission. Here we show that mitochondria are associated with cortical ER (cER) sheets underlying the plasma membrane in the bud tip and confirm that a deletion in YPT11, which inhibits cER accumulation in the bud tip, also inhibits bud tip anchorage of mitochondria. Time-lapse imaging reveals that mitochondria are anchored at specific sites in the bud tip. Mmr1p, a member of the DSL1 family of tethering proteins, localizes to punctate structures on opposing surfaces of mitochondria and cER sheets underlying the bud tip and is recovered with isolated mitochondria and ER. Deletion of MMR1 impairs bud tip anchorage of mitochondria without affecting mitochondrial velocity or cER distribution. Deletion of the phosphatase PTC1 results in increased Mmr1p phosphorylation, mislocalization of Mmr1p, defects in association of Mmr1p with mitochondria and ER, and defects in bud tip anchorage of mitochondria. These findings indicate that Mmr1p contributes to mitochondrial inheritance as a mediator of anchorage of mitochondria to cER sheets in the yeast bud tip and that Ptc1p regulates Mmr1p phosphorylation, localization, and function. Copyright © 2011 Elsevier Ltd. All rights reserved.

Characterization and genetic mapping of eceriferum-ym (cer-ym), a cutin deficient barley mutant with impaired leaf water retention capacity.

PubMed

Li, Chao; Liu, Cheng; Ma, Xiaoying; Wang, Aidong; Duan, Ruijun; Nawrath, Christiane; Komatsuda, Takao; Chen, Guoxiong

2015-09-01

The cuticle covers the aerial parts of land plants, where it serves many important functions, including water retention. Here, a recessive cuticle mutant, eceriferum-ym (cer-ym), of Hordeum vulgare L. (barley) showed abnormally glossy spikes, sheaths, and leaves. The cer-ym mutant plant detached from its root system was hypersensitive to desiccation treatment compared with wild type plants, and detached leaves of mutant lost 41.8% of their initial weight after 1 h of dehydration under laboratory conditions, while that of the wild type plants lost only 7.1%. Stomata function was not affected by the mutation, but the mutant leaves showed increased cuticular permeability to water, suggesting a defective leaf cuticle, which was confirmed by toluidine blue staining. The mutant leaves showed a substantial reduction in the amounts of the major cutin monomers and a slight increase in the main wax component, suggesting that the enhanced cuticle permeability was a consequence of cutin deficiency. cer-ym was mapped within a 0.8 cM interval between EST marker AK370363 and AK251484, a pericentromeric region on chromosome 4H. The results indicate that the desiccation sensitivity of cer-ym is caused by a defect in leaf cutin, and that cer-ym is located in a chromosome 4H pericentromeric region.

Characterization and genetic mapping of eceriferum-ym (cer-ym), a cutin deficient barley mutant with impaired leaf water retention capacity

PubMed Central

Li, Chao; Liu, Cheng; Ma, Xiaoying; Wang, Aidong; Duan, Ruijun; Nawrath, Christiane; Komatsuda, Takao; Chen, Guoxiong

2015-01-01

The cuticle covers the aerial parts of land plants, where it serves many important functions, including water retention. Here, a recessive cuticle mutant, eceriferum-ym (cer-ym), of Hordeum vulgare L. (barley) showed abnormally glossy spikes, sheaths, and leaves. The cer-ym mutant plant detached from its root system was hypersensitive to desiccation treatment compared with wild type plants, and detached leaves of mutant lost 41.8% of their initial weight after 1 h of dehydration under laboratory conditions, while that of the wild type plants lost only 7.1%. Stomata function was not affected by the mutation, but the mutant leaves showed increased cuticular permeability to water, suggesting a defective leaf cuticle, which was confirmed by toluidine blue staining. The mutant leaves showed a substantial reduction in the amounts of the major cutin monomers and a slight increase in the main wax component, suggesting that the enhanced cuticle permeability was a consequence of cutin deficiency. cer-ym was mapped within a 0.8 cM interval between EST marker AK370363 and AK251484, a pericentromeric region on chromosome 4H. The results indicate that the desiccation sensitivity of cer-ym is caused by a defect in leaf cutin, and that cer-ym is located in a chromosome 4H pericentromeric region. PMID:26366115

77 FR 23710 - Combined Notice of Filings #2

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-20

..., Exelon Generation Company, LLC, Exelon Energy Company, Calvert Cliffs Nuclear Power Plant LLC, CER Generation, LLC, Commonwealth Edison Company, Constellation NewEnergy, Inc., CER Generation II, LLC...

76 FR 7555 - Combined Notice of Filings #2

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-10

...Energy, Inc., CER Generation II, LLC, Safe Harbor Water Power Corporation, Handsome Lake Energy, LLC, Constellation Energy Commodities Group M, CER Generation, LLC, Criterion Power Partners, LLC. Description...