Multiplex analysis inflammatory cytokines in human blood, breath condensate, and urine matrices

EPA Science Inventory

Scientific evidence suggests that inflammation is associated with human health effects and health endpoints, yet most studies have focused on human populations that are already considered “unhealthy”.  As such, it is pertinent to measure inflammatory biomarkers in human biologica...

Comparison of reference doses (RfDs) developed for the protection of wildlife species in contrast to humans

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

Valoppi, L.; Carlisle, J.; Polisini, J.

1995-12-31

A component of both human health and ecological risk assessments is the evaluation of toxicity values. A comparison between the methodology for the development of Reference Doses (RfDs) to be protective of humans, and that developed for vertebrate wildlife species is presented. For all species, a chronic No Observable Adverse Effect Level (NOAEL) is developed by applying uncertainty factors (UFs) to literature-based toxicity values. Uncertainty factors are used to compensate for the length of exposure, sensitivity of endpoints, and cross-species extrapolations between the test species and the species being assessed. Differences between human and wildlife species could include the toxicologicalmore » endpoint, the critical study, and the magnitude of the cross-species extrapolation factor. Case studies for select chemicals are presented which contrast RfDs developed for humans and those developed for avian and mammalian wildlife.« less

Maintaining homeostasis by decision-making.

PubMed

Korn, Christoph W; Bach, Dominik R

2015-05-01

Living organisms need to maintain energetic homeostasis. For many species, this implies taking actions with delayed consequences. For example, humans may have to decide between foraging for high-calorie but hard-to-get, and low-calorie but easy-to-get food, under threat of starvation. Homeostatic principles prescribe decisions that maximize the probability of sustaining appropriate energy levels across the entire foraging trajectory. Here, predictions from biological principles contrast with predictions from economic decision-making models based on maximizing the utility of the endpoint outcome of a choice. To empirically arbitrate between the predictions of biological and economic models for individual human decision-making, we devised a virtual foraging task in which players chose repeatedly between two foraging environments, lost energy by the passage of time, and gained energy probabilistically according to the statistics of the environment they chose. Reaching zero energy was framed as starvation. We used the mathematics of random walks to derive endpoint outcome distributions of the choices. This also furnished equivalent lotteries, presented in a purely economic, casino-like frame, in which starvation corresponded to winning nothing. Bayesian model comparison showed that--in both the foraging and the casino frames--participants' choices depended jointly on the probability of starvation and the expected endpoint value of the outcome, but could not be explained by economic models based on combinations of statistical moments or on rank-dependent utility. This implies that under precisely defined constraints biological principles are better suited to explain human decision-making than economic models based on endpoint utility maximization.

Maintaining Homeostasis by Decision-Making

PubMed Central

Korn, Christoph W.; Bach, Dominik R.

2015-01-01

Living organisms need to maintain energetic homeostasis. For many species, this implies taking actions with delayed consequences. For example, humans may have to decide between foraging for high-calorie but hard-to-get, and low-calorie but easy-to-get food, under threat of starvation. Homeostatic principles prescribe decisions that maximize the probability of sustaining appropriate energy levels across the entire foraging trajectory. Here, predictions from biological principles contrast with predictions from economic decision-making models based on maximizing the utility of the endpoint outcome of a choice. To empirically arbitrate between the predictions of biological and economic models for individual human decision-making, we devised a virtual foraging task in which players chose repeatedly between two foraging environments, lost energy by the passage of time, and gained energy probabilistically according to the statistics of the environment they chose. Reaching zero energy was framed as starvation. We used the mathematics of random walks to derive endpoint outcome distributions of the choices. This also furnished equivalent lotteries, presented in a purely economic, casino-like frame, in which starvation corresponded to winning nothing. Bayesian model comparison showed that—in both the foraging and the casino frames—participants’ choices depended jointly on the probability of starvation and the expected endpoint value of the outcome, but could not be explained by economic models based on combinations of statistical moments or on rank-dependent utility. This implies that under precisely defined constraints biological principles are better suited to explain human decision-making than economic models based on endpoint utility maximization. PMID:26024504

HSP27 as a biomarker for predicting skin irritation in human skin and reconstructed organotypic skin model.

PubMed

Chen, Hongxia; Li, Shuhua; Meng, Tian; Zhang, Lei; Dai, Taoli; Xiang, Qi; Su, Zhijian; Zhang, Qihao; Huang, Yadong

2014-04-21

In vitro alternative tests aiming at replacing the traditional animal test for predicting the irritant potential of chemicals have been developed, but the assessing parameters or endpoints are still not sufficient. To discover novel endpoints for skin irritation responses, 2DE-based proteomics was used to analyze the protein expression in human skin exposed to sodium lauryl sulfate (SLS) following the test protocol of the European Centre for the Validation of Alternative Methods (ECVAM) in the present study. HSP27 was up-regulated most significantly among the eight identified proteins, consistent with our previous reports. Acid and basic chemicals were applied on human skin for further validation and results showed that the up-regulated expression of HSP27 was induced in 24h after the exposure. Skin-equivalent constructed with fibroblasts, basement membrane and keratinocytes was used to investigate the potential of HSP27 as a biomarker or additional endpoint for the hazard assessment of skin irritation. Our skin-equivalent (Reconstructed Organotypic Skin Model, ROSM) had excellent epidermal differentiation and was suitable for the skin irritation test. HSP27 also displayed an up-regulated expression in the ROSM in 24h after the irritants exposure for 15min. All these results suggest that HSP27 may represent a potential marker or additional endpoint for the hazard assessment of skin irritation caused by chemical products. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Human neuron-astrocyte 3D co-culture-based assay for evaluation of neuroprotective compounds.

PubMed

Terrasso, Ana Paula; Silva, Ana Carina; Filipe, Augusto; Pedroso, Pedro; Ferreira, Ana Lúcia; Alves, Paula Marques; Brito, Catarina

Central nervous system drug development has registered high attrition rates, mainly due to the lack of efficacy of drug candidates, highlighting the low reliability of the models used in early-stage drug development and the need for new in vitro human cell-based models and assays to accurately identify and validate drug candidates. 3D human cell models can include different tissue cell types and represent the spatiotemporal context of the original tissue (co-cultures), allowing the establishment of biologically-relevant cell-cell and cell-extracellular matrix interactions. Nevertheless, exploitation of these 3D models for neuroprotection assessment has been limited due to the lack of data to validate such 3D co-culture approaches. In this work we combined a 3D human neuron-astrocyte co-culture with a cell viability endpoint for the implementation of a novel in vitro neuroprotection assay, over an oxidative insult. Neuroprotection assay robustness and specificity, and the applicability of Presto Blue, MTT and CytoTox-Glo viability assays to the 3D co-culture were evaluated. Presto Blue was the adequate endpoint as it is non-destructive and is a simpler and reliable assay. Semi-automation of the cell viability endpoint was performed, indicating that the assay setup is amenable to be transferred to automated screening platforms. Finally, the neuroprotection assay setup was applied to a series of 36 test compounds and several candidates with higher neuroprotective effect than the positive control, Idebenone, were identified. The robustness and simplicity of the implemented neuroprotection assay with the cell viability endpoint enables the use of more complex and reliable 3D in vitro cell models to identify and validate drug candidates. Copyright © 2016 Elsevier Inc. All rights reserved.

Evaluating the Toxicity of Cigarette Whole Smoke Solutions in an Air-Liquid-Interface Human In Vitro Airway Tissue Model.

PubMed

Cao, Xuefei; Muskhelishvili, Levan; Latendresse, John; Richter, Patricia; Heflich, Robert H

2017-03-01

Exposure to cigarette smoke causes a multitude of pathological changes leading to tissue damage and disease. Quantifying such changes in highly differentiated in vitro human tissue models may assist in evaluating the toxicity of tobacco products. In this methods development study, well-differentiated human air-liquid-interface (ALI) in vitro airway tissue models were used to assess toxicological endpoints relevant to tobacco smoke exposure. Whole mainstream smoke solutions (WSSs) were prepared from 2 commercial cigarettes (R60 and S60) that differ in smoke constituents when machine-smoked under International Organization for Standardization conditions. The airway tissue models were exposed apically to WSSs 4-h per day for 1-5 days. Cytotoxicity, tissue barrier integrity, oxidative stress, mucin secretion, and matrix metalloproteinase (MMP) excretion were measured. The treatments were not cytotoxic and had marginal effects on tissue barrier properties; however, other endpoints responded in time- and dose-dependent manners, with the R60 resulting in higher levels of response than the S60 for many endpoints. Based on the lowest effect dose, differences in response to the WSSs were observed for mucin induction and MMP secretion. Mitigation of mucin induction by cotreatment of cultures with N-acetylcysteine suggests that oxidative stress contributes to mucus hypersecretion. Overall, these preliminary results suggest that quantifying disease-relevant endpoints using ALI airway models is a potential tool for tobacco product toxicity evaluation. Additional research using tobacco samples generated under smoking machine conditions that more closely approximate human smoking patterns will inform further methods development. Published by Oxford University Press on behalf of the Society of Toxicology 2017. This work is written by US Government employees and is in the public domain in the US.

On the Value of Estimating Human Arm Stiffness during Virtual Teleoperation with Robotic Manipulators

PubMed Central

Buzzi, Jacopo; Ferrigno, Giancarlo; Jansma, Joost M.; De Momi, Elena

2017-01-01

Teleoperated robotic systems are widely spreading in multiple different fields, from hazardous environments exploration to surgery. In teleoperation, users directly manipulate a master device to achieve task execution at the slave robot side; this interaction is fundamental to guarantee both system stability and task execution performance. In this work, we propose a non-disruptive method to study the arm endpoint stiffness. We evaluate how users exploit the kinetic redundancy of the arm to achieve stability and precision during the execution of different tasks with different master devices. Four users were asked to perform two planar trajectories following virtual tasks using both a serial and a parallel link master device. Users' arm kinematics and muscular activation were acquired and combined with a user-specific musculoskeletal model to estimate the joint stiffness. Using the arm kinematic Jacobian, the arm end-point stiffness was derived. The proposed non-disruptive method is capable of estimating the arm endpoint stiffness during the execution of virtual teleoperated tasks. The obtained results are in accordance with the existing literature in human motor control and show, throughout the tested trajectory, a modulation of the arm endpoint stiffness that is affected by task characteristics and hand speed and acceleration. PMID:29018319

Development of Cardiovascular and Neurodevelopmental Metrics as Sublethal Endpoints for the Fish Embryo Toxicity Test.

PubMed

Krzykwa, Julie C; Olivas, Alexis; Jeffries, Marlo K Sellin

2018-06-19

The fathead minnow fish embryo toxicity (FET) test has been proposed as a more humane alternative to current toxicity testing methods, as younger organisms are thought to experience less distress during toxicant exposure. However, the FET test protocol does not include endpoints that allow for the prediction of sublethal adverse outcomes, limiting its utility relative to other test types. Researchers have proposed the development of sublethal endpoints for the FET test to increase its utility. The present study 1) developed methods for previously unmeasured sublethal metrics in fathead minnows (i.e., spontaneous contraction frequency and heart rate) and 2) investigated the responsiveness of several sublethal endpoints related to growth (wet weight, length, and growth-related gene expression), neurodevelopment (spontaneous contraction frequency, and neurodevelopmental gene expression), and cardiovascular function and development (pericardial area, eye size and cardiovascular related gene expression) as additional FET test metrics using the model toxicant 3,4-dichloroaniline. Of the growth, neurological and cardiovascular endpoints measured, length, eye size and pericardial area were found to more responsive than the other endpoints, respectively. Future studies linking alterations in these endpoints to longer-term adverse impacts are needed to fully evaluate the predictive power of these metrics in chemical and whole effluent toxicity testing. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Impact of confinement housing on study end-points in the calf model of cryptosporidiosis.

PubMed

Graef, Geneva; Hurst, Natalie J; Kidder, Lance; Sy, Tracy L; Goodman, Laura B; Preston, Whitney D; Arnold, Samuel L M; Zambriski, Jennifer A

2018-04-01

Diarrhea is the second leading cause of death in children < 5 years globally and the parasite genus Cryptosporidium is a leading cause of that diarrhea. The global disease burden attributable to cryptosporidiosis is substantial and the only approved chemotherapeutic, nitazoxanide, has poor efficacy in HIV positive children. Chemotherapeutic development is dependent on the calf model of cryptosporidiosis, which is the best approximation of human disease. However, the model is not consistently applied across research studies. Data collection commonly occurs using two different methods: Complete Fecal Collection (CFC), which requires use of confinement housing, and Interval Collection (IC), which permits use of box stalls. CFC mimics human challenge model methodology but it is unknown if confinement housing impacts study end-points and if data gathered via this method is suitable for generalization to human populations. Using a modified crossover study design we compared CFC and IC and evaluated the impact of housing on study end-points. At birth, calves were randomly assigned to confinement (n = 14) or box stall housing (n = 9), or were challenged with 5 x 107 C. parvum oocysts, and followed for 10 days. Study end-points included fecal oocyst shedding, severity of diarrhea, degree of dehydration, and plasma cortisol. Calves in confinement had no significant differences in mean log oocysts enumerated per gram of fecal dry matter between CFC and IC samples (P = 0.6), nor were there diurnal variations in oocyst shedding (P = 0.1). Confinement housed calves shed significantly more oocysts (P = 0.05), had higher plasma cortisol (P = 0.001), and required more supportive care (P = 0.0009) than calves in box stalls. Housing method confounds study end-points in the calf model of cryptosporidiosis. Due to increased stress data collected from calves in confinement housing may not accurately estimate the efficacy of chemotherapeutics targeting C. parvum.

Connecting Ecosystem Service Production to Users as a Measure of Realized Benefits in Coastal Communities

EPA Science Inventory

Ecosystem goods and services are often produced in locations far away from where humans benefit from them. Human beneficiaries also use specific spatial pathways to access the Final Ecosystem Goods and Services (FEGS), the ecological endpoints directly beneficial to human well-b...

Toxicologic Pathology: The Basic Building Block of Risk Assessment

EPA Science Inventory

Human health risk assessment is a critical factor in many risk management decisions. Evaluation of human health risk requires research the provides information that appropriately characterizes potential hazards from exposure. Pathology endpoints are the central response around ...

METABOLOMICS IN SMALL FISH TOXICOLOGY AND ECOLOGICAL RISK ASSESSMENTS

EPA Science Inventory

The US EPA is tasked with protecting not only humans, but also ecosystems from potentially harmful effects of chemical pollutants. Although lagging behind applications targeted to human endpoints, metabolomics offers great potential in ecotoxicology. Indeed, the advantages of met...

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

Wellman, Dawn M.; Freshley, Mark D.; Truex, Michael J.

Current requirements for site remediation and closure are standards-based and are often overly conservative, costly, and in some cases, technically impractical to achieve. Use of risk-informed alternate endpoints provide a means to achieve remediation goals that are permitted by regulations and are protective of human health and the environment. Alternate endpoints enable establishing a path for cleanup that may include intermediate remedial milestones and transition points and/or regulatory alternatives to standards-based remediation. A framework is presented that is centered around developing and refining conceptual models in conjunction with assessing risks and potential endpoints as part of a system-based assessment thatmore » integrates site data with scientific understanding of processes that control the distribution and transport of contaminants in the subsurface and pathways to receptors. This system based assessment and subsequent implementation of the remediation strategy with appropriate monitoring are targeted at providing a holistic approach to addressing risks to human health and the environment. This holistic approach also enables effective predictive analysis of contaminant behavior to provide defensible criteria and data for making long-term decisions. Developing and implementing an alternate endpoint-based approach for remediation and waste site closure presents a number of challenges and opportunities. Categories of these challenges include scientific and technical, regulatory, institutional, and budget and resource allocation issues. Opportunities exist for developing and implementing systems-based approaches with respect to supportive characterization, monitoring, predictive modeling, and remediation approaches.« less

78 FR 63981 - Availability of Interaction Profile for Chlorinated Dibenzo-p -Dioxins, Polybrominated Diphenol...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-25

... found in human blood, adipose tissue, and breast milk. The purpose of this interaction profile is to... endpoints in humans. This interaction profile has undergone external peer-review and review by ATSDR's... DEPARTMENT OF HEALTH AND HUMAN SERVICES Agency for Toxic Substances and Disease Registry [Docket...

Approaches to extrapolating animal toxicity data on organic solvents to public health

EPA Science Inventory

Developing predictive relationships between exposure and toxicity in humans is difficult because 1) available data are usually derived from experimental animals whose sensitivity to the chemical relative to humans is unknown; 2) the specific neurotoxic endpoints measured in labor...

Improvement in latent variable indirect response modeling of multiple categorical clinical endpoints: application to modeling of guselkumab treatment effects in psoriatic patients.

PubMed

Hu, Chuanpu; Randazzo, Bruce; Sharma, Amarnath; Zhou, Honghui

2017-10-01

Exposure-response modeling plays an important role in optimizing dose and dosing regimens during clinical drug development. The modeling of multiple endpoints is made possible in part by recent progress in latent variable indirect response (IDR) modeling for ordered categorical endpoints. This manuscript aims to investigate the level of improvement achievable by jointly modeling two such endpoints in the latent variable IDR modeling framework through the sharing of model parameters. This is illustrated with an application to the exposure-response of guselkumab, a human IgG1 monoclonal antibody in clinical development that blocks IL-23. A Phase 2b study was conducted in 238 patients with psoriasis for which disease severity was assessed using Psoriasis Area and Severity Index (PASI) and Physician's Global Assessment (PGA) scores. A latent variable Type I IDR model was developed to evaluate the therapeutic effect of guselkumab dosing on 75, 90 and 100% improvement of PASI scores from baseline and PGA scores, with placebo effect empirically modeled. The results showed that the joint model is able to describe the observed data better with fewer parameters compared with the common approach of separately modeling the endpoints.

Application of the Aggregate Exposure Pathway and Adverse Outcome Pathway frameworks to advance cumulative risk assessment by integrating human health and ecological endpoints

EPA Science Inventory

Evaluating risk of adverse outcomes from chemical exposure is essential for understanding the impacts of environmental contaminants. While human health outcomes are of primary concern and are often the focus of risk assessments, important non-human species are also exposed to co...

Proximal Versus Distal Control of Two-Joint Planar Reaching Movements in the Presence of Neuromuscular Noise

PubMed Central

Nguyen, Hung P.; Dingwell, Jonathan B.

2012-01-01

Determining how the human nervous system contends with neuro-motor noise is vital to understanding how humans achieve accurate goal-directed movements. Experimentally, people learning skilled tasks tend to reduce variability in distal joint movements more than in proximal joint movements. This suggests that they might be imposing greater control over distal joints than proximal joints. However, the reasons for this remain unclear, largely because it is not experimentally possible to directly manipulate either the noise or the control at each joint independently. Therefore, this study used a 2 degree-of-freedom torque driven arm model to determine how different combinations of noise and/or control independently applied at each joint affected the reaching accuracy and the total work required to make the movement. Signal-dependent noise was simultaneously and independently added to the shoulder and elbow torques to induce endpoint errors during planar reaching. Feedback control was then applied, independently and jointly, at each joint to reduce endpoint error due to the added neuromuscular noise. Movement direction and the inertia distribution along the arm were varied to quantify how these biomechanical variations affected the system performance. Endpoint error and total net work were computed as dependent measures. When each joint was independently subjected to noise in the absence of control, endpoint errors were more sensitive to distal (elbow) noise than to proximal (shoulder) noise for nearly all combinations of reaching direction and inertia ratio. The effects of distal noise on endpoint errors were more pronounced when inertia was distributed more toward the forearm. In contrast, the total net work decreased as mass was shifted to the upper arm for reaching movements in all directions. When noise was present at both joints and joint control was implemented, controlling the distal joint alone reduced endpoint errors more than controlling the proximal joint alone for nearly all combinations of reaching direction and inertia ratio. Applying control only at the distal joint was more effective at reducing endpoint errors when more of the mass was more proximally distributed. Likewise, controlling the distal joint alone required less total net work than controlling the proximal joint alone for nearly all combinations of reaching distance and inertia ratio. It is more efficient to reduce endpoint error and energetic cost by selectively applying control to reduce variability in the distal joint than the proximal joint. The reasons for this arise from the biomechanical configuration of the arm itself. PMID:22757504

Proximal versus distal control of two-joint planar reaching movements in the presence of neuromuscular noise.

PubMed

Nguyen, Hung P; Dingwell, Jonathan B

2012-06-01

Determining how the human nervous system contends with neuro-motor noise is vital to understanding how humans achieve accurate goal-directed movements. Experimentally, people learning skilled tasks tend to reduce variability in distal joint movements more than in proximal joint movements. This suggests that they might be imposing greater control over distal joints than proximal joints. However, the reasons for this remain unclear, largely because it is not experimentally possible to directly manipulate either the noise or the control at each joint independently. Therefore, this study used a 2 degree-of-freedom torque driven arm model to determine how different combinations of noise and/or control independently applied at each joint affected the reaching accuracy and the total work required to make the movement. Signal-dependent noise was simultaneously and independently added to the shoulder and elbow torques to induce endpoint errors during planar reaching. Feedback control was then applied, independently and jointly, at each joint to reduce endpoint error due to the added neuromuscular noise. Movement direction and the inertia distribution along the arm were varied to quantify how these biomechanical variations affected the system performance. Endpoint error and total net work were computed as dependent measures. When each joint was independently subjected to noise in the absence of control, endpoint errors were more sensitive to distal (elbow) noise than to proximal (shoulder) noise for nearly all combinations of reaching direction and inertia ratio. The effects of distal noise on endpoint errors were more pronounced when inertia was distributed more toward the forearm. In contrast, the total net work decreased as mass was shifted to the upper arm for reaching movements in all directions. When noise was present at both joints and joint control was implemented, controlling the distal joint alone reduced endpoint errors more than controlling the proximal joint alone for nearly all combinations of reaching direction and inertia ratio. Applying control only at the distal joint was more effective at reducing endpoint errors when more of the mass was more proximally distributed. Likewise, controlling the distal joint alone required less total net work than controlling the proximal joint alone for nearly all combinations of reaching distance and inertia ratio. It is more efficient to reduce endpoint error and energetic cost by selectively applying control to reduce variability in the distal joint than the proximal joint. The reasons for this arise from the biomechanical configuration of the arm itself.

Analysis of inflammatory cytokines in human blood, breath condensate, and urine using a multiplex immunoassay platform

EPA Science Inventory

A change in the expression of cytokines in human biological media indicates an inflammatory response to external stressors and reflects an early step along the adverse outcome pathway (AOP) for various health endpoints. To characterize and interpret this inflammatory response, m...

Ecological Threshold for Toxicological Concern (eco-TTC): exploring the importance of non-standard species

EPA Science Inventory

The Threshold for Toxicological Concern (TTC) is well-established for assessing human safety of indirect food-contact substances and has been applied to a variety of endpoints. Recently, we have proposed an extension to the human safety TTC concept for environmental applications,...

78 FR 49530 - Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics; Public Workshop

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-14

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2013-N-0001... American Society for Pediatric Gastroenterology, Hepatology, and Nutrition, and the Pediatric IBD... patients and representatives from the Eunice Kennedy Shriver National Institute of Child Health and Human...

HOMOLOGOUS MEASURES OF COGNITIVE FUNCTION IN HUMAN INFANTS AND LABORATORY ANIMALS TO IDENTIFY ENVIRONMENTAL HEALTH RISKS TO CHILDREN

EPA Science Inventory

The importance of including neurodevelopmental endpoints in environmental studies is clear. A validated measure of cognitive fucntion in human infants that also has a parallel test in laboratory animal studies will provide a valuable approach for largescale studies. Such a ho...

77 FR 73289 - Hazardous Substances and Articles; Administration and Enforcement Regulations: Revisions to...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-10

... recommends this approach to manufacturers who are labeling substances to indicate a hazard. Accordingly, the... test animals. Additionally, the routine use of topical anesthetics, systemic analgesics, and humane..., systemic analgesics, and humane endpoints to avoid or minimize pain and distress in ocular safety testing...

DEVELOPMENT OF QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIPS TO PREDICT TOXICITY FOR A VARIETY OF HUMAN AND ECOLOGICAL ENDPOINTS

EPA Science Inventory

The number of chemicals released into the environment has significantly increased over the past few years, leading to increased risk of human exposure through inhalation, ingestion, or dermal uptake. In addition, the risk also increases with increasing toxicity of the chemical. ...

Can joint sound assess soft and hard endpoints of the Lachman test?: A preliminary study.

PubMed

Hattori, Koji; Ogawa, Munehiro; Tanaka, Kazunori; Matsuya, Ayako; Uematsu, Kota; Tanaka, Yasuhito

2016-05-12

The Lachman test is considered to be a reliable physical examination for anterior cruciate ligament (ACL) injury. Patients with a damaged ACL demonstrate a soft endpoint feeling. However, examiners judge the soft and hard endpoints subjectively. The purpose of our study was to confirm objective performance of the Lachman test using joint auscultation. Human and porcine knee joints were examined. Knee joint sound during the Lachman test (Lachman sound) was analyzed by fast Fourier transformation. As quantitative indices of Lachman sound, the peak sound as the maximum relative amplitude (acoustic pressure) and its frequency were used. The mean Lachman peak sound for healthy volunteer knees was 86.9 ± 12.9 Hz in frequency and -40 ± 2.5 dB in acoustic pressure. The mean Lachman peak sound for intact porcine knees was 84.1 ± 9.4 Hz and -40.5 ± 1.7 dB. Porcine knees with ACL deficiency had a soft endpoint feeling during the Lachman test. The Lachman peak sounds of porcine knees with ACL deficiency were dispersed into four distinct groups, with center frequencies of around 40, 160, 450, and 1600. The Lachman peak sound was capable of assessing soft and hard endpoints of the Lachman test objectively.

An approach for development of alternative test methods based on mechanisms of skin irritation.

PubMed

Osborne, R; Perkins, M A

1994-02-01

Recent advances in techniques for culture of human skin cells have led to their potential for use as in vitro models for skin irritation testing to augment or replace existing rabbit skin patch tests. Our work is directed towards the development of cultured human skin cells, together with endpoints that can be linked to in vivo mechanisms of skin irritation, as in vitro models for prediction of human skin irritation, and for study of mechanisms of contact irritant dermatitis. Three types of commercial human skin cell cultures have been evaluated, epidermal keratinocytes and partially or fully cornified keratinocyte-dermal fibroblast co-cultures. Human epidermal keratinocyte cultures (Clonetics) were treated with product ingredients and formulations, and the extent of cell damage was assessed by incorporation of the vital dye neutral red. Cell damage correlated with human skin patch data for ingredient chemicals with the exception of acids and alkalis, but did not correlate with skin irritation to surfactant-containing product formulations. Cultures of human skin equivalents were evaluated as potential models for measurement of responses to test materials that could not be measured in the keratinocyte/neutral red assay. We developed a battery of in vitro endpoints to measure responses to prototype ingredients and formulations in human epidermal keratinocyte-dermal fibroblast co-cultures grown on a nylon mesh ('Skin2' from Advanced Tissue Sciences) or on a collagen gel ('Testskin' from Organogenesis). The endpoints measure cytotoxicity (neutral red and MTT vital dye staining, lactate dehydrogenase and N-acetyl glucosaminidase release, glucose utilization) and inflammatory mediator (prostaglandin E2) release. Initial experiments indicate a promising correlation between responses of the Skin2 model to prototype surfactants and in vivo human skin irritation. The responses of Testskin cultures to acids and alkalis help to prove the concept that a topical application model can measure responses to these materials. These results suggest that human skin cell models can provide useful systems for preclinical skin irritation assessments, as alternatives to rabbits, for at least certain classes of test substances.

Comparison of toxicity values across zebrafish early life stages and mammalian studies: Implications for chemical testing.

PubMed

Ducharme, Nicole A; Reif, David M; Gustafsson, Jan-Ake; Bondesson, Maria

2015-08-01

With the high cost and slow pace of toxicity testing in mammals, the vertebrate zebrafish has become a tractable model organism for high throughput toxicity testing. We present here a meta-analysis of 600 chemicals tested for toxicity in zebrafish embryos and larvae. Nineteen aggregated and 57 individual toxicity endpoints were recorded from published studies yielding 2695 unique data points. These data points were compared to lethality and reproductive toxicology endpoints analyzed in rodents and rabbits and to exposure values for humans. We show that although many zebrafish endpoints did not correlate to rodent or rabbit acute toxicity data, zebrafish could be used to accurately predict relative acute toxicity through the rat inhalation, rabbit dermal, and rat oral exposure routes. Ranking of the chemicals based on toxicity and teratogenicity in zebrafish, as well as human exposure levels, revealed that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), benzo(a)pyrene, and chlorpyrifos ranked in the top nine of all chemicals for these three categories, and as such should be considered high priority chemicals for testing in higher vertebrates. Copyright © 2014 Elsevier Inc. All rights reserved.

Community-Based Networks for Challenged Environments

ERIC Educational Resources Information Center

Vigil-Hayes, Morgan Ashlee

2017-01-01

The Internet as a networked system has been rendered more complex than ever before as human endpoints are grafted into the system via increasingly pervasive and personalized networked devices. According to the United Nations, the Internet is a transnational enabler of a number of human rights, and as such, access to the Internet has been…

Clinical endpoints in the controlled human challenge model for Shigella: A call for standardization and the development of a disease severity score

PubMed Central

Lynen, Amanda; Riddle, Mark S.; Talaat, Kawsar; Sack, David; Gutiérrez, Ramiro L.; McKenzie, Robin; DeNearing, Barbara; Feijoo, Brittany; Kaminski, Robert W.; Taylor, David N.; Kirkpatrick, Beth D.; Bourgeois, A. Louis

2018-01-01

Background Since 1946 the controlled human infection model (CHIM) for Shigella has been used to improve understanding of disease pathogenesis, describe clinical and immunologic responses to infection and as a tool for vaccine development. As the frequency and intent for use in vaccine comparisons increases, standardization of the primary endpoint definition is necessary. Methods Subject-level data were obtained from previously conducted experimental Shigella CHIM studies. Signs and symptoms severity were categorized consistently across all studies. Sign and symptom correlations were estimated and univariate models were utilized to describe the association between stool output and other Shigella-attributable signs and symptoms. Multiple correspondence and hierarchical clustering analyses were performed to describe the co-occurrence of signs and symptoms. A disease score is proposed based on the co-occurrence of these events. Results Data were obtained on 54 subjects receiving 800 to 2000 colony forming units (cfu) of S. flexneri. The median maximum 24 hour stool output was 514 ml (IQR: 300, 998 ml) with a median frequency of 6 (IQR: 4, 9). Subjects reported abdominal pain or cramps (81.5%), headache (66.7%) and anorexia (64.8%), 50.0% had a fever and 27.8% had gross blood in multiple loose stools. Multiple correspondence analyses highlighted co-occurrence of symptoms based on severity. A 3-parameter disease severity score predicted shigellosis endpoints and better differentiated disease spectrum. Conclusion Dichotomous endpoints for Shigella CHIM fail to fully account for disease variability. An ordinal disease score characterizing the breadth of disease severity may enable a better characterization of shigellosis and can decrease sample size requirements. Furthermore, the disease severity score may be a useful tool for portfolio management by enabling prioritization across vaccine candidates with comparable efficacy estimates using dichotomous endpoints. PMID:29590182

Towards better environmental performance of wastewater sludge treatment using endpoint approach in LCA methodology.

PubMed

Alyaseri, Isam; Zhou, Jianpeng

2017-03-01

The aim of this study is to use the life cycle assessment method to measure the environmental performance of the sludge incineration process in a wastewater treatment plant and to propose an alternative that can reduce the environmental impact. To show the damages caused by the treatment processes, the study aimed to use an endpoint approach in evaluating impacts on human health, ecosystem quality, and resources due to the processes. A case study was taken at Bissell Point Wastewater Treatment Plant in Saint Louis, Missouri, U.S. The plant-specific data along with literature data from technical publications were used to build an inventory, and then analyzed the environmental burdens from sludge handling unit in the year 2011. The impact assessment method chosen was ReCipe 2008. The existing scenario (dewatering-multiple hearth incineration-ash to landfill) was evaluated and three alternative scenarios (fluid bed incineration and anaerobic digestion with and without land application) with energy recovery from heat or biogas were proposed and analyzed to find the one with the least environmental impact. The existing scenario shows that the most significant impacts are related to depletion in resources and damage to human health. These impacts mainly came from the operation phase (electricity and fuel consumption and emissions related to combustion). Alternatives showed better performance than the existing scenario. Using ReCipe endpoint methodology, and among the three alternatives tested, the anaerobic digestion had the best overall environmental performance. It is recommended to convert to fluid bed incineration if the concerns were more about human health or to anaerobic digestion if the concerns were more about depletion in resources. The endpoint approach may simplify the outcomes of this study as follows: if the plant is converted to fluid bed incineration, it could prevent an average of 43.2 DALYs in human life, save 0.059 species in the area from extinction, and make a 62% reduction in the plant's current expenses needed by future generations to extract resources per year. At the same time it may prevent 36.1 DALYs in humans, save 0.157 species, and make a 101% reduction in current expenses on resources per year, if converting to anaerobic digestion.

A new respirometric endpoint-based biosensor to assess the relative toxicity of chemicals on immobilized human cells.

PubMed

Dragone, Roberto; Frazzoli, Chiara; Grappelli, Claudio; Campanella, Luigi

2009-01-01

Several functional and biochemical parameters have been proposed as biomarkers of effect of environmental pollutants. A rapid biosensor working with immobilized human U-937 cells was developed and applied to environmentally relevant chemicals with different structures and toxicological pathways, i.e. benzalkonium chloride, clofibric acid, diclofenac, mercury nitrate, ofloxacin, and sodium dodecyl sulphate. Respiration of cells was relied upon as a comprehensive biochemical effect for screening purposes. Analytical parameter (DeltappmO(2)) and toxicological index (respiratory inhibition, delta%) measured after 1h of exposure were utilized for dose-response relationship study. Results (toxicity rating scales based on delta(50)% and steepness) were compared with those obtained by the same approach previously optimized on Saccharomyces cerevisiae. The toxicity rating scale obtained by the biomarker based on human mitochondrial and cell metabolic activities compared well with previous scale obtained on yeast cells and with available in-vivo acute toxicity indexes; respiration was confirmed as toxicological endpoint reliably measurable by the biosensor.

Test of neural inertia in humans during general anaesthesia.

PubMed

Kuizenga, M H; Colin, P J; Reyntjens, K M E M; Touw, D J; Nalbat, H; Knotnerus, F H; Vereecke, H E M; Struys, M M R F

2018-03-01

Neural inertia is defined as the tendency of the central nervous system to resist transitions between arousal states. This phenomenon has been observed in mice and Drosophila anaesthetized with volatile anaesthetics: the effect-site concentration required to induce anaesthesia in 50% of the population (C 50 ) was significantly higher than the effect-site concentration for 50% of the population to recover from anaesthesia. We evaluated this phenomenon in humans using propofol or sevoflurane (both with or without remifentanil) as anaesthetic agents. Thirty-six healthy volunteers received four sessions of anaesthesia with different drug combinations in a step-up/step-down design. Propofol or sevoflurane was administered with or without remifentanil. Serum concentrations of propofol and remifentanil were measured from arterial blood samples. Loss and return of responsiveness (LOR-ROR), response to pain (PAIN), Patient State Index (PSI) and spectral edge frequency (SEF) were modeled with NONMEM®. For propofol, the C 50 for induction and recovery of anaesthesia was not significantly different across the different endpoints. For sevoflurane, for all endpoints except SEF, significant differences were found. For some endpoints (LOR and PAIN) the difference was significant only when sevoflurane was combined with remifentanil. Our results nuance earlier findings with volatile anaesthetics in mice and Drosophila. Methodological aspects of the study, such as the measured endpoint, influence the detection of neural inertia. A more thorough definition of neural inertia, with a robust methodological framework for clinical studies is required to advance our knowledge of this phenomenon. NCT 02043938. Copyright © 2017 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

Biomechanical constraints on the feedforward regulation of endpoint stiffness.

PubMed

Hu, Xiao; Murray, Wendy M; Perreault, Eric J

2012-10-01

Although many daily tasks tend to destabilize arm posture, it is still possible to have stable interactions with the environment by regulating the multijoint mechanics of the arm in a task-appropriate manner. For postural tasks, this regulation involves the appropriate control of endpoint stiffness, which represents the stiffness of the arm at the hand. Although experimental studies have been used to evaluate endpoint stiffness control, including the orientation of maximal stiffness, the underlying neural strategies remain unknown. Specifically, the relative importance of feedforward and feedback mechanisms has yet to be determined due to the difficulty separately identifying the contributions of these mechanisms in human experiments. This study used a previously validated three-dimensional musculoskeletal model of the arm to quantify the degree to which the orientation of maximal endpoint stiffness could be changed using only steady-state muscle activations, used to represent feedforward motor commands. Our hypothesis was that the feedforward control of endpoint stiffness orientation would be significantly constrained by the biomechanical properties of the musculoskeletal system. Our results supported this hypothesis, demonstrating substantial biomechanical constraints on the ability to regulate endpoint stiffness throughout the workspace. The ability to regulate stiffness orientation was further constrained by additional task requirements, such as the need to support the arm against gravity or exert forces on the environment. Together, these results bound the degree to which slowly varying feedforward motor commands can be used to regulate the orientation of maximum arm stiffness and provide a context for better understanding conditions in which feedback control may be needed.

Challenging conventional risk assessment with respect to human exposure to multiple food contaminants in food: A case study using maize.

PubMed

Clarke, R; Connolly, L; Frizzell, C; Elliott, C T

2015-10-01

Mycotoxins and heavy metals are ubiquitous in the environment and contaminate many foods. The widespread use of pesticides in crop production to control disease contributes further to the chemical contamination of foods. Thus multiple chemical contaminants threaten the safety of many food commodities; hence the present study used maize as a model crop to identify the severity in terms of human exposure when multiple contaminants are present. High Content Analysis (HCA) measuring multiple endpoints was used to determine cytotoxicity of complex mixtures of mycotoxins, heavy metals and pesticides. Endpoints included nuclear intensity (NI), nuclear area (NA), plasma membrane permeability (PMP), mitochondrial membrane potential (MMP) and mitochondrial mass (MM). At concentrations representing legal limits of each individual contaminant in maize (3ng/ml ochratoxin A (OTA), 1μg/ml fumonisin B1 (FB1), 2ng/ml aflatoxin B1 (AFB1), 100ng/ml cadmium (Cd), 150ng/ml arsenic (As), 50ng/ml chlorpyrifos (CP) and 5μg/ml pirimiphos methyl (PM), the mixtures (tertiary mycotoxins plus Cd/As) and (tertiary mycotoxins plus Cd/As/CP/PM) were cytotoxic for NA and MM endpoints with a difference of up to 13.6% (p≤0.0001) and 12% (p≤0.0001) respectively from control values. The most cytotoxic mixture was (tertiary mycotoxins plus Cd/As/CP/PM) across all 4 endpoints (NA, NI, MM and MMP) with increases up to 61.3%, 23.0%, 61.4% and 36.3% (p≤0.0001) respectively. Synergy was evident for two endpoints (NI and MM) at concentrations contaminating maize above legal limits, with differences between expected and measured values of (6.2-12.4% (p≤0.05-p≤0.001) and 4.5-12.3% (p≤0.05-p≤0.001) for NI and MM, respectively. The study introduces for the first time, a holistic approach to identify the impact in terms of toxicity to humans when multiple chemical contaminants are present in foodstuffs. Governmental regulatory bodies must begin to contemplate how to safeguard the population when such mixtures of contaminants are found in foods and this study starts to address this critical issue. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Engineered Nanomaterials Elicit Cellular Stress Responses

EPA Science Inventory

Engineered nanomaterials are being developed continuously and incorporated into consumer products, resulting in increased human exposures. The study of engineered nanomaterials has focused largely on toxicity endpoints without further investigating potential mechanisms or pathway...

Cellular Stress Responses Elicited by Engineered Nanomaterials

EPA Science Inventory

Engineered nanomaterials are being incorporated continuously into consumer products, resulting in increased human exposures. The study of engineered nanomaterials has focused largely on oxidative stress and inflammation endpoints without further investigation of underlying pathwa...

The use of recombinant human LH (lutropin alfa) in the late stimulation phase of assisted reproduction cycles: a double-blind, randomized, prospective study.

PubMed

Tarlatzis, B; Tavmergen, E; Szamatowicz, M; Barash, A; Amit, A; Levitas, E; Shoham, Z

2006-01-01

The effect of recombinant human LH (r-hLH; lutropin alfa) in women undergoing controlled ovarian stimulation with recombinant human FSH (r-hFSH) prior to IVF was investigated. After down-regulation with the GnRH agonist, buserelin, 114 normo-ovulatory women (aged 18-37 years) received r-hFSH alone until the lead follicle reached a diameter of 14 mm. Patients were then randomized in a double-blind fashion to receive r-hFSH in addition to r-hLH, 75 IU s.c., or placebo daily for a maximum of 10 days prior to oocyte retrieval and IVF. The primary end-point was the number of metaphase II oocytes. There were no significant differences between treatment groups for the primary end-point. Serum estradiol concentrations on the day of HCG administration were significantly higher in the group receiving r-hLH plus r-hFSH than in the group receiving r-hFSH alone (P = 0.0001), but there were no significant differences between the groups in dose and duration of r-hFSH treatment required, oocyte maturation, fertilization rate, pregnancy rate and live birth rate. In this patient population, the addition of r-hLH during the late follicular phase of a long GnRH agonist and r-hFSH stimulation cycle provides no further benefit in terms of oocyte maturation or other end-points.

Assessment of cosmetic ingredients in the in vitro reconstructed human epidermis test method EpiSkin™ using HPLC/UPLC-spectrophotometry in the MTT-reduction assay.

PubMed

Alépée, N; Hibatallah, J; Klaric, M; Mewes, K R; Pfannenbecker, U; McNamee, P

2016-06-01

Cosmetics Europe recently established HPLC/UPLC-spectrophotometry as a suitable alternative endpoint detection system for measurement of formazan in the MTT-reduction assay of reconstructed human tissue test methods irrespective of the test system involved. This addressed a known limitation for such test methods that use optical density for measurement of formazan and may be incompatible for evaluation of strong MTT reducer and/or coloured chemicals. To build on the original project, Cosmetics Europe has undertaken a second study that focuses on evaluation of chemicals with functionalities relevant to cosmetic products. Such chemicals were primarily identified from the Scientific Committee on Consumer Safety (SCCS) 2010 memorandum (addendum) on the in vitro test EpiSkin™ for skin irritation testing. Fifty test items were evaluated in which both standard photometry and HPLC/UPLC-spectrophotometry were used for endpoint detection. The results obtained in this study: 1) provide further support for Within Laboratory Reproducibility of HPLC-UPLC-spectrophotometry for measurement of formazan; 2) demonstrate, through use a case study with Basazol C Blue pr. 8056, that HPLC/UPLC-spectrophotometry enables determination of an in vitro classification even when this is not possible using standard photometry and 3) addresses the question raised by SCCS in their 2010 memorandum (addendum) to consider an endpoint detection system not involving optical density quantification in in vitro reconstructed human epidermis skin irritation test methods. Copyright © 2016 Elsevier Ltd. All rights reserved.

A U.S. Human Well-being Index (HWBI) for Multiple Scales: Linking Services Provisioning to Human Well-being Endpoints (2000-2010)

EPA Science Inventory

objective of this report is to characterize well-being at multiple scales in order to evaluate the relationship of service flows in terms of sustainable well-being. The HWBI results presented represent snapshot assessments for the 2000-2010 time period. Based on the spatial and t...

Induction of molecular endpoints by reactive oxygen species in human lung cells predicted by physical chemical properties of engineered nanoparticles

EPA Science Inventory

A series of six titanium dioxide and two cerium oxide engineered nanomaterials were assessed for their ability to induce cytotoxicity, reactive oxygen species (ROS), and various types of DNA and protein damage in human respiratory BEAS-2B cells exposed in vitro for 72 hours at se...

METABOLOMICS IN SMALL FISH TOXICOLOGY AND OTHER ENVIRONMENTAL APPLICATIONS

EPA Science Inventory

Although lagging behind applications targeted to human endpoints, metabolomics offers great potential in environmental applications, including ecotoxicology. Indeed, the advantages of metabolomics (relative to other 'omic techniques) may be more tangible in ecotoxicology because...

An argument against the focus on Community Resilience in Public Health

PubMed Central

2014-01-01

Background It has been suggested that Public Health professionals focus on community resilience in tackling chronic problems, such as poverty and deprivation; is this approach useful? Discussion Resilience is always i) of something ii) to something iii) to an endpoint, as in i) a rubber ball, ii) to a blunt force, iii) to its original shape. “Community resilience” might be: of a neighbourhood, to a flu pandemic, with the endpoint, to return to normality. In these two examples, the endpoint is as-you-were. This is unsuitable for some examples of resilience. A child that is resilient to an abusive upbringing has an endpoint of living a happy life despite that upbringing: this is an as-you-should-be endpoint. Similarly, a chronically deprived community cannot have the endpoint of returning to chronic deprivation: so what is its endpoint? Roughly, it is an as-you-should-be endpoint: to provide an environment for inhabitants to live well. Thus resilient communities will be those that do this in the face of challenges. How can they be identified? One method uses statistical outliers, neighbourhoods that do better than would be expected on a range of outcomes given a range of stressors. This method tells us that a neighbourhood is resilient but not why it is. In response, a number of researchers have attributed characteristics to resilient communities; however, these generally fail to distinguish characteristics of a good community from those of a resilient one. Making this distinction is difficult and we have not seen it successfully done; more importantly, it is arguably unnecessary. There already exist approaches in Public Health to assessing and developing communities faced with chronic problems, typically tied to notions such as Social Capital. Community resilience to chronic problems, if it makes sense at all, is likely to be a property that emerges from the various assets in a community such as human capital, built capital and natural capital. Summary Public Health professionals working with deprived neighbourhoods would be better to focus on what neighbourhoods have or could develop as social capital for living well, rather than on the vague and tangential notion of community resilience. PMID:24447588

An argument against the focus on community resilience in public health.

PubMed

Allmark, Peter; Bhanbhro, Sadiq; Chrisp, Tom

2014-01-21

It has been suggested that Public Health professionals focus on community resilience in tackling chronic problems, such as poverty and deprivation; is this approach useful? Resilience is always i) of something ii) to something iii) to an endpoint, as in i) a rubber ball, ii) to a blunt force, iii) to its original shape. "Community resilience" might be: of a neighbourhood, to a flu pandemic, with the endpoint, to return to normality. In these two examples, the endpoint is as-you-were. This is unsuitable for some examples of resilience. A child that is resilient to an abusive upbringing has an endpoint of living a happy life despite that upbringing: this is an as-you-should-be endpoint. Similarly, a chronically deprived community cannot have the endpoint of returning to chronic deprivation: so what is its endpoint? Roughly, it is an as-you-should-be endpoint: to provide an environment for inhabitants to live well. Thus resilient communities will be those that do this in the face of challenges. How can they be identified?One method uses statistical outliers, neighbourhoods that do better than would be expected on a range of outcomes given a range of stressors. This method tells us that a neighbourhood is resilient but not why it is. In response, a number of researchers have attributed characteristics to resilient communities; however, these generally fail to distinguish characteristics of a good community from those of a resilient one. Making this distinction is difficult and we have not seen it successfully done; more importantly, it is arguably unnecessary.There already exist approaches in Public Health to assessing and developing communities faced with chronic problems, typically tied to notions such as Social Capital. Community resilience to chronic problems, if it makes sense at all, is likely to be a property that emerges from the various assets in a community such as human capital, built capital and natural capital. Public Health professionals working with deprived neighbourhoods would be better to focus on what neighbourhoods have or could develop as social capital for living well, rather than on the vague and tangential notion of community resilience.

Time-Course Determination of Cellular Stress Responses Elicited by Engineered Nanomaterials

EPA Science Inventory

Engineered nanomaterials are being incorporated continuously into consumer products, resulting in increased human exposures. The study of engineered nanomaterials has focused largely on oxidative stress and inflammation endpoints without further investigating potential pathways. ...

Randomized Phase Ib/II Trial of Rilotumumab or Ganitumab with Panitumumab versus Panitumumab Alone in Patients with Wild-type KRAS Metastatic Colorectal Cancer

PubMed Central

Cutsem, Eric Van; Eng, Cathy; Nowara, Elzbieta; Świeboda-Sadlej, Anna; Tebbutt, Niall C.; Mitchell, Edith; Davidenko, Irina; Stephenson, Joe; Elez, Elena; Prenen, Hans; Deng, Hongjie; Tang, Rui; McCaffery, Ian; Oliner, Kelly S.; Chen, Lisa; Gansert, Jennifer; Loh, Elwyn; Smethurst, Dominic; Tabernero, Josep

2015-01-01

Purpose Panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody (mAb), has demonstrated efficacy in patients with wild-type KRAS metastatic colorectal cancer (mCRC). Rilotumumab and ganitumab are investigational, fully human mAbs against hepatocyte growth factor (HGF)/scatter factor and IGF1R, respectively. Here we evaluate combining rilotumumab or ganitumab with panitumumab in previously treated patients with wild-type KRAS mCRC. Experimental Design Part 1 was a phase Ib dose-finding study of panitumumab plus rilotumumab. The primary endpoint was the incidence of dose-limiting toxicities (DLT). Part 2 was a randomized phase II trial of panitumumab in combination with rilotumumab, ganitumab, or placebo. The primary endpoint was objective response rate (ORR); safety, progression-free survival (PFS), and overall survival (OS) were secondary endpoints. Archival tissue specimens were collected for exploratory correlative work. Results In part 1, no DLTs were reported. A recommended phase II dose of 10 mg/kg rilotumumab was selected. In part 2, for the panitumumab plus rilotumumab (n = 48), panitumumab plus ganitumab (n = 46), and panitumumab plus placebo arms (n = 48), the ORRs were 31%, 22%, and 21%, respectively. The median PFS was 5.2, 5.3, and 3.7 months and median OS 13.8,10.6, and 11.6 months, respectively. Adverse events were tolerable. Exploratory biomarker analyses, including MET and IGF-related protein expression, failed to indicate conclusive predictive evidence on efficacy endpoints. Conclusions Panitumumab plus rilotumumab met the prespecified criterion for improvement in ORR whereas ganitumab did not. This is the first study to suggest a benefit for combining an HGF inhibitor (rilotumumab) with panitumumab in previously treated patients with wild-type KRAS mCRC. PMID:24919569

Intranasal carbetocin reduces hyperphagia in individuals with Prader-Willi syndrome.

PubMed

Dykens, Elisabeth M; Miller, Jennifer; Angulo, Moris; Roof, Elizabeth; Reidy, Michael; Hatoum, Hind T; Willey, Richard; Bolton, Guy; Korner, Paul

2018-06-21

Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder of life-threatening hyperphagia, obesity, intellectual deficits, compulsivity, and other behavioral problems. The efficacy and safety of i.n. carbetocin, an oxytocin analog, was evaluated in a prospective, randomized, double-blinded trial in adolescents with PWS. Eligible patients aged 10-18 years with genetically confirmed PWS were randomized (1:1) to i.n. carbetocin or placebo 3 times daily for 14 days. The primary efficacy endpoint was change in parent/caregiver-rated Hyperphagia in PWS Questionnaire-Responsiveness (HPWSQ-R) total score. Secondary efficacy endpoints included HPWSQ-R behavior, drive, and severity domains; clinician-rated HPWSQ; Children's Yale-Brown Obsessive-Compulsive Severity Scale; food domain of the Reiss Profile; and Clinical Global Impression-Improvement scale. Endpoints were assessed using analysis of covariance. Relationship between primary and secondary endpoints was assessed using Pearson correlation coefficients. Safety was assessed throughout the study. Demographics and clinical characteristics were similar between treatment groups (carbetocin, n = 17; placebo, n = 20). Patients receiving carbetocin had statistically significant reductions in HPWSQ-R total score at study end (-15.6) versus patients receiving placebo (-8.9; P = 0.029); several secondary efficacy endpoints also demonstrated significant differences (P < 0.05). Treatment effects for the primary and secondary endpoints were highly correlated (P ≤ 0.0001). Incidence of adverse events (AEs) was similar between treatment groups. I.n. carbetocin was well tolerated and improved hyperphagia and behavioral symptoms of PWS. ClinicalTrials.gov: NCT01968187FUNDING. The study was funded by Ferring Pharmaceuticals. Recruitment was aided by ongoing work in PWS performed through Eunice Kennedy Shriver National Institute of Child Health and Human Development grant U54 HD083211.

Fred Hutchinson Cancer Research Center (FHCRC1): Identification of Candidate Therapeutic Targets in Head and Neck Cancer Using Functional Kinomics | Office of Cancer Genomics

Cancer.gov

Kinome-wide siRNA screens targeting 713 human (MISSION® siRNA Human Gene Family Set, Sigma) were performed with viability as the phenotypic endpoint on five HNSCC lines: JHU-019; PCI15A and 15B; UM-SCC14A and 14C. Read the abstract

Fred Hutchinson Cancer Research Center (FHCRC-1): Identification of Candidate Therapeutic Targets in Head and Neck Cancer Using Functional Kinomics | Office of Cancer Genomics

Cancer.gov

Kinome-wide siRNA screens targeting 713 human (MISSION® siRNA Human Gene Family Set, Sigma) were performed with viability as the phenotypic endpoint on five HNSCC lines: JHU-019; PCI15A and 15B; UM-SCC14A and 14C. Read the abstract

An exclusive human milk-based diet in extremely premature infants reduces the probability of remaining on total parenteral nutrition: A reanalysis of the data

USDA-ARS?s Scientific Manuscript database

We have previously shown that an exclusively human-milk-based diet is beneficial for extremely premature infants who are at risk for necrotizing enterocolitis (NEC). However, no significant difference in the other primary study endpoint, the length of time on total parenteral nutrition (TPN), was fo...

Early and Late Damages in Chromosome 3 of Human Lymphocytes After Radiation Exposure

NASA Technical Reports Server (NTRS)

Sunagawa, Mayumi; Mangala, Lingegowda; Zhang, Ye; Kahdim, Munira; Wilson, Bobby; Cucinotta, Francis A.; Wu, Honglu

2011-01-01

Tumor formation in humans or animals is a multi-step process. An early stage of cancer development is believed to be genomic instability (GI) which accelerates the mutation rate in the descendants of the cells surviving radiation exposure. GI is defined as elevated or persistent genetic damages occurring many generations after the cells are exposed. While early studies have demonstrated radiation-induced GI in several cell types as detected in endpoints such as mutation, apoptosis and damages in chromosomes, the dependence of GI on the quality of radiation remains uncertain. To investigate GI in human lymphocytes induced by both low- and high-LET radiation, we initially exposed white blood cells collected from healthy subjects to gamma rays in vitro, and cultured the cells for multiple generations. Chromosome aberrations were analyzed in cells collected at first mitosis post irradiation and at several intervals during the culture period. Among a number of biological endpoints planned for the project, the multi-color banding fluorescent in situ hybridization (mBAND) allows identification of inversions that were expected to be stable. We present here early and late chromosome aberrations detected with mBAND in chromosome 3 after gamma exposure. Comparison of chromosome damages in between human lymphocytes and human epithelial cells is also discussed

Ultraviolet-B radiation induces modulation of antigen presentation of herpes simplex virus by human epidermal cells.

PubMed

van der Molen, R G; Out-Luiting, C; Claas, F H; Norval, M; Koerten, H K; Mommaas, A M

2001-06-01

Although ultraviolet (UV) B radiation is known to be immunosuppressive, there is little information regarding a relevant immunological endpoint to assess human subjects in vivo. Therefore, we have examined the effect of in vivo UV radiation on the ability of human epidermal cells (EC) to present herpes simplex virus (HSV) antigens to memory T cells. Human volunteers, who were seropositive for HSV, were exposed to one minimal erythemal dose (MED) for four consecutive days. EC, prepared from suction blister roofs, were co-cultured with autologous T cells in the presence of HSV. HSV antigen presentation by UV-exposed EC was increased compared with control, nonexposed EC. This up-regulation correlated with an influx of macrophages into the epidermis, which are considered to be associated with UV-induced tolerance. Altering the UV protocol to a sub-erythemal UV dose for four consecutive days or to a single high dose of 2 MED, resulted in suppressed HSV antigen presentation, without the influx of the UV-macrophages. One of the goals of the present study was to eventually use this HSV system to investigate sunscreen immunoprotection. A pilot study with a TiO2-containing sunscreen suggested that the endpoint for UV-induced immunosuppression presented here is promising to be used for human in vivo sunscreen immunoprotection studies.

Softened food reduces weight loss in the streptozotocin-induced male mouse model of diabetic nephropathy.

PubMed

Nørgaard, Sisse A; Sand, Fredrik W; Sørensen, Dorte B; Abelson, Klas Sp; Søndergaard, Henrik

2018-01-01

The streptozotocin (STZ)-induced diabetic mouse is a widely used model of diabetes and diabetic nephropathy (DN). However, it is a well-known issue that this model is challenged by high weight loss, which despite supportive measures often results in high euthanization rates. To overcome these issues, we hypothesized that supplementing STZ-induced diabetic mice with water-softened chow in addition to normal chow would reduce weight loss, lower the need for supportive treatment, and reduce the number of mice reaching the humane endpoint of 20% weight loss. In a 15 week STZ-induced DN study we demonstrated that diabetic male mice receiving softened chow had reduced acute weight loss following STZ treatment ( p = 0.045) and additionally fewer mice were euthanized due to weight loss. By supplementing the diabetic mice with softened chow, no mice reached 20% weight loss whereas 37.5% of the mice without this supplement reached this humane endpoint ( p = 0.0027). Excretion of corticosterone metabolites in faeces was reduced in diabetic mice on softened chow ( p = 0.0007), suggesting lower levels of general stress. Finally, it was demonstrated that the water-softened chow supplement did not significantly affect the induction of key disease parameters, i.e. %HbA1C and albuminuria nor result in abnormal teeth wear. In conclusion, supplementation of softened food is refining the STZ-induced diabetic mouse model significantly by reducing stress, weight loss and the number of animals sacrificed due to humane endpoints, while maintaining the key phenotypes of diabetes and nephropathy.

Metabolomics in Small Fish Toxicology: Assessing the Impacts of Model EDCs

EPA Science Inventory

Although lagging behind applications targeted to human endpoints, metabolomics offers great potential in environmental applications, including ecotoxicology. Indeed, the advantages of metabolomics (relative to other ‘omic techniques) may be more tangible in ecotoxicology because...

A Tox21 Approach to Altered Epigenetic Landscapes: Assessing Epigenetic Toxicity Pathways Leading to Altered Gene Expression and Oncogenic Transformation In Vitro

PubMed Central

Parfett, Craig L.; Desaulniers, Daniel

2017-01-01

An emerging vision for toxicity testing in the 21st century foresees in vitro assays assuming the leading role in testing for chemical hazards, including testing for carcinogenicity. Toxicity will be determined by monitoring key steps in functionally validated molecular pathways, using tests designed to reveal chemically-induced perturbations that lead to adverse phenotypic endpoints in cultured human cells. Risk assessments would subsequently be derived from the causal in vitro endpoints and concentration vs. effect data extrapolated to human in vivo concentrations. Much direct experimental evidence now shows that disruption of epigenetic processes by chemicals is a carcinogenic mode of action that leads to altered gene functions playing causal roles in cancer initiation and progression. In assessing chemical safety, it would therefore be advantageous to consider an emerging class of carcinogens, the epigenotoxicants, with the ability to change chromatin and/or DNA marks by direct or indirect effects on the activities of enzymes (writers, erasers/editors, remodelers and readers) that convey the epigenetic information. Evidence is reviewed supporting a strategy for in vitro hazard identification of carcinogens that induce toxicity through disturbance of functional epigenetic pathways in human somatic cells, leading to inactivated tumour suppressor genes and carcinogenesis. In the context of human cell transformation models, these in vitro pathway measurements ensure high biological relevance to the apical endpoint of cancer. Four causal mechanisms participating in pathways to persistent epigenetic gene silencing were considered: covalent histone modification, nucleosome remodeling, non-coding RNA interaction and DNA methylation. Within these four interacting mechanisms, 25 epigenetic toxicity pathway components (SET1, MLL1, KDM5, G9A, SUV39H1, SETDB1, EZH2, JMJD3, CBX7, CBX8, BMI, SUZ12, HP1, MPP8, DNMT1, DNMT3A, DNMT3B, TET1, MeCP2, SETDB2, BAZ2A, UHRF1, CTCF, HOTAIR and ANRIL) were found to have experimental evidence showing that functional perturbations played “driver” roles in human cellular transformation. Measurement of epigenotoxicants presents challenges for short-term carcinogenicity testing, especially in the high-throughput modes emphasized in the Tox21 chemicals testing approach. There is need to develop and validate in vitro tests to detect both, locus-specific, and genome-wide, epigenetic alterations with causal links to oncogenic cellular phenotypes. Some recent examples of cell-based high throughput chemical screening assays are presented that have been applied or have shown potential for application to epigenetic endpoints. PMID:28587163

The CGL1 (HeLa × Normal Skin Fibroblast) Human Hybrid Cell Line: A History of Ionizing Radiation Induced Effects on Neoplastic Transformation and Novel Future Directions in SNOLAB.

PubMed

Pirkkanen, Jake S; Boreham, Douglas R; Mendonca, Marc S

2017-10-01

Cellular transformation assays have been utilized for many years as powerful in vitro methods for examining neoplastic transformation potential/frequency and mechanisms of carcinogenesis for both chemical and radiological carcinogens. These mouse and human cell based assays are labor intensive but do provide quantitative information on the numbers of neoplastically transformed foci produced after carcinogenic exposure and potential molecular mechanisms involved. Several mouse and human cell systems have been generated to undertake these studies, and they vary in experimental length and endpoint assessment. The CGL1 human cell hybrid neoplastic model is a non-tumorigenic pre-neoplastic cell that was derived from the fusion of HeLa cervical cancer cells and a normal human skin fibroblast. It has been utilized for the several decades to study the carcinogenic/neoplastic transformation potential of a variety of ionizing radiation doses, dose rates and radiation types, including UV, X ray, gamma ray, neutrons, protons and alpha particles. It is unique in that the CGL1 assay has a relatively short assay time of 18-21 days, and rather than relying on morphological endpoints to detect neoplastic transformation utilizes a simple staining method that detects the tumorigenic marker alkaline phosphatase on the neoplastically transformed cells cell surface. In addition to being of human origin, the CGL1 assay is able to detect and quantify the carcinogenic potential of very low doses of ionizing radiation (in the mGy range), and utilizes a neoplastic endpoint (re-expression of alkaline phosphatase) that can be detected on both viable and paraformaldehyde fixed cells. In this article, we review the history of the CGL1 neoplastic transformation model system from its initial development through the wide variety of studies examining the effects of all types of ionizing radiation on neoplastic transformation. In addition, we discuss the potential of the CGL1 model system to investigate the effects of near zero background radiation levels available within the radiation biology lab we have established in SNOLAB.

Heavy Metals in ToxCast: Relevance to Food Safety (SOT)

EPA Science Inventory

Human exposure to heavy metals occurs through food contamination due to industrial processes, vehicle emissions and farming methods. Specific toxicity endpoints have been associated with metal exposures, e.g. lead and neurotoxicity; however, numerous varieties of heavy metals hav...

Selection and quantification of infection endpoints for trials of vaccines against intestinal helminths

PubMed Central

Alexander, Neal; Cundill, Bonnie; Sabatelli, Lorenzo; Bethony, Jeffrey M.; Diemert, David; Hotez, Peter; Smith, Peter G.; Rodrigues, Laura C.; Brooker, Simon

2011-01-01

Vaccines against human helminths are being developed but the choice of optimal parasitological endpoints and effect measures to assess their efficacy has received little attention. Assuming negative binomial distributions for the parasite counts, we rank the statistical power of three measures of efficacy: ratio of mean parasite intensity at the end of the trial, the odds ratio of infection at the end of the trial, and the rate ratio of incidence of infection during the trial. We also use a modelling approach to estimate the likely impact of trial interventions on the force of infection, and hence statistical power. We conclude that (1) final mean parasite intensity is a suitable endpoint for later phase vaccine trials, and (2) mass effects of trial interventions are unlikely to appreciably reduce the force of infection in the community – and hence statistical power – unless there is a combination of high vaccine efficacy and a large proportion of the population enrolled. PMID:21435404

Pilot study on quantitative assessment of muscle imbalance: differences of muscle synergies, equilibrium-point trajectories, and endpoint stiffness in normal and pathological upper-limb movements.

PubMed

Oku, Takanori; Uno, Kanna; Nishi, Tomoki; Kageyama, Masayuki; Phatiwuttipat, Pipatthana; Koba, Keitaro; Yamashita, Yuto; Murakami, Kenta; Uemura, Mitsunori; Hirai, Hiroaki; Miyazaki, Fumio; Naritomi, Hiroaki

2014-01-01

This paper proposes a novel method for assessment of muscle imbalance based on muscle synergy hypothesis and equilibrium point (EP) hypothesis of motor control. We explain in detail the method for extracting muscle synergies under the concept of agonist-antagonist (AA) muscle pairs and for estimating EP trajectories and endpoint stiffness of human upper limbs in a horizontal plane using an electromyogram. The results of applying this method to the reaching movement of one normal subject and one hemiplegic subject suggest that (1) muscle synergies (the balance among coactivation of AA muscle pairs), particularly the synergies that contributes to the angular directional kinematics of EP and the limb stiffness, are quite different between the normal subject and the hemiplegic subject; (2) the concomitant EP trajectory is also different between the normal and hemiplegic subjects, corresponding to the difference of muscle synergies; and (3) the endpoint (hand) stiffness ellipse of the hemiplegic subject becomes more elongated and orientation of the major axis rotates clockwise more than that of the normal subject. The level of motor impairment would be expected to be assessed from a comparison of these differences of muscle synergies, EP trajectories, and endpoint stiffness among normal and pathological subjects using the method.

Differences in end-point force trajectories elicited by electrical stimulation of individual human calf muscles

PubMed Central

Giordano, S B; Segal, R L; Abelew, T A

2009-01-01

The purpose of this study was to investigate the end-point force trajectories of the fibularis longus (FIB), lateral gastrocnemius (LG) and medial gastrocnemius (MG) muscles. Most information about individual muscle function has come from studies which use models based on electromyographic (EMG) recordings. In this study (N=20 subjects) we used electrical stimulation (20Hz) to elicit activity in individual muscles, recorded the end-point forces at the foot and verified the selectivity of stimulation by using magnetic resonance imaging. Unexpectedly, no significant differences were found between LG and MG force directions. Stimulation of LG and MG resulted in downward and medial or lateral forces depending on the subject. We found FIB end-point forces to be significantly different than those of LG and MG. In all subjects, stimulation of FIB resulted in downward and lateral forces. Based on our results, we suggest that there are multiple factors determining when and whether LG or MG will produce a medial or lateral force and FIB consistently plays a significant role in eversion/abduction and plantarflexion. We suggest that the inter-subject variability we found is not simply an artifact of experimental or technical error but is functionally relevant and should be addressed in future studies and models. PMID:20095454

Prognostic significance of tumor histology and computed tomographic staging for radiation treatment response of canine nasal tumors.

PubMed

Adams, William M; Kleiter, Miriam M; Thrall, Donald E; Klauer, Julia M; Forrest, Lisa J; La Due, Tracy A; Havighurst, Thomas C

2009-01-01

Prognostic significance of tumor histology and four computed tomography (CT) staging methods was tested retrospectively in dogs from three treatment centers that underwent intent-to-cure-radiotherapy for intranasal neoplasia. Disease-free and overall survival times were available for 94 dogs. A grouping of anaplastic, squamous cell, and undifferentiated carcinomas had a significantly shorter median disease-free survival (4.4 mo) than a grouping of all sarcomas (10.6 months). Disease-free survivals were not significantly different, when all carcinomas were compared with all sarcomas. The published original and modified WHO staging methods did not significantly relate to either survival endpoint. A modified human maxillary tumor staging system previously applied to canine nasal tumors was prognostically significant for both survival endpoints; a further modified version of that CT-based staging system resulted in improved significance for both survival endpoints. Dogs with unilateral intranasal involvement without bone destruction beyond the turbinates on CT, had longest median survival (23.4 months); CT evidence of cribriform plate involvement was associated with shortest median survival (6.7 months). Combining CT and histology statistically improved prognostic significance for both survival endpoints over the proposed CT staging method alone. Significance was lost when CT stages were collapsed to < four categories or histopathology groupings were collapsed to < three categories.

NEUROXOTOXICITY PRODUCED BY DIBROMOACETIC ACID IN DRINKING WATER OF RATS.

EPA Science Inventory

The Safe Drinking Water Act requires that EPA consider noncancer endpoints for the assessment of adverse human health effects of disinfection byproducts (DBPs). Dibromoacetic acid (DBA) is one of many DBPs produced by the chlorination of drinking water. Its chlorinated analog, ...

Evaluating the Effectiveness of Passive Sampling as a Surrogate for Organism Bioaccumulation.

EPA Science Inventory

Measurement of hydrophobic organic contaminants (HOCs) and the subsequent evaluation of their ecological and human health risks are common endpoints in aquatic environmental monitoring. Due to their hydrophobicity, many anthropogenic HOCs will partition from the water into organi...

Evaluating the Effectiveness of Passive Sampling as a Surrogate for Organism Bioaccumulation

EPA Science Inventory

Measurement of hydrophobic organic contaminants (HOCs) and the subsequent evaluation of their ecological and human health risks are common endpoints in aquatic environmental monitoring. Due to their hydrophobicity, many anthropogenic HOCs will partition from the water into organi...

THE ROLE OF MAMMALIAN DATA IN DETERMINING PHARMACEUTICAL RESPONSES IN AQUATIC SPECIES

EPA Science Inventory

Human pharmaceuticals are designed to be biologically active, and are extensively studies for physicalchemical, pharmacological, and toxicological properties. In those studies, efficacy and safety endpoints ED50s, LCSOs, NOAELs, LOAELs, etc.) are linked to plasma exposures (Cmax ...

Change in Gene Expression in Zebrafish as an Endpoint for Developmental Neurotoxicity Screening

EPA Science Inventory

Chemicals that adversely affect the developing nervous system may have long-term consequences on human health. Little information exists on a large number of environmental chemicals to guide the risk assessments for developmental neurotoxicity (DNT). As traditional developmental ...

EPA'S REGIONAL VULNERABILITY ASSESSMENT PROGRAM: TOOLS TO FACILITATE REGIONAL TO LOCAL DECISION-MAKING

EPA Science Inventory

EPA's Regional Vulnerability Assessment (ReVA) program is developing and testing approaches to conducting comparative environmental risk assessments at the regional scale, considering impacts to ecological human, and fiscal health endpoints. It seeks an objective and quantifiable...

Interactive toxicity of usnic acid and lipopolysaccharides in human liver HepG2 cells.

PubMed

Sahu, Saura C; O'Donnell, Michael W; Sprando, Robert L

2012-09-01

Usnic acid (UA), a natural botanical product, is a constituent of some dietary supplements used for weight loss. It has been associated with clinical hepatotoxicity leading to liver failure in humans. The present study was undertaken to evaluate the interactive toxicity, if any, of UA with lipopolysaccarides (LPS), a potential contaminant of food, at low non-toxic concentrations. The human hepatoblastoma HepG2 cells were treated with the vehicle control and test agents, separately and in a binary mixture, for 24 h at 37°C in 5% CO2. After the treatment period, the cells were evaluated by the traditional biochemical endpoints of toxicity in combination with the toxicogenomic endpoints that included cytotoxicity, oxidative stress, mitochondrial injury and changes in pathway-focused gene expression profiles. Compared with the controls, low non-toxic concentrations of UA and LPS separately showed no effect on the cells as determined by the biochemical endpoints. However, the simultaneous mixed exposure of the cells to their binary mixture resulted in increased cytotoxicity, oxidative stress and mitochondrial injury. The pathway-focused gene expression analysis resulted in the altered expression of several genes out of 84 genes examined. Most altered gene expressions induced by the binary mixture of UA and LPS were different from those induced by the individual constituents. The genes affected by the mixture were not modulated by either UA or LPS. The results of the present study suggest that the interactions of low nontoxic concentrations of UA and LPS produce toxicity in HepG2 cells. Published 2012. This article is a US Government work and is in the public domain in the USA.

Epigenetic alterations induced by genotoxic occupational and environmental human chemical carcinogens: A systematic literature review.

PubMed

Chappell, Grace; Pogribny, Igor P; Guyton, Kathryn Z; Rusyn, Ivan

2016-01-01

Accumulating evidence suggests that epigenetic alterations play an important role in chemically-induced carcinogenesis. Although the epigenome and genome may be equally important in carcinogenicity, the genotoxicity of chemical agents and exposure-related transcriptomic responses have been more thoroughly studied and characterized. To better understand the evidence for epigenetic alterations of human carcinogens, and the potential association with genotoxic endpoints, we conducted a systematic review of published studies of genotoxic carcinogens that reported epigenetic endpoints. Specifically, we searched for publications reporting epigenetic effects for the 28 agents and occupations included in Monograph Volume 100F of the International Agency for the Research on Cancer (IARC) that were classified as "carcinogenic to humans" (Group 1) with strong evidence of genotoxic mechanisms of carcinogenesis. We identified a total of 158 studies that evaluated epigenetic alterations for 12 of these 28 carcinogenic agents and occupations (1,3-butadiene, 4-aminobiphenyl, aflatoxins, benzene, benzidine, benzo[a]pyrene, coke production, formaldehyde, occupational exposure as a painter, sulfur mustard, and vinyl chloride). Aberrant DNA methylation was most commonly studied, followed by altered expression of non-coding RNAs and histone changes (totaling 85, 59 and 25 studies, respectively). For 3 carcinogens (aflatoxins, benzene and benzo[a]pyrene), 10 or more studies reported epigenetic effects. However, epigenetic studies were sparse for the remaining 9 carcinogens; for 4 agents, only 1 or 2 published reports were identified. While further research is needed to better identify carcinogenesis-associated epigenetic perturbations for many potential carcinogens, published reports on specific epigenetic endpoints can be systematically identified and increasingly incorporated in cancer hazard assessments. Copyright © 2016 Elsevier B.V. All rights reserved.

Evaluation of anti-hyperalgesic and analgesic effects of two benzodiazepines in human experimental pain: a randomized placebo-controlled study.

PubMed

Vuilleumier, Pascal H; Besson, Marie; Desmeules, Jules; Arendt-Nielsen, Lars; Curatolo, Michele

2013-01-01

Compounds that act on GABA-receptors produce anti-hyperalgesia in animal models, but little is known on their effects in humans. The aim of this study was to explore the potential usefulness of GABA-agonism for the control of pain in humans. Two agonists at the benzodiazepine-binding site of GABAA-receptors (clobazam and clonazepam) were studied using multiple experimental pain tests. Positive results would support further investigation of GABA agonism for the control of clinical pain. In a randomized double-blind crossover design, 16 healthy male volunteers received clobazam 20 mg, clonazepam 1 mg and tolterodine 1 mg (active placebo). The area of static hyperalgesia after intradermal capsaicin injection was the primary endpoint. Secondary endpoints were: area of dynamic hyperalgesia, response to von Frey hair stimulation, pressure pain thresholds, conditioned pain modulation, cutaneous and intramuscular electrical pain thresholds (1, 5 and 20 repeated stimulation), and pain during cuff algometry. For the primary endpoint, an increase in the area of static hyperalgesia was observed after administration of placebo (p<0.001), but not after clobazam and clonazepam. Results suggestive for an anti-hyperalgesic effect of the benzodiazepines were obtained with all three intramuscular pain models and with cuff algometry. No effect could be detected with the other pain models employed. Collectively, the results are suggestive for a possible anti-hyperalgesic effect of drugs acting at the GABAA-receptors in humans, particularly in models of secondary hyperalgesia and deep pain. The findings are not conclusive, but support further clinical research on pain modulation by GABAergic drugs. Because of the partial results, future research should focus on compounds acting selectively on subunits of the GABA complex, which may allow the achievement of higher receptor occupancy than unselective drugs. Our data also provide information on the most suitable experimental models for future investigation of GABAergic compounds. ClinicalTrials.gov NCT01011036.

Evaluation of Anti-Hyperalgesic and Analgesic Effects of Two Benzodiazepines in Human Experimental Pain: A Randomized Placebo-Controlled Study

PubMed Central

Vuilleumier, Pascal H.; Besson, Marie; Desmeules, Jules; Arendt-Nielsen, Lars; Curatolo, Michele

2013-01-01

Background and Aims Compounds that act on GABA-receptors produce anti-hyperalgesia in animal models, but little is known on their effects in humans. The aim of this study was to explore the potential usefulness of GABA-agonism for the control of pain in humans. Two agonists at the benzodiazepine-binding site of GABAA-receptors (clobazam and clonazepam) were studied using multiple experimental pain tests. Positive results would support further investigation of GABA agonism for the control of clinical pain. Methods In a randomized double-blind crossover design, 16 healthy male volunteers received clobazam 20 mg, clonazepam 1 mg and tolterodine 1 mg (active placebo). The area of static hyperalgesia after intradermal capsaicin injection was the primary endpoint. Secondary endpoints were: area of dynamic hyperalgesia, response to von Frey hair stimulation, pressure pain thresholds, conditioned pain modulation, cutaneous and intramuscular electrical pain thresholds (1, 5 and 20 repeated stimulation), and pain during cuff algometry. Results For the primary endpoint, an increase in the area of static hyperalgesia was observed after administration of placebo (p<0.001), but not after clobazam and clonazepam. Results suggestive for an anti-hyperalgesic effect of the benzodiazepines were obtained with all three intramuscular pain models and with cuff algometry. No effect could be detected with the other pain models employed. Conclusions Collectively, the results are suggestive for a possible anti-hyperalgesic effect of drugs acting at the GABAA-receptors in humans, particularly in models of secondary hyperalgesia and deep pain. The findings are not conclusive, but support further clinical research on pain modulation by GABAergic drugs. Because of the partial results, future research should focus on compounds acting selectively on subunits of the GABA complex, which may allow the achievement of higher receptor occupancy than unselective drugs. Our data also provide information on the most suitable experimental models for future investigation of GABAergic compounds. Trial Registration ClinicalTrials.gov NCT01011036 PMID:23554851

Review of genotoxicity biomonitoring studies of glyphosate-based formulations

PubMed Central

Kier, Larry D.

2015-01-01

Abstract Human and environmental genotoxicity biomonitoring studies involving exposure to glyphosate-based formulations (GBFs) were reviewed to complement an earlier review of experimental genotoxicity studies of glyphosate and GBFs. The environmental and most of the human biomonitoring studies were not informative because there was either a very low frequency of GBF exposure or exposure to a large number of pesticides without analysis of specific pesticide effects. One pesticide sprayer biomonitoring study indicated there was not a statistically significant relationship between frequency of GBF exposure reported for the last spraying season and oxidative DNA damage. There were three studies of human populations in regions of GBF aerial spraying. One study found increases for the cytokinesis-block micronucleus endpoint but these increases did not show statistically significant associations with self-reported spray exposure and were not consistent with application rates. A second study found increases for the blood cell comet endpoint at high exposures causing toxicity. However, a follow-up to this study 2 years after spraying did not indicate chromosomal effects. The results of the biomonitoring studies do not contradict an earlier conclusion derived from experimental genotoxicity studies that typical GBFs do not appear to present significant genotoxic risk under normal conditions of human or environmental exposures. PMID:25687244

Establishing a group of endpoints to support collective operations without specifying unique identifiers for any endpoints

DOEpatents

Archer, Charles J.; Blocksom, Michael A.; Ratterman, Joseph D.; Smith, Brian E.; Xue, Hanghon

2016-02-02

A parallel computer executes a number of tasks, each task includes a number of endpoints and the endpoints are configured to support collective operations. In such a parallel computer, establishing a group of endpoints receiving a user specification of a set of endpoints included in a global collection of endpoints, where the user specification defines the set in accordance with a predefined virtual representation of the endpoints, the predefined virtual representation is a data structure setting forth an organization of tasks and endpoints included in the global collection of endpoints and the user specification defines the set of endpoints without a user specification of a particular endpoint; and defining a group of endpoints in dependence upon the predefined virtual representation of the endpoints and the user specification.

A simple and rapid Hepatitis A Virus (HAV) titration assay based on antibiotic resistance of infected cells: evaluation of the HAV neutralization potency of human immune globulin preparations

PubMed Central

Konduru, Krishnamurthy; Virata-Theimer, Maria Luisa; Yu, Mei-ying W; Kaplan, Gerardo G

2008-01-01

Background Hepatitis A virus (HAV), the causative agent of acute hepatitis in humans, is an atypical Picornaviridae that grows poorly in cell culture. HAV titrations are laborious and time-consuming because the virus in general does not cause cytopathic effect and is detected by immunochemical or molecular probes. Simple HAV titration assays could be developed using currently available viral construct containing selectable markers. Results We developed an antibiotic resistance titration assay (ARTA) based on the infection of human hepatoma cells with a wild type HAV construct containing a blasticidin (Bsd) resistance gene. Human hepatoma cells infected with the HAV-Bsd construct survived selection with 2 μg/ml of blasticidin whereas uninfected cells died within a few days. At 8 days postinfection, the color of the pH indicator phenol red in cell culture media correlated with the presence of HAV-Bsd-infected blasticidin-resistant cells: an orange-to-yellow color indicated the presence of growing cells whereas a pink-to-purple color indicated that the cells were dead. HAV-Bsd titers were determined by an endpoint dilution assay based on the color of the cell culture medium scoring orange-to-yellow wells as positive and pink-to-purple wells as negative for HAV. As a proof-of-concept, we used the ARTA to evaluate the HAV neutralization potency of two commercially available human immune globulin (IG) preparations and a WHO International Standard for anti-HAV. The three IG preparations contained comparable levels of anti-HAV antibodies that neutralized approximately 1.5 log of HAV-Bsd. Similar neutralization results were obtained in the absence of blasticidin by an endpoint dilution ELISA at 2 weeks postinfection. Conclusion The ARTA is a simple and rapid method to determine HAV titers without using HAV-specific probes. We determined the HAV neutralization potency of human IG preparations in 8 days by ARTA compared to the 14 days required by the endpoint dilution ELISA. The ARTA reduced the labour, time, and cost of HAV titrations making it suitable for high throughput screening of sera and antivirals, determination of anti-HAV antibodies in human immune globulin preparations, and research applications that involve the routine evaluation of HAV titers. PMID:19094229

Multi-muscle FES force control of the human arm for arbitrary goals.

PubMed

Schearer, Eric M; Liao, Yu-Wei; Perreault, Eric J; Tresch, Matthew C; Memberg, William D; Kirsch, Robert F; Lynch, Kevin M

2014-05-01

We present a method for controlling a neuroprosthesis for a paralyzed human arm using functional electrical stimulation (FES) and characterize the errors of the controller. The subject has surgically implanted electrodes for stimulating muscles in her shoulder and arm. Using input/output data, a model mapping muscle stimulations to isometric endpoint forces measured at the subject's hand was identified. We inverted the model of this redundant and coupled multiple-input multiple-output system by minimizing muscle activations and used this inverse for feedforward control. The magnitude of the total root mean square error over a grid in the volume of achievable isometric endpoint force targets was 11% of the total range of achievable forces. Major sources of error were random error due to trial-to-trial variability and model bias due to nonstationary system properties. Because the muscles working collectively are the actuators of the skeletal system, the quantification of errors in force control guides designs of motion controllers for multi-joint, multi-muscle FES systems that can achieve arbitrary goals.

Development of World Health Organization (WHO) recommendations for appropriate clinical trial endpoints for next-generation Human Papillomavirus (HPV) vaccines.

PubMed

Prabhu, Malavika; Eckert, Linda O

2016-12-01

The World Health Organization (WHO) serves as a key organization to bring together experts along the continuum of vaccine development and regulatory approval, among its other functions. Using the revision of WHO's guidelines on prophylactic human papillomavirus (HPV) vaccine as an example, we describe the process by which (1) a need to revise the guidelines was identified; (2) a group of stakeholders with complementary expertise and key questions were identified; (3) a scientific review was conducted; (4) consensus on revisions was achieved; (5) guidelines were updated, reviewed widely, and approved. This multi-year process resulted in the consensus that regulatory agencies could consider additional endpoints, such as persistent HPV infection or immune equivalence, depending on the design of the HPV vaccine trials. Updating the guidelines will now accelerate vaccine development, reduce costs of clinical trials, and lead to faster regulatory approval. Copyright © 2016. Published by Elsevier B.V.

Alternative Endpoints and Approaches Selected for the Remediation of Contaminated Groundwater at Complex Sites

NASA Astrophysics Data System (ADS)

Deeb, R. A.; Hawley, E.

2011-12-01

This presentation will focus on findings, statistics, and case studies from a recently-completed report for the Department of Defense's Environmental Security Technology Certification Program (ESTCP) (Project ER-0832) on alternative endpoints and alternative remedial strategies for groundwater remediation under a variety of Federal and state cleanup programs, including technical impracticability (TI) and other Applicable or Relevant and Appropriate Requirement (ARAR) waivers, state and local designations such as groundwater management zones, Alternate Concentration Limits (ACLs), use of monitored natural attenuation (MNA) over long timeframes, and more. The primary objective of the project was to provide environmental managers and regulators with tools, metrics, and information needed to evaluate alternative endpoints for groundwater remediation at complex sites. A statistical analysis of Comprehensive Environmental Response, Compensation and Liability Act (CERCLA) sites receiving TI waivers will be presented as well as case studies of other types of alternative endpoints and alternative remedial strategies to illustrate the variety of approaches used at complex sites and the technical analyses used to predict and document cost, timeframe, and potential remedial effectiveness. Case studies provide examples of the flexible, site-specific, application of alternative endpoints and alternative remedial strategies that have been used in the past to manage and remediate groundwater contamination at complex sites. For example, at least 13 states consider some designation for groundwater containment in their corrective action policies, such as groundwater management zones, containment zones, and groundwater classification exemption areas. These designations typically indicate that groundwater contamination is present above permissible levels. Soil and groundwater within these zones are managed to protect human health and the environment. Lesson learned for the analyses conducted and the case studies evaluated allow for a more careful consideration of alternative, beneficial, and cost-effective cleanup objectives and metrics that can be achieved over the short-term (while eventually meeting long-term cleanup objectives or demonstrating the applicability of alternative endpoints), thus improving the site cleanup process at complex sites where appropriate.

Establishing a group of endpoints in a parallel computer

DOEpatents

Archer, Charles J.; Blocksome, Michael A.; Ratterman, Joseph D.; Smith, Brian E.; Xue, Hanhong

2016-02-02

A parallel computer executes a number of tasks, each task includes a number of endpoints and the endpoints are configured to support collective operations. In such a parallel computer, establishing a group of endpoints receiving a user specification of a set of endpoints included in a global collection of endpoints, where the user specification defines the set in accordance with a predefined virtual representation of the endpoints, the predefined virtual representation is a data structure setting forth an organization of tasks and endpoints included in the global collection of endpoints and the user specification defines the set of endpoints without a user specification of a particular endpoint; and defining a group of endpoints in dependence upon the predefined virtual representation of the endpoints and the user specification.

Use of ferrets for electrophysiologic monitoring of ion transport

PubMed Central

Kaza, Niroop; Raju, S. Vamsee; Cadillac, Joan M.; Trombley, John A.; Rasmussen, Lawrence; Tang, Liping; Dohm, Erik; Harrod, Kevin S.

2017-01-01

Limited success achieved in translating basic science discoveries into clinical applications for chronic airway diseases is attributed to differences in respiratory anatomy and physiology, poor approximation of pathologic processes, and lack of correlative clinical endpoints between humans and laboratory animal models. Here, we discuss advantages of using ferrets (Mustela putorus furo) as a model for improved understanding of human airway physiology and demonstrate assays for quantifying airway epithelial ion transport in vivo and ex vivo, and establish air-liquid interface cultures of ferret airway epithelial cells as a complementary in vitro model for mechanistic studies. We present data here that establishes the feasibility of measuring these human disease endpoints in ferrets. Briefly, potential difference across the nasal and the lower airway epithelium in ferrets could be consistently assessed, were highly reproducible, and responsive to experimental interventions. Additionally, ferret airway epithelial cells were amenable to primary cell culture methods for in vitro experiments as was the use of ferret tracheal explants as an ex vivo system for assessing ion transport. The feasibility of conducting multiple assessments of disease outcomes supports the adoption of ferrets as a highly relevant model for research in obstructive airway diseases. PMID:29077751

Use of ferrets for electrophysiologic monitoring of ion transport.

PubMed

Kaza, Niroop; Raju, S Vamsee; Cadillac, Joan M; Trombley, John A; Rasmussen, Lawrence; Tang, Liping; Dohm, Erik; Harrod, Kevin S; Rowe, Steven M

2017-01-01

Limited success achieved in translating basic science discoveries into clinical applications for chronic airway diseases is attributed to differences in respiratory anatomy and physiology, poor approximation of pathologic processes, and lack of correlative clinical endpoints between humans and laboratory animal models. Here, we discuss advantages of using ferrets (Mustela putorus furo) as a model for improved understanding of human airway physiology and demonstrate assays for quantifying airway epithelial ion transport in vivo and ex vivo, and establish air-liquid interface cultures of ferret airway epithelial cells as a complementary in vitro model for mechanistic studies. We present data here that establishes the feasibility of measuring these human disease endpoints in ferrets. Briefly, potential difference across the nasal and the lower airway epithelium in ferrets could be consistently assessed, were highly reproducible, and responsive to experimental interventions. Additionally, ferret airway epithelial cells were amenable to primary cell culture methods for in vitro experiments as was the use of ferret tracheal explants as an ex vivo system for assessing ion transport. The feasibility of conducting multiple assessments of disease outcomes supports the adoption of ferrets as a highly relevant model for research in obstructive airway diseases.

The biological effects of ionising radiation on Crustaceans: A review.

PubMed

Fuller, Neil; Lerebours, Adélaïde; Smith, Jim T; Ford, Alex T

2015-10-01

Historic approaches to radiation protection are founded on the conjecture that measures to safeguard humans are adequate to protect non-human organisms. This view is disparate with other toxicants wherein well-developed frameworks exist to minimise exposure of biota. Significant data gaps for many organisms, coupled with high profile nuclear incidents such as Chernobyl and Fukushima, have prompted the re-evaluation of our approach toward environmental radioprotection. Elucidating the impacts of radiation on biota has been identified as priority area for future research within both scientific and regulatory communities. The crustaceans are ubiquitous in aquatic ecosystems, comprising greater than 66,000 species of ecological and commercial importance. This paper aims to assess the available literature of radiation-induced effects within this subphylum and identify knowledge gaps. A literature search was conducted pertaining to radiation effects on four endpoints as stipulated by a number of regulatory bodies: mortality, morbidity, reproduction and mutation. A major finding of this review was the paucity of data regarding the effects of environmentally relevant radiation doses on crustacean biology. Extremely few studies utilising chronic exposure durations or wild populations were found across all four endpoints. The dose levels at which effects occur was found to vary by orders of magnitude thus presenting difficulties in developing phyla-specific benchmark values and reference levels for radioprotection. Based on the limited data, mutation was found to be the most sensitive endpoint of radiation exposure, with mortality the least sensitive. Current phyla-specific dose levels and limits proposed by major regulatory bodies were found to be inadequate to protect species across a range of endpoints including morbidity, mutation and reproduction and examples are discussed within. These findings serve to prioritise areas for future research that will significantly advance understanding of radiation-induced effects in aquatic invertebrates and consequently enhance ability to predict the impacts of radioactive releases on the environment. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

A Pharmacokinetics Phase 1 Bioequivalence Study of the Trastuzumab Biosimilar MYL-1401O vs EU-Trastuzumab and US-Trastuzumab.

PubMed

Waller, Cornelius F; Vutikullird, Apinya; Lawrence, Tracey E; Shaw, Andrew; Liu, Mark Shiyao; Baczkowski, Mark; Sharma, Rajiv; Barve, Abhijit; Goyal, Parag; Donnelly, Charles; Sengupta, Nilanjan; Pennella, Eduardo J

2018-06-21

Trastuzumab is a humanized monoclonal antibody that binds the human epidermal growth factor receptor 2 (HER2) oncoprotein and is an effective therapy for HER2-overexpressing breast cancer. MYL-1401O is a trastuzumab biosimilar. Here, we report results from a phase 1 study that investigated bioequivalence among MYL-1401O, reference EU-trastuzumab, and US-trastuzumab. This single-center, randomized, double-blind, three-arm, parallel-group, phase 1 study was conducted in healthy adult male volunteers. Subjects were randomized 1:1:1 to receive a single 8 mg kg -1 dose of MYL-1401O, EU-trastuzumab, or US-trastuzumab as a 90-minute intravenous infusion. Primary objective was to assess PK similarity among all three products. Primary endpoints assessed were peak serum concentration (Cmax), area under the serum concentration-time curve from time of dosing to time of last quantifiable concentration (AUC 0-last ), and AUC from time of dosing to infinity (AUC 0-∞ ). Secondary endpoints included time of Cmax (tmax), elimination rate constant (λz), half-life (t ½ ), safety, and immunogenicity. Of 132 subjects enrolled (44/treatment), 120 (MYL-1401O, n=42; EU-trastuzumab, n=41; US-trastuzumab, n=37) were included in the PK analysis. The 90% CIs of the ratios of geometric means for the primary endpoints were bounded within the predefined bioequivalence criterion of 80% to 125%. Secondary endpoints tmax, λz, and t ½ were similar among groups. All treatment-emergent adverse events were mild or moderate, similar across groups, and no serious adverse events were reported. No treatment-related antidrug antibodies were detected. MYL-1401O was well tolerated, and demonstrated PK and safety profiles similar to EU-trastuzumab and US-trastuzumab in healthy volunteers (ClinicalTrials.gov, NCT02594761). This article is protected by copyright. All rights reserved.

Prevention of colonic neoplasia with polyethylene glycol: A short term randomized placebo-controlled double-blinded trial.

PubMed

Wali, Ramesh K; Bianchi, Laura; Kupfer, Sonia; De La Cruz, Mart; Jovanovic, Borko; Weber, Christopher; Goldberg, Michael J; Rodriguez, L M; Bergan, Raymond; Rubin, David; Tull, Mary Beth; Richmond, Ellen; Parker, Beth; Khan, Seema; Roy, Hemant K

2018-01-01

Chemoprevention represents an attractive modality against colorectal cancer (CRC) although widespread clinical implementation of promising agents (e.g. aspirin/NSAIDS) have been stymied by both suboptimal efficacy and concerns over toxicity. This highlights the need for better agents. Several groups, including our own, have reported that the over-the-counter laxative polyethylene glycol (PEG) has remarkable efficacy in rodent models of colon carcinogenesis. In this study, we undertook the first randomized human trial to address the role of PEG in prevention of human colonic neoplasia. This was a double-blind, placebo-controlled, three-arm trial where eligible subjects were randomized to 8g PEG-3350 (n = 27) or 17g PEG-3350 (n = 24), or placebo (n = 24; maltodextrin) orally for a duration of six months. Our initial primary endpoint was rectal aberrant crypt foci (ACF) but this was changed during protocol period to rectal mucosal epidermal growth factor receptor (EGFR). Of the 87 patients randomized, 48 completed study primary endpoints and rectal EGFR unchanged PEG treatment. Rectal ACF had a trend suggesting potentially reduction with PEG treatment (pre-post change 1.7 in placebo versus -0.3 in PEG 8+ 17g doses, p = 0.108). Other endpoints (proliferation, apoptosis, expression of SNAIL and E-cadherin), previously noted to be modulated in rodent models, appeared unchanged with PEG treatment in this clinical trial. We conclude that PEG was generally well tolerated with the trial failing to meet primary efficacy endpoints. However, rectal ACFs demonstrated a trend (albeit statistically insignificant) for suppression with PEG. Moreover, all molecular assays including EGFR were unaltered with PEG underscoring issues with lack of translatability of biomarkers from preclinical to clinical trials. This data may provide the impetus for future clinical trials on PEG using more robust biomarkers of chemoprevention. ClinicalTrials.gov NCT00828984.

Prevention of colonic neoplasia with polyethylene glycol: A short term randomized placebo-controlled double-blinded trial

PubMed Central

Wali, Ramesh K.; Bianchi, Laura; Kupfer, Sonia; De La Cruz, Mart; Jovanovic, Borko; Weber, Christopher; Goldberg, Michael J.; Rodriguez, L. M.; Bergan, Raymond; Rubin, David; Tull, Mary Beth; Richmond, Ellen; Parker, Beth; Khan, Seema

2018-01-01

Chemoprevention represents an attractive modality against colorectal cancer (CRC) although widespread clinical implementation of promising agents (e.g. aspirin/NSAIDS) have been stymied by both suboptimal efficacy and concerns over toxicity. This highlights the need for better agents. Several groups, including our own, have reported that the over-the-counter laxative polyethylene glycol (PEG) has remarkable efficacy in rodent models of colon carcinogenesis. In this study, we undertook the first randomized human trial to address the role of PEG in prevention of human colonic neoplasia. This was a double-blind, placebo-controlled, three-arm trial where eligible subjects were randomized to 8g PEG-3350 (n = 27) or 17g PEG-3350 (n = 24), or placebo (n = 24; maltodextrin) orally for a duration of six months. Our initial primary endpoint was rectal aberrant crypt foci (ACF) but this was changed during protocol period to rectal mucosal epidermal growth factor receptor (EGFR). Of the 87 patients randomized, 48 completed study primary endpoints and rectal EGFR unchanged PEG treatment. Rectal ACF had a trend suggesting potentially reduction with PEG treatment (pre-post change 1.7 in placebo versus -0.3 in PEG 8+ 17g doses, p = 0.108). Other endpoints (proliferation, apoptosis, expression of SNAIL and E-cadherin), previously noted to be modulated in rodent models, appeared unchanged with PEG treatment in this clinical trial. We conclude that PEG was generally well tolerated with the trial failing to meet primary efficacy endpoints. However, rectal ACFs demonstrated a trend (albeit statistically insignificant) for suppression with PEG. Moreover, all molecular assays including EGFR were unaltered with PEG underscoring issues with lack of translatability of biomarkers from preclinical to clinical trials. This data may provide the impetus for future clinical trials on PEG using more robust biomarkers of chemoprevention. Trial registration: ClinicalTrials.gov NCT00828984 PMID:29617381

21 CFR 884.4100 - Endoscopic electrocautery and accessories.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Endoscopic electrocautery and accessories. 884.4100 Section 884.4100 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... ammeters: continue electrode activation for 5 seconds after the visual endpoint (tissue blanching) is...

Linking mechanistic data to endpoints of regulatory concern using the adverse outcome pathway framework.

EPA Science Inventory

In order to increase the uptake and use of high throughput screening data in environmental risk assessment, it is important to establish scientifically credible links between measures of biological pathway perturbation and apical adverse outcomes in humans and wildlife. The adver...

Ecosystem services as assessment endpoints for ecological risk assessment

EPA Science Inventory

Ecosystem services (ES) are defined as the outputs of ecological processes that contribute to human welfare or have the potential to do so in the future, and include the production of food and drinking water, purification of air and water, pollination, and nutrient cycling. The n...

Using Quantitative Structure-Activity Relationship Modeling to Quantitatively Predict the Developmental Toxicity of Halogenated Azole compounds

EPA Science Inventory

Developmental toxicity is a relevant endpoint for the comprehensive assessment of human health risk from chemical exposure. However, animal developmental toxicity studies remain unavailable for many environmental contaminants due to the complexity and cost of these types of analy...

Advancing the adverse outcome pathway framework and its applications through a global horizon scanning exercise

EPA Science Inventory

Regulatory agencies worldwide are confronted with the challenging task of assessing the risks of thousands of chemicals to protect both human health and the environment. Traditional toxicity testing largely relies on apical endpoints from whole animal studies, which, in addition...

Use of epidemiologic data in Integrated Risk Information System (IRIS) assessments

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

Persad, Amanda S.; Cooper, Glinda S.

2008-11-15

In human health risk assessment, information from epidemiologic studies is typically utilized in the hazard identification step of the risk assessment paradigm. However, in the assessment of many chemicals by the Integrated Risk Information System (IRIS), epidemiologic data, both observational and experimental, have also been used in the derivation of toxicological risk estimates (i.e., reference doses [RfD], reference concentrations [RfC], oral cancer slope factors [CSF] and inhalation unit risks [IUR]). Of the 545 health assessments posted on the IRIS database as of June 2007, 44 assessments derived non-cancer or cancer risk estimates based on human data. RfD and RfC calculationsmore » were based on a spectrum of endpoints from changes in enzyme activity to specific neurological or dermal effects. There are 12 assessments with IURs based on human data, two assessments that extrapolated human inhalation data to derive CSFs and one that used human data to directly derive a CSF. Lung or respiratory cancer is the most common endpoint for cancer assessments based on human data. To date, only one chemical, benzene, has utilized human data for derivation of all three quantitative risk estimates (i.e., RfC, RfD, and dose-response modeling for cancer assessment). Through examples from the IRIS database, this paper will demonstrate how epidemiologic data have been used in IRIS assessments for both adding to the body of evidence in the hazard identification process and in the quantification of risk estimates in the dose-response component of the risk assessment paradigm.« less

A mathematical analysis to address the 6 degree-of-freedom segmental power imbalance.

PubMed

Ebrahimi, Anahid; Collins, John D; Kepple, Thomas M; Takahashi, Kota Z; Higginson, Jill S; Stanhope, Steven J

2018-01-03

Segmental power is used in human movement analyses to indicate the source and net rate of energy transfer between the rigid bodies of biomechanical models. Segmental power calculations are performed using segment endpoint dynamics (kinetic method). A theoretically equivalent method is to measure the rate of change in a segment's mechanical energy state (kinematic method). However, these two methods have not produced experimentally equivalent results for segments proximal to the foot, with the difference in methods deemed the "power imbalance." In a 6 degree-of-freedom model, segments move independently, resulting in relative segment endpoint displacement and non-equivalent segment endpoint velocities at a joint. In the kinetic method, a segment's distal end translational velocity may be defined either at the anatomical end of the segment or at the location of the joint center (defined here as the proximal end of the adjacent distal segment). Our mathematical derivations revealed the power imbalance between the kinetic method using the anatomical definition and the kinematic method can be explained by power due to relative segment endpoint displacement. In this study, we tested this analytical prediction through experimental gait data from nine healthy subjects walking at a typical speed. The average absolute segmental power imbalance was reduced from 0.023 to 0.046 W/kg using the anatomical definition to ≤0.001 W/kg using the joint center definition in the kinetic method (95.56-98.39% reduction). Power due to relative segment endpoint displacement in segmental power analyses is substantial and should be considered in analyzing energetic flow into and between segments. Copyright © 2017 Elsevier Ltd. All rights reserved.

Adaptation in a rotating artificial gravity environment

NASA Technical Reports Server (NTRS)

Lackner, J. R.; DiZio, P.

1998-01-01

The centripetal force generated by a rotating space vehicle is a potential source of artificial gravity. Minimizing the cost of such a vehicle dictates using the smallest radius and highest rotation rate possible, but head movements made at high rotation rates generate disorienting, nauseogenic cross-coupled semicircular canal stimulation. Early studies suggested 3 or 4 rpm as the highest rate at which humans could adapt to this vestibular stimulus. These studies neglected the concomitant Coriolis force actions on the head/neck system. We assessed non-vestibular Coriolis effects by measuring arm and leg movements made in the center of a rotating room turning at 10 rpm and found that movement endpoints and trajectories are initially deviated; however, subjects readily adapt with 10-20 additional movements, even without seeing their errors. Equilibrium point theories of motor control errantly predict that Coriolis forces will not cause movement endpoint errors so that subjects will not have to adapt their reaching movements during rotation. Adaptation of movement trajectory acquired during Coriolis force perturbations of one arm transfers to the unexposed arm but there is no intermanual transfer of endpoint adaptation indicating that neuromotor representations of movement endpoint and trajectory are separable and can adapt independently, also contradictory to equilibrium point theories. Touching a surface at the end of reaching movements is required for complete endpoint adaptation in darkness but trajectory adapts completely with or without terminal contact. We have also made the first kinematic measurements of unconstrained head movements during rotation, these movements show rapid adaptation to Coriolis force perturbations. Our results point to methods for achieving full compensation for rotation up to 10 rpm. Copyright 1998 Published by Elsevier Science B.V.

Adaptation in a rotating artificial gravity environment.

PubMed

Lackner, J R; DiZio, P

1998-11-01

The centripetal force generated by a rotating space vehicle is a potential source of artificial gravity. Minimizing the cost of such a vehicle dictates using the smallest radius and highest rotation rate possible, but head movements made at high rotation rates generate disorienting, nauseogenic cross-coupled semicircular canal stimulation. Early studies suggested 3 or 4 rpm as the highest rate at which humans could adapt to this vestibular stimulus. These studies neglected the concomitant Coriolis force actions on the head/neck system. We assessed non-vestibular Coriolis effects by measuring arm and leg movements made in the center of a rotating room turning at 10 rpm and found that movement endpoints and trajectories are initially deviated; however, subjects readily adapt with 10-20 additional movements, even without seeing their errors. Equilibrium point theories of motor control errantly predict that Coriolis forces will not cause movement endpoint errors so that subjects will not have to adapt their reaching movements during rotation. Adaptation of movement trajectory acquired during Coriolis force perturbations of one arm transfers to the unexposed arm but there is no intermanual transfer of endpoint adaptation indicating that neuromotor representations of movement endpoint and trajectory are separable and can adapt independently, also contradictory to equilibrium point theories. Touching a surface at the end of reaching movements is required for complete endpoint adaptation in darkness but trajectory adapts completely with or without terminal contact. We have also made the first kinematic measurements of unconstrained head movements during rotation, these movements show rapid adaptation to Coriolis force perturbations. Our results point to methods for achieving full compensation for rotation up to 10 rpm. Copyright 1998 Published by Elsevier Science B.V.

Human adverse reproductive outcomes and electromagnetic field exposures: review of epidemiologic studies.

PubMed Central

Shaw, G M; Croen, L A

1993-01-01

Concerns have been raised regarding a relation between residential and occupational electromagnetic (EM) field exposures and adverse reproductive effects. This paper reviews the epidemiologic evidence for this possible relation, including some pertinent methodologic issues, notes relevant findings from the experimental literature, and discusses areas for future research. Evidence is lacking for a strong association between a woman's use of a video display terminal (VDT) during pregnancy and spontaneous abortion. The evidence for a strong association between a women's use of a VDT and other adverse reproductive endpoints is also lacking, with some suggestive findings for congenital malformations and too few data to reach a conclusion about other endpoints. With respect to low-level EM field exposures other than VDTs, the paucity of data prevents one from determining whether there are reproductive health risks associated with such exposures. Therefore, this is an area that needs further investigation. Given that altered growth may be an underlying biologic effect of EM field exposures, endpoints that might be pursued in future studies include congenital malformations not associated with chromosomal anomalies, intrauterine growth retardation, and chromosomally normal spontaneous abortions. PMID:8206019

The utility of a composite biological endpoint in HIV/STI prevention trials.

PubMed

Hartwell, Tyler D; Pequegnat, Willo; Moore, Janet L; Parker, Corette B; Strader, Lisa C; Green, Annette M; Quinn, Thomas C; Wasserheit, Judith N; Klausner, Jeffrey D

2013-11-01

A human immunodeficiency virus (HIV) as a biological endpoint in HIV prevention trials may not be feasible, so investigators have used surrogate biological outcomes. In a multisite trial, the epidemiology of STIs may be different across sites and preclude using one STI as the outcome. This study explored using a composite STI outcome to address that problem. The combined biological endpoint was the incidence of any of six new STIs (chlamydia, gonorrhea, trichomonas (women only), syphilis, herpes simplex virus type 2 infection and HIV) during a 24-month follow up period. We investigated how a composite STI outcome would perform compared to single and dual STI outcomes under various conditions. We simulated outcomes for four populations that represented a wide range of sex and age distributions, and STI prevalences. The simulations demonstrated that a combined biologic outcome was superior to single and dual STI outcomes in assessing intervention effects in 82 % of the cases. A composite biological outcome was effective in detecting intervention effects and might allow more investigations to incorporate multiple biological outcomes in the assessment of behavioral intervention trials for HIV prevention.

Stimulus-category competition, inhibition, and affective devaluation: a novel account of the uncanny valley.

PubMed

Ferrey, Anne E; Burleigh, Tyler J; Fenske, Mark J

2015-01-01

Stimuli that resemble humans, but are not perfectly human-like, are disliked compared to distinctly human and non-human stimuli. Accounts of this "Uncanny Valley" effect often focus on how changes in human resemblance can evoke different emotional responses. We present an alternate account based on the novel hypothesis that the Uncanny Valley is not directly related to 'human-likeness' per se, but instead reflects a more general form of stimulus devaluation that occurs when inhibition is triggered to resolve conflict between competing stimulus-related representations. We consider existing support for this inhibitory-devaluation hypothesis and further assess its feasibility through tests of two corresponding predictions that arise from the link between conflict-resolving inhibition and aversive response: (1) that the pronounced disliking of Uncanny-type stimuli will occur for any image that strongly activates multiple competing stimulus representations, even in the absence of any human-likeness, and (2) that the negative peak of an 'Uncanny Valley' should occur at the point of greatest stimulus-related conflict and not (in the presence of human-likeness) always closer to the 'human' end of a perceptual continuum. We measured affective responses to a set of line drawings representing non-human animal-animal morphs, in which each continuum midpoint was a bistable image (Experiment 1), as well as to sets of human-robot and human-animal computer-generated morphs (Experiment 2). Affective trends depicting classic Uncanny Valley functions occurred for all continua, including the non-human stimuli. Images at continua midpoints elicited significantly more negative affect than images at endpoints, even when the continua included a human endpoint. This illustrates the feasibility of the inhibitory-devaluation hypothesis and the need for further research into the possibility that the strong dislike of Uncanny-type stimuli reflects the negative affective consequences of cognitive inhibition.

78 FR 66743 - Draft Guidance for Industry on Bioequivalence Recommendations for Iron Sucrose; Availability

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-06

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2007-D-0369] Draft Guidance for Industry on Bioequivalence Recommendations for Iron Sucrose; Availability AGENCY... guidance, FDA recommended an in vivo fasting BE study with pharmacokinetic endpoints and in vitro studies...

NEUROTOXICOLOGICAL EVALUATION OF TWO DISINFECTION BY-PRODUCTS, BROMODICHLOROMETHANE AND DIBROMOACETONITRILE, IN RATS.

EPA Science Inventory

The Safe Drinking Water Act requires that the U.S. EPA consider noncancer endpoints for the assessment of adverse human health effects of disinfection by-products (DBPs). As an extension of our studies in which we demonstrated neurotoxicity at relatively low levels of dibromo- an...

Detection and characterization of gene-gene and gene-environment interactions in common human diseases and complex clinical endpoints

EPA Science Inventory

Biological organisms are complex systems that dynamically integrate inputs from a multitude of physiological and environmental factors. Therefore, in addressing questions concerning the etiology of complex health outcomes, it is essential that the systemic nature of biology be ta...

Integrating Exposure, Pharmacokinetics, And Dosimetry With In Vitro Dose-Response Data To Evaluate Chemical Risk

EPA Science Inventory

High throughput in vitro toxicity testing of hundreds to thousands of chemicals across any number of biological endpoints allows for rapidly assessing human and ecosystem health impacts, thus reducing resources associated with traditional animal testing. In order to apply these i...

The Effects of Oral Triclosan Exposure on Reproductive Endpoints in the Female Wistar Rat.

EPA Science Inventory

Triclosan (TCS) is an antimicrobial agent commonly found in household personal care and consumer products such as soaps, toothpaste and kitchen utensils. Measurable amounts of TCS have been detected in human blood, urine, and breast milk. Recently, we and others have demonstrated...

Generalization of Conditioned Fear along a Dimension of Increasing Fear Intensity

ERIC Educational Resources Information Center

Dunsmoor, Joseph E.; Mitroff, Stephen R.; LaBar, Kevin S.

2009-01-01

The present study investigated the extent to which fear generalization in humans is determined by the amount of fear intensity in nonconditioned stimuli relative to a perceptually similar conditioned stimulus. Stimuli consisted of graded emotionally expressive faces of the same identity morphed between neutral and fearful endpoints. Two…

EVALUATION AND INTERPRETATION OF NEURODEVELOPMENTAL ENDPOINTS FOR HUMAN HEALTH RISK ASSESSMENT -- POSITIVE CONTROL STUDIES, NORMAL VARIABILITY AND STATISTICAL ISSUES.

EPA Science Inventory

ILSI Research Foundation/Risk Science Institute convened an expert working group to assess the lessons learned from the implementation of the EPA Developmental Neurotoxicity (DNT) Guideline and provide guidance for future use. The group prepared manuscripts in five areas: public ...

MECHANISTIC DATA & CANCER RISK ASSESSMENT: THE NEED FOR QUANTITATIVE MOLECULAR ENDPOINTS

EPA Science Inventory

The cancer risk assessment process as currently proposed by the U.S. Environmental Protection Agency allows for the use of mechanistic data to inform the low dose tumor response in humans and in laboratory animals. The aim is to reduce the reliance on defaults that introduce a re...

Acute and Subchronic Toxicity of Inhaled Toluene in Male Long-Evans Rats: Oxidative Stress Markers in Brain

EPA Science Inventory

The effects of exposure to volatile organic compounds (VOCs), which are of concern to the EPA, are poorly understood, in part because of insufficient characterization of how human exposure duration impacts VOC effects. Two inhalation studies with multiple endpoints, one acute an...

Acute Exposure to Particulate Matter (PM) Alters Physiologic and Toxicologic Endpoints in a Rat Model of Heart Failure

EPA Science Inventory

Human exposure to ambient PM from fossil-fuel emissions is linked to cardiovascular disease and death. This association strengthens in people with preexisting cardiopulmonary diseases—especially heart failure (HF). We previously examined the effects of PM on HF by exposing Sponta...

A Developmental Toxicity Database to Support Computational Toxicology; A Collaborative Project for Data Sharing and Harmonization

EPA Science Inventory

Developmental toxicity is one of the most important non-cancer endpoints for both environmental and human health. Despite the fact that numerous developmental studies are being conducted, as required for regulatory decisions, there are not yet sufficient data available to develop...

Modified HWBI Model(s) Linking Service Flows to Well-Being Endpoints: Accounting for Environmental Quality

EPA Science Inventory

This report describes an approach for modifying ORD’s Human Well-Being Index (HWBI) to increase its utility by introducing a composite index developed independently of the HWBI effort. Using ORD’s Environmental Quality Index (EQI), this research examines the potential...

Genotoxicity of gemfibrozil in the gilthead seabream (Sparus aurata).

PubMed

Barreto, A; Luis, L G; Soares, A M V M; Paíga, P; Santos, L H M L M; Delerue-Matos, C; Hylland, K; Loureiro, S; Oliveira, M

2017-09-01

Widespread use of pharmaceuticals and suboptimal wastewater treatment have led to increased levels of these substances in aquatic ecosystems. Lipid-lowering drugs such as gemfibrozil, which are among the most abundant human pharmaceuticals in the environment, may have deleterious effects on aquatic organisms. We examined the genotoxicity of gemfibrozil in a fish species, the gilthead seabream (Sparus aurata), which is commercially important in southern Europe. Following 96-h waterborne exposure, molecular (erythrocyte DNA strand breaks) and cytogenetic (micronuclei and other nuclear abnormalities in cells) endpoints were measured. Gemfibrozil was positive in both endpoints, at environmentally relevant concentrations, a result that raises concerns about the potential genotoxic effects of the drug in recipient waters. Copyright © 2017 Elsevier B.V. All rights reserved.

Data communications in a parallel active messaging interface of a parallel computer

DOEpatents

Archer, Charles J; Blocksome, Michael A; Ratterman, Joseph D; Smith, Brian E

2015-02-03

Data communications in a parallel active messaging interface (`PAMI`) of a parallel computer, the PAMI composed of data communications endpoints, each endpoint including a specification of data communications parameters for a thread of execution on a compute node, including specifications of a client, a context, and a task, endpoints coupled for data communications through the PAMI and through data communications resources, including receiving in an origin endpoint of the PAMI a SEND instruction, the SEND instruction specifying a transmission of transfer data from the origin endpoint to a first target endpoint; transmitting from the origin endpoint to the first target endpoint a Request-To-Send (`RTS`) message advising the first target endpoint of the location and size of the transfer data; assigning by the first target endpoint to each of a plurality of target endpoints separate portions of the transfer data; and receiving by the plurality of target endpoints the transfer data.

Data communications in a parallel active messaging interface of a parallel computer

DOEpatents

Archer, Charles J; Blocksome, Michael A; Ratterman, Joseph D; Smith, Brian E

2014-11-18

Data communications in a parallel active messaging interface (`PAMI`) of a parallel computer, the PAMI composed of data communications endpoints, each endpoint including a specification of data communications parameters for a thread of execution on a compute node, including specifications of a client, a context, and a task, endpoints coupled for data communications through the PAMI and through data communications resources, including receiving in an origin endpoint of the PAMI a SEND instruction, the SEND instruction specifying a transmission of transfer data from the origin endpoint to a first target endpoint; transmitting from the origin endpoint to the first target endpoint a Request-To-Send (`RTS`) message advising the first target endpoint of the location and size of the transfer data; assigning by the first target endpoint to each of a plurality of target endpoints separate portions of the transfer data; and receiving by the plurality of target endpoints the transfer data.

Stimulus-category competition, inhibition, and affective devaluation: a novel account of the uncanny valley

PubMed Central

Ferrey, Anne E.; Burleigh, Tyler J.; Fenske, Mark J.

2015-01-01

Stimuli that resemble humans, but are not perfectly human-like, are disliked compared to distinctly human and non-human stimuli. Accounts of this “Uncanny Valley” effect often focus on how changes in human resemblance can evoke different emotional responses. We present an alternate account based on the novel hypothesis that the Uncanny Valley is not directly related to ‘human-likeness’ per se, but instead reflects a more general form of stimulus devaluation that occurs when inhibition is triggered to resolve conflict between competing stimulus-related representations. We consider existing support for this inhibitory-devaluation hypothesis and further assess its feasibility through tests of two corresponding predictions that arise from the link between conflict-resolving inhibition and aversive response: (1) that the pronounced disliking of Uncanny-type stimuli will occur for any image that strongly activates multiple competing stimulus representations, even in the absence of any human-likeness, and (2) that the negative peak of an ‘Uncanny Valley’ should occur at the point of greatest stimulus-related conflict and not (in the presence of human-likeness) always closer to the ‘human’ end of a perceptual continuum. We measured affective responses to a set of line drawings representing non-human animal–animal morphs, in which each continuum midpoint was a bistable image (Experiment 1), as well as to sets of human-robot and human-animal computer-generated morphs (Experiment 2). Affective trends depicting classic Uncanny Valley functions occurred for all continua, including the non-human stimuli. Images at continua midpoints elicited significantly more negative affect than images at endpoints, even when the continua included a human endpoint. This illustrates the feasibility of the inhibitory-devaluation hypothesis and the need for further research into the possibility that the strong dislike of Uncanny-type stimuli reflects the negative affective consequences of cognitive inhibition. PMID:25821439

Movement trajectory smoothness is not associated with the endpoint accuracy of rapid multi-joint arm movements in young and older adults

PubMed Central

Poston, Brach; Van Gemmert, Arend W.A.; Sharma, Siddharth; Chakrabarti, Somesh; Zavaremi, Shahrzad H.; Stelmach, George

2013-01-01

The minimum variance theory proposes that motor commands are corrupted by signal-dependent noise and smooth trajectories with low noise levels are selected to minimize endpoint error and endpoint variability. The purpose of the study was to determine the contribution of trajectory smoothness to the endpoint accuracy and endpoint variability of rapid multi-joint arm movements. Young and older adults performed arm movements (4 blocks of 25 trials) as fast and as accurately as possible to a target with the right (dominant) arm. Endpoint accuracy and endpoint variability along with trajectory smoothness and error were quantified for each block of trials. Endpoint error and endpoint variance were greater in older adults compared with young adults, but decreased at a similar rate with practice for the two age groups. The greater endpoint error and endpoint variance exhibited by older adults were primarily due to impairments in movement extent control and not movement direction control. The normalized jerk was similar for the two age groups, but was not strongly associated with endpoint error or endpoint variance for either group. However, endpoint variance was strongly associated with endpoint error for both the young and older adults. Finally, trajectory error was similar for both groups and was weakly associated with endpoint error for the older adults. The findings are not consistent with the predictions of the minimum variance theory, but support and extend previous observations that movement trajectories and endpoints are planned independently. PMID:23584101

A critical review of perfluorooctanoate and perfluorooctanesulfonate exposure and immunological health conditions in humans

PubMed Central

Chang, Ellen T.; Adami, Hans-Olov; Boffetta, Paolo; Wedner, H. James; Mandel, Jack S.

2016-01-01

Abstract Whether perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS), two widely used and biopersistent synthetic chemicals, are immunotoxic in humans is unclear. Accordingly, this article systematically and critically reviews the epidemiologic evidence on the association between exposure to PFOA and PFOS and various immune-related health conditions in humans. Twenty-four epidemiologic studies have reported associations of PFOA and/or PFOS with immune-related health conditions, including ten studies of immune biomarker levels or gene expression patterns, ten studies of atopic or allergic disorders, five studies of infectious diseases, four studies of vaccine responses, and five studies of chronic inflammatory or autoimmune conditions (with several studies evaluating multiple endpoints). Asthma, the most commonly studied condition, was evaluated in seven studies. With few, often methodologically limited studies of any particular health condition, generally inconsistent results, and an inability to exclude confounding, bias, or chance as an explanation for observed associations, the available epidemiologic evidence is insufficient to reach a conclusion about a causal relationship between exposure to PFOA and PFOS and any immune-related health condition in humans. When interpreting such studies, an immunodeficiency should not be presumed to exist when there is no evidence of a clinical abnormality. Large, prospective studies with repeated exposure assessment in independent populations are needed to confirm some suggestive associations with certain endpoints. PMID:26761418

Sensitivity of submersed freshwater macrophytes and endpoints in laboratory toxicity tests.

PubMed

Arts, Gertie H P; Belgers, J Dick M; Hoekzema, Conny H; Thissen, Jac T N M

2008-05-01

The toxicological sensitivity and variability of a range of macrophyte endpoints were statistically tested with data from chronic, non-axenic, macrophyte toxicity tests. Five submersed freshwater macrophytes, four pesticides/biocides and 13 endpoints were included in the statistical analyses. Root endpoints, reflecting root growth, were most sensitive in the toxicity tests, while endpoints relating to biomass, growth and shoot length were less sensitive. The endpoints with the lowest coefficients of variation were not necessarily the endpoints, which were toxicologically most sensitive. Differences in sensitivity were in the range of 10-1000 for different macrophyte-specific endpoints. No macrophyte species was consistently the most sensitive. Criteria to select endpoints in macrophyte toxicity tests should include toxicological sensitivity, variance and ecological relevance. Hence, macrophyte toxicity tests should comprise an array of endpoints, including very sensitive endpoints like those relating to root growth.

ECVAM and new technologies for toxicity testing.

PubMed

Bouvier d'Yvoire, Michel; Bremer, Susanne; Casati, Silvia; Ceridono, Mara; Coecke, Sandra; Corvi, Raffaella; Eskes, Chantra; Gribaldo, Laura; Griesinger, Claudius; Knaut, Holger; Linge, Jens P; Roi, Annett; Zuang, Valérie

2012-01-01

The development of alternative empirical (testing) and non-empirical (non-testing) methods to traditional toxicological tests for complex human health effects is a tremendous task. Toxicants may potentially interfere with a vast number of physiological mechanisms thereby causing disturbances on various levels of complexity of human physiology. Only a limited number of mechanisms relevant for toxicity ('pathways' of toxicity) have been identified with certainty so far and, presumably, many more mechanisms by which toxicants cause adverse effects remain to be identified. Recapitulating in empirical model systems (i.e., in vitro test systems) all those relevant physiological mechanisms prone to be disturbed by toxicants and relevant for causing the toxicity effect in question poses an enormous challenge. First, the mechanism(s) of action of toxicants in relation to the most relevant adverse effects of a specific human health endpoint need to be identified. Subsequently, these mechanisms need to be modeled in reductionist test systems that allow assessing whether an unknown substance may operate via a specific (array of) mechanism(s). Ideally, such test systems should be relevant for the species of interest, i.e., based on human cells or modeling mechanisms present in humans. Since much of our understanding about toxicity mechanisms is based on studies using animal model systems (i.e., experimental animals or animal-derived cells), designing test systems that model mechanisms relevant for the human situation may be limited by the lack of relevant information from basic research. New technologies from molecular biology and cell biology, as well as progress in tissue engineering, imaging techniques and automated testing platforms hold the promise to alleviate some of the traditional difficulties associated with improving toxicity testing for complex endpoints. Such new technologies are expected (1) to accelerate the identification of toxicity pathways with human relevance that need to be modeled in test methods for toxicity testing (2) to enable the reconstruction of reductionist test systems modeling at a reduced level of complexity the target system/organ of interest (e.g., through tissue engineering, use of human-derived cell lines and stem cells etc.), (3) to allow the measurement of specific mechanisms relevant for a given health endpoint in such test methods (e.g., through gene and protein expression, changes in metabolites, receptor activation, changes in neural activity etc.), (4) to allow to measure toxicity mechanisms at higher throughput rates through the use of automated testing. In this chapter, we discuss the potential impact of new technologies on the development, optimization and use of empirical testing methods, grouped according to important toxicological endpoints. We highlight, from an ECVAM perspective, the areas of topical toxicity, skin absorption, reproductive and developmental toxicity, carcinogenicity/genotoxicity, sensitization, hematopoeisis and toxicokinetics and discuss strategic developments including ECVAM's database service on alternative methods. Neither the areas of toxicity discussed nor the highlighted new technologies represent comprehensive listings which would be an impossible endeavor in the context of a book chapter. However, we feel that these areas are of utmost importance and we predict that new technologies are likely to contribute significantly to test development in these fields. We summarize which new technologies are expected to contribute to the development of new alternative testing methods over the next few years and point out current and planned ECVAM projects for each of these areas.

Integrating human health and ecological data into cumulative risk assessment through the Aggregate Exposure Pathway and Adverse Outcome Pathway frameworks

EPA Science Inventory

Cumulative risk assessment (CRA) methods promote the use of a conceptual site model (CSM) to apportion exposures and integrate risk from relevant stressors across different species. Integration is important to provide a more complete assessment of risk, but evaluating endpoints a...

Survey of ecotoxicologically-relevant reproductive endpoint coverage within the ECOTOX database across ToxCast ER agonists (ASCCT)

EPA Science Inventory

The U.S. EPA’s Endocrine Disruptor Screening Program (EDSP) has been charged with screening thousands of chemicals for their potential to affect the endocrine systems of humans and wildlife. In vitro high throughput screening (HTS) assays have been proposed as a way to prioritize...

Posture and Movement

NASA Technical Reports Server (NTRS)

1997-01-01

Session TP3 includes short reports on: (1) Modification of Goal-Directed Arm Movements During Inflight Adaptation to Microgravity; (2) Quantitative Analysis of Motion control in Long Term Microgravity; (3) Does the Centre of Gravity Remain the Stabilised Reference during Complex Human Postural Equilibrium Tasks in Weightlessness?; and (4) Arm End-Point Trajectories Under Normal and Microgravity Environments.

ALTERATION OF ESTROUS CYCLICITY BY THE DRINKING WATER DISINFECTION BY-PRODUCT DIBROMOACETIC ACID: RELATIONSHIP TO AN EFFECT ON ESTRADIOL METABOLISM?

EPA Science Inventory

A number of chemicals formed by disinfection of municipal drinking water have been suspected to cause reproductive alterations in humans and test animals. One class of these chemicals, the haloacetic acids, have been reported to alter a number of rat testicular endpoints, includ...

76 FR 12916 - Benzocaine; Weight Control Drug Products for Over-the-Counter Human Use

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-09

... endpoint. Reports purporting to be two studies by Collipp (one published and one unpublished) were..., OTC weight control drug products containing benzocaine will require an approved NDA or ANDA. Studies...., a manufacturer of OTC weight control drug products, submitted two citizen petitions, one in 1990 and...

DEVELOPMENT OF QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIPS (QSARS) TO PREDICT TOXICITY FOR A VARIETY OF HUMAN AND ECOLOGICAL ENDPOINTS

EPA Science Inventory

In general, the accuracy of a predicted toxicity value increases with increase in similarity between the query chemical and the chemicals used to develop a QSAR model. A toxicity estimation methodology employing this finding has been developed. A hierarchical based clustering t...

Somatosensory Gating Is Dependent on the Rate of Force Recruitment in the Human Orofacial System

ERIC Educational Resources Information Center

Andreatta, Richard D.; Barlow, Steven M.

2009-01-01

Purpose: Functional orofacial behaviors vary in their force endpoint and rate of recruitment. This study assessed the gating of orofacial cutaneous somatosensation during different cyclic lip force recruitment rates. Understanding how differences in the rate of force recruitment influences trigeminal system function is an important step toward…

Determining significant endpoints for ecological risk analyses. 1997 annual progress report

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

Hinton, T.G.; Congdon, J.; Rowe, C.

1997-11-01

'This report summarizes the first year''s progress of research funded under the Department of Energy''s Environmental Management Science Program. The research was initiated to better determine ecological risks from toxic and radioactive contaminants. More precisely, the research is designed to determine the relevancy of sublethal cellular damage to the performance of individuals and to identify characteristics of non-human populations exposed to chronic, low-level radiation, as is typically found on many DOE sites. The authors propose to establish a protocol to assess risks to non-human species at higher levels of biological organization by relating molecular damage to more relevant responses thatmore » reflect population health. They think that they can achieve this by coupling changes in metabolic rates and energy allocation patterns to meaningful population response variables, and by using novel biological dosimeters in controlled, manipulative dose/effects experiments. They believe that a scientifically defensible endpoint for measuring ecological risks can only be determined once its understood the extent to which molecular damage from contaminant exposure is detrimental at the individual and population levels of biological organization.'« less

Cancer Registries and Monitoring the Impact of Prophylactic Human Papillomavirus Vaccines: The Potential Role

PubMed Central

Saraiya, Mona; Goodman, Marc T.; Datta, S. Deblina; Chen, Vivien W.; Wingo, Phyllis A.

2009-01-01

The recent US Food and Drug Administration licensure of a prophylactic vaccine against oncogenic human papillomavirus (HPV) types 16 and 18, the first of its kind, poses unique challenges in postmarketing vaccine surveillance, especially in measuring vaccine effectiveness against biologic endpoints of HPV infection. Historically, the national system of population-based cancer registries in the US has provided high-quality data on cancer incidence and mortality for the most important biologic endpoints, namely, anogenital cancers and some oral cavity/oropharyngeal cancers. There also has been some data collection on cancer precursors; however, this activity has been inconsistent and of lower priority. Because effectiveness against HPV-associated cancers will not be measurable for several decades, strengthening and possibly expanding the capacity of registries to collect precancer data, which are earlier manifestations of infection, must be considered. Collecting type-specific data on HPV-associated precancers and cancers. While keeping in mind the current limitations of registry operations, they discuss resources that may be needed to implement and sustain these types of activities. PMID:18980287

Novel genotype of Ehrlichia canis detected in samples of human blood bank donors in Costa Rica.

PubMed

Bouza-Mora, Laura; Dolz, Gaby; Solórzano-Morales, Antony; Romero-Zuñiga, Juan José; Salazar-Sánchez, Lizbeth; Labruna, Marcelo B; Aguiar, Daniel M

2017-01-01

This study focuses on the detection and identification of DNA and antibodies to Ehrlichia spp. in samples of blood bank donors in Costa Rica using molecular and serological techniques. Presence of Ehrlichia canis was determined in 10 (3.6%) out of 280 blood samples using polymerase chain reaction (PCR) targeting the ehrlichial dsb conserved gene. Analysis of the ehrlichial trp36 polymorphic gene in these 10 samples revealed substantial polymorphism among the E. canis genotypes, including divergent tandem repeat sequences. Nucleotide sequences of dsb and trp36 amplicons revealed a novel genotype of E. canis in blood bank donors from Costa Rica. Indirect immunofluorescence assay (IFA) detected antibodies in 35 (35%) of 100 serum samples evaluated. Thirty samples showed low endpoint titers (64-256) to E. canis, whereas five sera yielded high endpoint titers (1024-8192); these five samples were also E. canis-PCR positive. These findings represent the first report of the presence of E. canis in humans in Central America. Copyright © 2016 Elsevier GmbH. All rights reserved.

Three Degree of Freedom Parallel Mechanical Linkage

NASA Technical Reports Server (NTRS)

Adelstein, Bernard D. (Inventor)

1998-01-01

A three degree of freedom parallel mechanism or linkage that couples three degree of freedom translational displacements at an endpoint, such as a handle, a hand grip, or a robot tool, to link rotations about three axes that are fixed with respect to a common base or ground link. The mechanism includes a three degree of freedom spherical linkage formed of two closed loops, and a planar linkage connected to the endpoint. The closed loops are rotatably interconnected, and made of eight rigid links connected by a plurality of single degree of freedom revolute joints. Three of these revolute joints are base joints and are connected to a common ground. such that the axis lines passing through the revolute joints intersect at a common fixed center point K forming the center of a spherical work volume in which the endpoint is capable of moving. 'Me three degrees of freedom correspond to the spatial displacement of the endpoint, for instance. The mechanism provides a new overall spatial kinematic linkage composed of a minimal number of rigid links and rotary joints. The mechanism has improved mechanical stiffness, and conveys mechanical power bidirectionally between the human operator and the electromechanical actuators. It does not require gears, belts. cable, screw or other types of transmission elements, and is useful in applications requiring full backdrivability. Thus, this invention can serve as the mechanical linkage for actively powered devices such as compliant robotic manipulators and force-reflecting hand controllers, and passive devices such as manual input devices for computers and other systems.

Diet-Gene Interactions and PUFA Metabolism: A Potential Contributor to Health Disparities and Human Diseases

PubMed Central

Chilton, Floyd H.; Murphy, Robert C.; Wilson, Bryan A.; Sergeant, Susan; Ainsworth, Hannah; Seeds, Michael C.; Mathias, Rasika A.

2014-01-01

The “modern western” diet (MWD) has increased the onset and progression of chronic human diseases as qualitatively and quantitatively maladaptive dietary components give rise to obesity and destructive gene-diet interactions. There has been a three-fold increase in dietary levels of the omega-6 (n-6) 18 carbon (C18), polyunsaturated fatty acid (PUFA) linoleic acid (LA; 18:2n-6), with the addition of cooking oils and processed foods to the MWD. Intense debate has emerged regarding the impact of this increase on human health. Recent studies have uncovered population-related genetic variation in the LCPUFA biosynthetic pathway (especially within the fatty acid desaturase gene (FADS) cluster) that is associated with levels of circulating and tissue PUFAs and several biomarkers and clinical endpoints of cardiovascular disease (CVD). Importantly, populations of African descent have higher frequencies of variants associated with elevated levels of arachidonic acid (ARA), CVD biomarkers and disease endpoints. Additionally, nutrigenomic interactions between dietary n-6 PUFAs and variants in genes that encode for enzymes that mobilize and metabolize ARA to eicosanoids have been identified. These observations raise important questions of whether gene-PUFA interactions are differentially driving the risk of cardiovascular and other diseases in diverse populations, and contributing to health disparities, especially in African American populations. PMID:24853887

Identifying and designing chemicals with minimal acute aquatic toxicity

PubMed Central

Kostal, Jakub; Voutchkova-Kostal, Adelina; Anastas, Paul T.; Zimmerman, Julie Beth

2015-01-01

Industrial ecology has revolutionized our understanding of material stocks and flows in our economy and society. For this important discipline to have even deeper impact, we must understand the inherent nature of these materials in terms of human health and the environment. This paper focuses on methods to design synthetic chemicals to reduce their intrinsic ability to cause adverse consequence to the biosphere. Advances in the fields of computational chemistry and molecular toxicology in recent decades allow the development of predictive models that inform the design of molecules with reduced potential to be toxic to humans or the environment. The approach presented herein builds on the important work in quantitative structure–activity relationships by linking toxicological and chemical mechanistic insights to the identification of critical physical–chemical properties needed to be modified. This in silico approach yields design guidelines using boundary values for physiochemical properties. Acute aquatic toxicity serves as a model endpoint in this study. Defining value ranges for properties related to bioavailability and reactivity eliminates 99% of the chemicals in the highest concern for acute aquatic toxicity category. This approach and its future implementations are expected to yield very powerful tools for life cycle assessment practitioners and molecular designers that allow rapid assessment of multiple environmental and human health endpoints and inform modifications to minimize hazard. PMID:24639521

Identifying and designing chemicals with minimal acute aquatic toxicity.

PubMed

Kostal, Jakub; Voutchkova-Kostal, Adelina; Anastas, Paul T; Zimmerman, Julie Beth

2015-05-19

Industrial ecology has revolutionized our understanding of material stocks and flows in our economy and society. For this important discipline to have even deeper impact, we must understand the inherent nature of these materials in terms of human health and the environment. This paper focuses on methods to design synthetic chemicals to reduce their intrinsic ability to cause adverse consequence to the biosphere. Advances in the fields of computational chemistry and molecular toxicology in recent decades allow the development of predictive models that inform the design of molecules with reduced potential to be toxic to humans or the environment. The approach presented herein builds on the important work in quantitative structure-activity relationships by linking toxicological and chemical mechanistic insights to the identification of critical physical-chemical properties needed to be modified. This in silico approach yields design guidelines using boundary values for physiochemical properties. Acute aquatic toxicity serves as a model endpoint in this study. Defining value ranges for properties related to bioavailability and reactivity eliminates 99% of the chemicals in the highest concern for acute aquatic toxicity category. This approach and its future implementations are expected to yield very powerful tools for life cycle assessment practitioners and molecular designers that allow rapid assessment of multiple environmental and human health endpoints and inform modifications to minimize hazard.

Assessing neurodevelopmental effects of arsenolipids in pre-differentiated human neurons.

PubMed

Witt, Barbara; Ebert, Franziska; Meyer, Sören; Francesconi, Kevin A; Schwerdtle, Tanja

2017-11-01

In the general population exposure to arsenic occurs mainly via diet. Highest arsenic concentrations are found in seafood, where arsenic is present predominantly in its organic forms including arsenolipids. Since recent studies have provided evidence that arsenolipids could reach the brain of an organism and exert toxicity in fully differentiated human neurons, this work aims to assess the neurodevelopmental toxicity of arsenolipids. Neurodevelopmental effects of three arsenic-containing hydrocarbons (AsHC), two arsenic-containing fatty acids (AsFA), arsenite and dimethylarsinic acid (DMA V ) were characterized in pre-differentiated human neurons. AsHCs and arsenite caused substantial cytotoxicity in a similar, low concentration range, whereas AsFAs and DMA V were less toxic. AsHCs were highly accessible for cells and exerted pronounced neurodevelopmental effects, with neurite outgrowth and the mitochondrial membrane potential being sensitive endpoints; arsenite did not substantially decrease those two endpoints. In fully differentiated neurons, arsenite and AsHCs caused neurite toxicity. These results indicate for a neurodevelopmental potential of AsHCs. Taken into account the possibility that AsHCs might easily reach the developing brain when exposed during early life, neurotoxicity and neurodevelopmental toxicity cannot be excluded. Further studies are needed in order to progress the urgently needed risk assessment. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Epigenetic alterations induced by genotoxic occupational and environmental human chemical carcinogens: A systematic literature review

PubMed Central

Chappell, Grace; Pogribny, Igor P.; Guyton, Kathryn Z.; Rusyn, Ivan

2016-01-01

Accumulating evidence suggests that epigenetic alterations play an important role in chemically-induced carcinogenesis. Although the epigenome and genome may be equally important in carcinogenicity, the genotoxicity of chemical agents and exposure-related transcriptomic responses have been more thoroughly studied and characterized. To better understand the evidence for epigenetic alterations of human carcinogens, and the potential association with genotoxic endpoints, we conducted a systematic review of published studies of genotoxic carcinogens that reported epigenetic endpoints. Specifically, we searched for publications reporting epigenetic effects for the 28 agents and occupations included in Monograph Volume 100F of the International Agency for the Research on Cancer (IARC) that were classified as “carcinogenic to humans” (Group 1) with strong evidence of genotoxic mechanisms of carcinogenesis. We identified a total of 158 studies that evaluated epigenetic alterations for 12 of these 28 carcinogenic agents and occupations (1,3-butadiene, 4-aminobiphenyl, aflatoxins, benzene, benzidine, benzo[a]pyrene, coke production, formaldehyde, occupational exposure as a painter, sulfur mustard, and vinyl chloride). Aberrant DNA methylation was most commonly studied, followed by altered expression of non-coding RNAs and histone changes (totaling 85, 59 and 25 studies, respectively). For 3 carcinogens (aflatoxins, benzene and benzo[a]pyrene), 10 or more studies reported epigenetic effects. However, epigenetic studies were sparse for the remaining 9 carcinogens; for 4 agents, only 1 or 2 published reports were identified. While further research is needed to better identify carcinogenesis-associated epigenetic perturbations for many potential carcinogens, published reports on specific epigenetic endpoints can be systematically identified and increasingly incorporated in cancer hazard assessments. PMID:27234561

Weight Loss and Reduced Body Temperature Determine Humane Endpoints in a Mouse Model of Ocular Herpesvirus Infection

PubMed Central

Hankenson, F Claire; Ruskoski, Nicholas; van Saun, Marjorie; Ying, Gui-Shuang; Oh, Jaewook; Fraser, Nigel W

2013-01-01

Herpes simplex virus (HSV) has been studied in well-established mouse models to generate latently infected animals for investigations into viral pathogenesis, latency mechanisms, and reactivation. Mice exhibit clinical signs of debilitating infection, during which time they may become severely ill before recovery or die spontaneously. Because the cohort of mice that does survive provides valuable data on latency, there is keen interest in developing methodologies for earlier detection and treatment of severe disease to ultimately increase survival rates. Here, BALB/c mice were inoculated ocularly with either a wildtype (LAT+) or mutant (LAT–) strain of HSV1. Mice were monitored daily through day 30 after infection; trigeminal ganglia were harvested at day 60 to assess viral DNA load. Cages were provided with nesting material, and fluid supplementation was administered to mice with body temperatures of 35 °C or lower, as measured by subcutaneous microchip thermometry. The results showed that infected mice with temperatures less than 34.5 °C did not recover to normothermia and were euthanized or spontaneously died, regardless of infective viral strain. By using a combination of criteria including body temperature (less than 34.5 °C) and weight loss (more than 0.05 g daily) for removal of animals from the study, approximately 98% of mice that died spontaneously could have been euthanized prior to death, without concern of potential recovery to the experimental endpoint (100% specificity). Frequent monitoring of alterations to general wellbeing, body temperature, and weight was crucial for establishing humane endpoints in this ocular HSV model. PMID:23849410

Evaluation of a human neurite growth assay as specific screen for developmental neurotoxicants.

PubMed

Krug, Anne K; Balmer, Nina V; Matt, Florian; Schönenberger, Felix; Merhof, Dorit; Leist, Marcel

2013-12-01

Organ-specific in vitro toxicity assays are often highly sensitive, but they lack specificity. We evaluated here examples of assay features that can affect test specificity, and some general procedures are suggested on how positive hits in complex biological assays may be defined. Differentiating human LUHMES cells were used as potential model for developmental neurotoxicity testing. Forty candidate toxicants were screened, and several hits were obtained and confirmed. Although the cells had a definitive neuronal phenotype, the use of a general cell death endpoint in these cultures did not allow specific identification of neurotoxicants. As alternative approach, neurite growth was measured as an organ-specific functional endpoint. We found that neurite extension of developing LUHMES was specifically inhibited by diverse compounds such as colchicine, vincristine, narciclasine, rotenone, cycloheximide, or diquat. These compounds reduced neurite growth at concentrations that did not compromise cell viability, and neurite growth was affected more potently than the integrity of developed neurites of mature neurons. A ratio of the EC50 values of neurite growth inhibition and cell death of >4 provided a robust classifier for compounds associated with a developmental neurotoxic hazard. Screening of unspecific toxicants in the test system always yielded ratios <4. The assay identified also compounds that accelerated neurite growth, such as the rho kinase pathway modifiers blebbistatin or thiazovivin. The negative effects of colchicine or rotenone were completely inhibited by a rho kinase inhibitor. In summary, we suggest that assays using functional endpoints (neurite growth) can specifically identify and characterize (developmental) neurotoxicants.

Weight loss and reduced body temperature determine humane endpoints in a mouse model of ocular herpesvirus infection.

PubMed

Hankenson, F Claire; Ruskoski, Nicholas; van Saun, Marjorie; Ying, Gui-Shuang; Oh, Jaewook; Fraser, Nigel W

2013-01-01

Herpes simplex virus (HSV) has been studied in well-established mouse models to generate latently infected animals for investigations into viral pathogenesis, latency mechanisms, and reactivation. Mice exhibit clinical signs of debilitating infection, during which time they may become severely ill before recovery or die spontaneously. Because the cohort of mice that does survive provides valuable data on latency, there is keen interest in developing methodologies for earlier detection and treatment of severe disease to ultimately increase survival rates. Here, BALB/c mice were inoculated ocularly with either a wildtype (LAT(+)) or mutant (LAT(-)) strain of HSV1. Mice were monitored daily through day 30 after infection; trigeminal ganglia were harvested at day 60 to assess viral DNA load. Cages were provided with nesting material, and fluid supplementation was administered to mice with body temperatures of 35 °C or lower, as measured by subcutaneous microchip thermometry. The results showed that infected mice with temperatures less than 34.5 °C did not recover to normothermia and were euthanized or spontaneously died, regardless of infective viral strain. By using a combination of criteria including body temperature (less than 34.5 °C) and weight loss (more than 0.05 g daily) for removal of animals from the study, approximately 98% of mice that died spontaneously could have been euthanized prior to death, without concern of potential recovery to the experimental endpoint (100% specificity). Frequent monitoring of alterations to general wellbeing, body temperature, and weight was crucial for establishing humane endpoints in this ocular HSV model.

Taking a Bite out of Malaria: Controlled Human Malaria Infection by Needle and Syringe

DTIC Science & Technology

2013-01-01

sporozoites (PfSPZ Challenge).1 Because of the potential of this “challenge in a bottle” to standardize and dramatically expand the use of controlled human...to CHMI5,6 since CHMI using mosquitoes that had fed on in vitro cultures of P. falciparum was introduced in 1986.14 Investigators frommultiple...conduct of CHMI and a second document for the microscopy methods used to determine the patency endpoint.15 Nevertheless, CHMI based upon the bites of

Segmentation of human upper body movement using multiple IMU sensors.

PubMed

Aoki, Takashi; Lin, Jonathan Feng-Shun; Kulic, Dana; Venture, Gentiane

2016-08-01

This paper proposes an approach for the segmentation of human body movements measured by inertial measurement unit sensors. Using the angular velocity and linear acceleration measurements directly, without converting to joint angles, we perform segmentation by formulating the problem as a classification problem, and training a classifier to differentiate between motion end-point and within-motion points. The proposed approach is validated with experiments measuring the upper body movement during reaching tasks, demonstrating classification accuracy of over 85.8%.

Adapting human-machine interfaces to user performance.

PubMed

Danziger, Zachary; Fishbach, Alon; Mussa-Ivaldi, Ferdinando A

2008-01-01

The goal of this study was to create and examine machine learning algorithms that adapt in a controlled and cadenced way to foster a harmonious learning environment between the user of a human-machine interface and the controlled device. In this experiment, subjects' high-dimensional finger motions remotely controlled the joint angles of a simulated planar 2-link arm, which was used to hit targets on a computer screen. Subjects were required to move the cursor at the endpoint of the simulated arm.

Biomarkers and surrogate endpoints in glaucoma clinical trials

PubMed Central

Medeiros, Felipe A

2015-01-01

Surrogate endpoints are often used as replacements for true clinically relevant endpoints in several areas of medicine, as they enable faster and less expensive clinical trials. However, without proper validation, the use of surrogates may lead to incorrect conclusions about the efficacy and safety of treatments. This article reviews the general requirements for validating surrogate endpoints and provides a critical assessment of the use of intraocular pressure (IOP), visual fields, and structural measurements of the optic nerve as surrogate endpoints in glaucoma clinical trials. A valid surrogate endpoint must be able to predict the clinically relevant endpoint and fully capture the effect of an intervention on that endpoint. Despite its widespread use in clinical trials, no proper validation of IOP as a surrogate endpoint has ever been conducted for any class of IOP-lowering treatments. Evidence has accumulated with regard to the role of imaging measurements of optic nerve damage as surrogate endpoints in glaucoma. These measurements are predictive of functional losses in the disease and may explain, at least in part, treatment effects on clinically relevant endpoints. The use of composite endpoints in glaucoma trials may overcome weaknesses of the use of structural or functional endpoints in isolation. Unless research is dedicated to fully develop and validate suitable endpoints that can be used in glaucoma clinical trials, we run the risk of inappropriate judgments about the value of new therapies. PMID:25034049

The detrimental effect of friction on space microgravity robotics

NASA Technical Reports Server (NTRS)

Newman, Wyatt S.; Glosser, Gregory D.; Miller, Jeffrey H.; Rohn, Douglas

1992-01-01

The authors present an analysis of why control systems are ineffective in compensating for acceleration disturbances due to Coulomb friction. Linear arguments indicate that the effects of Coulomb friction on a body are most difficult to reject when the control actuator is separated from the body of compliance. The linear arguments were illustrated in a nonlinear simulation of optimal linear tracking control in the presence of nonlinear friction. The results of endpoint acceleration measurements for four robot designs are presented and are compared with simulation and to equivalent measurements on a human. It is concluded that Coulomb friction in common bearings and transmission induces unacceptable levels of endpoint acceleration, that these accelerations cannot be adequately attenuated by control, and that robots for microgravity work will require special design considerations for inherently low friction.

Proprioception Is Robust under External Forces

PubMed Central

Kuling, Irene A.; Brenner, Eli; Smeets, Jeroen B. J.

2013-01-01

Information from cutaneous, muscle and joint receptors is combined with efferent information to create a reliable percept of the configuration of our body (proprioception). We exposed the hand to several horizontal force fields to examine whether external forces influence this percept. In an end-point task subjects reached visually presented positions with their unseen hand. In a vector reproduction task, subjects had to judge a distance and direction visually and reproduce the corresponding vector by moving the unseen hand. We found systematic individual errors in the reproduction of the end-points and vectors, but these errors did not vary systematically with the force fields. This suggests that human proprioception accounts for external forces applied to the hand when sensing the position of the hand in the horizontal plane. PMID:24019959

Endpoints and surrogate endpoints in colorectal cancer: a review of recent developments.

PubMed

Piedbois, Pascal; Buyse, Marc

2008-07-01

The purpose of this review is to discuss recently published work on endpoints for early and advanced colorectal cancer, as well as the statistical approaches used to validate surrogate endpoints. Most attempts to validate surrogate endpoints have estimated the correlation between the surrogate and the true endpoint, and between the treatment effects on these endpoints. The correlation approach has made it possible to validate disease-free survival and progression-free survival as acceptable surrogates for overall survival in early and advanced disease, respectively. The search for surrogate endpoints will intensify over the coming years. In parallel, efforts to either standardize or extend the endpoints or both will improve the reliability and relevance of clinical trial results.

Characterization of transgenic mice--a comparison of protocols for welfare evaluation and phenotype characterization of mice with a suggestion on a future certificate of instruction.

PubMed

Jegstrup, I; Thon, R; Hansen, A K; Hoitinga, M Ritskes

2003-01-01

A thorough welfare evaluation performed as part of a general phenotype characterization for both transgenic and traditional mouse strains could not only contribute to the improvement of the welfare of laboratory animals, but could also be of benefit to scientists, laboratory veterinarians and the inspecting authorities. A literature review has been performed to identify and critically evaluate already existing protocols for phenotype and welfare characterization. There are several relevant schemes available, among others the SHIRPA method, the modified score sheet of Morton and Griffiths, the FRIMORFO phenotype characterization scheme and the behavioural phenotype schemes as described by Crawley. These protocols have been evaluated according to four goals: Their ability (1) to reveal any special needs or problems with a transgenic strain, (2) to cover the informational needs of the purchaser/user of the strain, (3) to refine the welfare of the transgenic animal model by identifying relevant humane endpoints, (4) to prevent the duplication of animal models that have already been developed. The protocols described are useful for characterizing the phenotype and judging welfare disturbances, however the total amount of information and the degree of detail varies considerably from one scheme to another. We present a proposal regarding the practical application of the various schemes that will secure proper treatment and the identification of humane endpoints. It is advocated that with every purchase of a particular strain, an instruction document should accompany the strain. This document needs to give detailed descriptions of the typical characteristics of the strain, as well as necessary actions concerning relevant treatment and humane endpoints. At the moment no such documents are required. The introduction of these types of documents will contribute to improvements in animal welfare as well as experimental results in laboratory animal experimentation.

Non-animal methodologies within biomedical research and toxicity testing.

PubMed

Knight, Andrew

2008-01-01

Laboratory animal models are limited by scientific constraints on human applicability, and increasing regulatory restrictions, driven by social concerns. Reliance on laboratory animals also incurs marked - and in some cases, prohibitive - logistical challenges, within high-throughput chemical testing programmes, such as those currently underway within Europe and the US. However, a range of non-animal methodologies is available within biomedical research and toxicity testing. These include: mechanisms to enhance the sharing and assessment of existing data prior to conducting further studies, and physicochemical evaluation and computerised modelling, including the use of structure-activity relationships and expert systems. Minimally-sentient animals from lower phylogenetic orders or early developmental vertebral stages may be used, as well as microorganisms and higher plants. A variety of tissue cultures, including immortalised cell lines, embryonic and adult stem cells, and organotypic cultures, are also available. In vitro assays utilising bacterial, yeast, protozoal, mammalian or human cell cultures exist for a wide range of toxic and other endpoints. These may be static or perfused, and may be used individually, or combined within test batteries. Human hepatocyte cultures and metabolic activation systems offer potential assessment of metabolite activity and organ-organ interaction. Microarray technology may allow genetic expression profiling, increasing the speed of toxin detection, well prior to more invasive endpoints. Enhanced human clinical trials utilising micro- dosing, staggered dosing, and more representative study populations and durations, as well as surrogate human tissues, advanced imaging modalities and human epidemiological, sociological and psycho- logical studies, may increase our understanding of illness aetiology and pathogenesis, and facilitate the development of safe and effective pharmacologic interventions. Particularly when human tissues are used, non-animal models may generate faster, cheaper results, more reliably predictive for humans, whilst yielding greater insights into human biochemical processes. Greater commitment to their development and implementation is necessary, however, to efficiently meet the needs of high-throughput chemical testing programmes, important emerging testing needs, and the ongoing development of human clinical interventions.

Genetic damage in human cells exposed to non-ionizing radiofrequency fields: a meta-analysis of the data from 88 publications (1990-2011).

PubMed

Vijayalaxmi; Prihoda, Thomas J

2012-12-12

Based on the 'limited' evidence suggesting an association between exposure to radiofrequency fields (RF) emitted from mobile phones and two types of brain cancer, glioma and acoustic neuroma, the International Agency for Research on Cancer has classified RF as 'possibly carcinogenic to humans' in group 2B. In view of this classification and the positive correlation between increased genetic damage and carcinogenesis, a meta-analysis was conducted to determine whether a significant increase in genetic damage in human cells exposed to RF provides a potential mechanism for its carcinogenic potential. The extent of genetic damage in human cells, assessed from various end-points, viz., single-/double-strand breaks in the DNA, incidence of chromosomal aberrations, micronuclei and sister chromatid exchanges, reported in a total of 88 peer-reviewed scientific publications during 1990-2011 was considered in the meta-analysis. Among the several variables in the experimental protocols used, the influence of five specific variables related to RF exposure characteristics was investigated: (i) frequency, (ii) specific absorption rate, (iii) exposure as continuous wave, pulsed wave and occupationally exposed/mobile phone users, (iv) duration of exposure, and (v) different cell types. The data indicated the following. (1) The magnitude of difference between RF-exposed and sham-/un-exposed controls was small with some exceptions. (2) In certain RF exposure conditions there was a statistically significant increase in genotoxicity assessed from some end-points: the effect was observed in studies with small sample size and was largely influenced by publication bias. Studies conducted within the generally recommended RF exposure guidelines showed a smaller effect. (3) The multiple regression analyses and heterogeneity goodness of fit data indicated that factors other than the above five variables as well as the quality of publications have contributed to the overall results. (4) More importantly, the mean indices for chromosomal aberrations, micronuclei and sister chromatid exchange end-points in RF-exposed and sham-/un-exposed controls were within the spontaneous levels reported in a large data-base. Thus, the classification of RF as possibly carcinogenic to humans in group 2B was not supported by genotoxicity-based mechanistic evidence. Copyright © 2012 Elsevier B.V. All rights reserved.

Challenges in translating endpoints from trials to observational cohort studies in oncology

PubMed Central

Ording, Anne Gulbech; Cronin-Fenton, Deirdre; Ehrenstein, Vera; Lash, Timothy L; Acquavella, John; Rørth, Mikael; Sørensen, Henrik Toft

2016-01-01

Clinical trials are considered the gold standard for examining drug efficacy and for approval of new drugs. Medical databases and population surveillance registries are valuable resources for post-approval observational research, which are increasingly used in studies of benefits and risk of new cancer drugs. Here, we address the challenges in translating endpoints from oncology trials to observational studies. Registry-based cohort studies can investigate real-world safety issues – including previously unrecognized concerns – by examining rare endpoints or multiple endpoints at once. In contrast to clinical trials, observational cohort studies typically do not exclude real-world patients from clinical practice, such as old and frail patients with comorbidity. The observational cohort study complements the clinical trial by examining the effectiveness of interventions applied in clinical practice and by providing evidence on long-term clinical outcomes, which are often not feasible to study in a clinical trial. Various endpoints can be included in clinical trials, such as hard endpoints, soft endpoints, surrogate endpoints, and patient-reported endpoints. Each endpoint has it strengths and limitations for use in research studies. Endpoints used in oncology trials are often not applicable in observational cohort studies which are limited by the setting of standard clinical practice and by non-standardized endpoint determination. Observational studies can be more helpful moving research forward if they restrict focus to appropriate and valid endpoints. PMID:27354827

Novel approach for classifying chemicals according to skin sensitizing potency by non-radioisotopic modification of the local lymph node assay.

PubMed

Takeyoshi, Masahiro; Iida, Kenji; Shiraishi, Keiji; Hoshuyama, Satsuki

2005-01-01

The murine local lymph node assay (LLNA) is currently recognized as a stand-alone sensitization test for determining the sensitizing potential of chemicals, and it has the advantage of yielding a quantitative endpoint that can be used to predict the sensitization potency of chemicals. The EC3 has been proposed as a parameter for classifying chemicals according to the sensitization potency. We previously developed a non-radioisotopic endpoint for the LLNA based on 5-bromo-2'-deoxyuridine (BrdU) incorporation (non-RI LLNA), and we are proposing a new procedure to predict the sensitization potency of chemicals based on comparisons with known human contact allergens. Nine chemicals (i.e. diphencyclopropenone, p-phenylenediamine, glutaraldehyde, cinnamicaldehyde, citral, eugenol, isopropyl myristate, propyleneglycol and hexane) categorized as human contact allergen classes 1-5 were tested by the non-RI LLNA with the following reference allergens: 2,4-dinitrochlorobenzene (DNCB) as a class 1 human contact allergen, isoeugenol as a class 2 human contact allergen and alpha-hexylcinnamic aldehyde (HCA) as a class 3 human contact allergen. Consequently, nine test chemicals were almost assigned to their correct allergen class. The results suggested that the new procedure for non-RI LLNA can provide correct sensitization potency data. Sensitization potency data are useful for evaluating the sensitization risk to humans of exposure to new chemical products. Accordingly, this approach would be an effective modification of LLNA with regard to its experimental design. Moreover, this procedure can be applied also to the standard LLNA with radioisotopes and to other modifications of the LLNA. Copyright 2005 John Wiley & Sons, Ltd.

Safety, Pharmacokinetic, and Functional Effects of the Nogo-A Monoclonal Antibody in Amyotrophic Lateral Sclerosis: A Randomized, First-In-Human Clinical Trial

PubMed Central

Meininger, Vincent; Pradat, Pierre-François; Corse, Andrea; Al-Sarraj, Safa; Rix Brooks, Benjamin; Caress, James B.; Cudkowicz, Merit; Kolb, Stephen J.; Lange, Dale; Leigh, P. Nigel; Meyer, Thomas; Milleri, Stefano; Morrison, Karen E.; Orrell, Richard W.; Peters, Gary; Rothstein, Jeffrey D.; Shefner, Jeremy; Lavrov, Arseniy; Williams, Nicola; Overend, Phil; Price, Jeffrey; Bates, Stewart; Bullman, Jonathan; Krull, David; Berges, Alienor; Abila, Bams; Meno-Tetang, Guy; Wurthner, Jens

2014-01-01

The neurite outgrowth inhibitor, Nogo-A, has been shown to be overexpressed in skeletal muscle in amyotrophic lateral sclerosis (ALS); it is both a potential biomarker and therapeutic target. We performed a double-blind, two-part, dose-escalation study, in subjects with ALS, assessing safety, pharmacokinetics (PK) and functional effects of ozanezumab, a humanized monoclonal antibody against Nogo-A. In Part 1, 40 subjects were randomized (3∶1) to receive single dose intravenous ozanezumab (0.01, 0.1, 1, 5, or 15 mg/kg) or placebo. In Part 2, 36 subjects were randomized (3∶1) to receive two repeat doses of intravenous ozanezumab (0.5, 2.5, or 15 mg/kg) or placebo, approximately 4 weeks apart. The primary endpoints were safety and tolerability (adverse events [AEs], vital signs, electrocardiogram (ECG), and clinical laboratory tests). Secondary endpoints included PK, immunogenicity, functional endpoints (clinical and electrophysiological), and biomarker parameters. Overall, ozanezumab treatment (0.01–15 mg/kg) was well tolerated. The overall incidence of AEs in the repeat dose 2.5 mg/kg and 15 mg/kg ozanezumab groups was higher than in the repeat dose placebo group and repeat dose 0.5 mg/kg ozanezumab group. The majority were considered not related to study drug by the investigators. Six serious AEs were reported in three subjects receiving ozanezumab; none were considered related to study drug. No study drug-related patterns were identified for ECG, laboratory, or vital signs parameters. One subject (repeat dose 15 mg/kg ozanezumab) showed a weak, positive anti-ozanezumab-antibody result. PK results were generally consistent with monoclonal antibody treatments. No apparent treatment effects were observed for functional endpoints or muscle biomarkers. Immunohistochemical staining showed dose-dependent co-localization of ozanezumab with Nogo-A in skeletal muscle. In conclusion, single and repeat dose ozanezumab treatment was well tolerated and demonstrated co-localization at the site of action. These findings support future studies with ozanezumab in ALS. Trial Registration ClinicalTrials.gov NCT00875446 GSK-ClinicalStudyRegister.com GSK ID 111330 PMID:24841795

Trends in Utilization of Surrogate Endpoints in Contemporary Cardiovascular Clinical Trials.

PubMed

Patel, Ravi B; Vaduganathan, Muthiah; Samman-Tahhan, Ayman; Kalogeropoulos, Andreas P; Georgiopoulou, Vasiliki V; Fonarow, Gregg C; Gheorghiade, Mihai; Butler, Javed

2016-06-01

Surrogate endpoints facilitate trial efficiency but are variably linked to clinical outcomes, and limited data are available exploring their utilization in cardiovascular clinical trials over time. We abstracted data regarding primary clinical, intermediate, and surrogate endpoints from all phase II to IV cardiovascular clinical trials from 2001 to 2012 published in the 8 highest Web of Science impact factor journals. Two investigators independently classified the type of primary endpoint. Of the 1,224 trials evaluated, 677 (55.3%) primary endpoints were clinical, 165 (13.5%) intermediate, and 382 (31.2%) surrogate. The relative proportions of these endpoints remained constant over time (p = 0.98). Trials using surrogate endpoints were smaller (187 vs 1,028 patients) and enrolled patients more expeditiously (1.4 vs 0.9 patients per site per month) compared with trials using clinical endpoints (p <0.001 for both comparisons). Surrogate endpoint trials were independently more likely to meet their primary endpoint compared to trials with clinical endpoints (adjusted odds ratio 1.56, 95% CI 1.05 to 2.34; p = 0.03). Rates of positive results in clinical endpoint trials have decreased over time from 66.1% in 2001 to 2003 to 47.2% in 2010 to 2012 (p = 0.001), whereas these rates have remained stable over the same period for surrogate (72.0% to 69.3%, p = 0.27) and intermediate endpoints (74.4% to 71.4%, p = 0.98). In conclusion, approximately a third of contemporary cardiovascular trials use surrogate endpoints. These trials are completed more expeditiously and are more likely to meet their primary outcomes. The overall scientific contribution of these surrogate endpoint trials requires further attention given their variable association with definitive outcomes. Copyright © 2016 Elsevier Inc. All rights reserved.

Differential Response to Abiraterone Acetate and Di-n-butyl Phthalate in an Androgen-Sensitive Human Fetal Testis Xenograft Bioassay

PubMed Central

Boekelheide, Kim

2014-01-01

In utero exposure to antiandrogenic xenobiotics such as di-n-butyl phthalate (DBP) has been linked to congenital defects of the male reproductive tract, including cryptorchidism and hypospadias, as well as later life effects such as testicular cancer and decreased sperm counts. Experimental evidence indicates that DBP has in utero antiandrogenic effects in the rat. However, it is unclear whether DBP has similar effects on androgen biosynthesis in human fetal testis. To address this issue, we developed a xenograft bioassay with multiple androgen-sensitive physiological endpoints, similar to the rodent Hershberger assay. Adult male athymic nude mice were castrated, and human fetal testis was xenografted into the renal subcapsular space. Hosts were treated with human chorionic gonadotropin for 4 weeks to stimulate testosterone production. During weeks 3 and 4, hosts were exposed to DBP or abiraterone acetate, a CYP17A1 inhibitor. Although abiraterone acetate (14 d, 75mg/kg/d po) dramatically reduced testosterone and the weights of androgen-sensitive host organs, DBP (14 d, 500mg/kg/d po) had no effect on androgenic endpoints. DBP did produce a near-significant trend toward increased multinucleated germ cells in the xenografts. Gene expression analysis showed that abiraterone decreased expression of genes related to transcription and cell differentiation while increasing expression of genes involved in epigenetic control of gene expression. DBP induced expression of oxidative stress response genes and altered expression of actin cytoskeleton genes. PMID:24284787

A toxicological review of the propylene glycols.

PubMed

Fowles, Jeff R; Banton, Marcy I; Pottenger, Lynn H

2013-04-01

The toxicological profiles of monopropylene glycol (MPG), dipropylene glycol (DPG), tripropylene glycol (TPG) and polypropylene glycols (PPG; including tetra-rich oligomers) are collectively reviewed, and assessed considering regulatory toxicology endpoints. The review confirms a rich data set for these compounds, covering all of the major toxicological endpoints of interest. The metabolism of these compounds share common pathways, and a consistent profile of toxicity is observed. The common metabolism provides scientific justification for adopting a read-across approach to describing expected hazard potential from data gaps that may exist for specific oligomers. None of the glycols reviewed presented evidence of carcinogenic, mutagenic or reproductive/developmental toxicity potential to humans. The pathologies reported in some animal studies either occurred at doses that exceeded experimental guidelines, or involved mechanisms that are likely irrelevant to human physiology and therefore are not pertinent to the exposures experienced by consumers or workers. At very high chronic doses, MPG causes a transient, slight decrease in hemoglobin in dogs and at somewhat lower doses causes Heinz bodies to form in cats in the absence of any clinical signs of anemia. Some evidence for rare, idiosyncratic skin reactions exists for MPG. However, the larger data set indicates that these compounds have low sensitization potential in animal studies, and therefore are unlikely to represent human allergens. The existing safety evaluations of the FDA, USEPA, NTP and ATSDR for these compounds are consistent and point to the conclusion that the propylene glycols present a very low risk to human health.

Where the Brain Appreciates the Final State of an Event: The Neural Correlates of Telicity

ERIC Educational Resources Information Center

Romagno, Domenica; Rota, Giuseppina; Ricciardi, Emiliano; Pietrini, Pietro

2012-01-01

In this study we investigated whether the human brain distinguishes between telic events that necessarily entail a specified endpoint (e.g., "reaching"), and atelic events with no delimitation or final state (e.g., "chasing"). We used functional magnetic resonance imaging to explore the patterns of neural response associated with verbs denoting…

Nonparametric Discrete Survival Function Estimation with Uncertain Endpoints Using an Internal Validation Subsample

PubMed Central

Zee, Jarcy; Xie, Sharon X.

2015-01-01

Summary When a true survival endpoint cannot be assessed for some subjects, an alternative endpoint that measures the true endpoint with error may be collected, which often occurs when obtaining the true endpoint is too invasive or costly. We develop an estimated likelihood function for the situation where we have both uncertain endpoints for all participants and true endpoints for only a subset of participants. We propose a nonparametric maximum estimated likelihood estimator of the discrete survival function of time to the true endpoint. We show that the proposed estimator is consistent and asymptotically normal. We demonstrate through extensive simulations that the proposed estimator has little bias compared to the naïve Kaplan-Meier survival function estimator, which uses only uncertain endpoints, and more efficient with moderate missingness compared to the complete-case Kaplan-Meier survival function estimator, which uses only available true endpoints. Finally, we apply the proposed method to a dataset for estimating the risk of developing Alzheimer's disease from the Alzheimer's Disease Neuroimaging Initiative. PMID:25916510

21 CFR 601.41 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 7 2014-04-01 2014-04-01 false Approval based on a surrogate endpoint or on an... Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or... uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical...

21 CFR 601.41 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 7 2013-04-01 2013-04-01 false Approval based on a surrogate endpoint or on an... Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or... uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical...

21 CFR 601.41 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 7 2012-04-01 2012-04-01 false Approval based on a surrogate endpoint or on an... Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or... uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical...

21 CFR 601.41 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 7 2011-04-01 2010-04-01 true Approval based on a surrogate endpoint or on an... Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or... uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical...

21 CFR 601.41 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 7 2010-04-01 2010-04-01 false Approval based on a surrogate endpoint or on an... Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or... uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical...

Biomarkers and surrogate endpoints in glaucoma clinical trials.

PubMed

Medeiros, Felipe A

2015-05-01

Surrogate endpoints are often used as replacements for true clinically relevant endpoints in several areas of medicine, as they enable faster and less expensive clinical trials. However, without proper validation, the use of surrogates may lead to incorrect conclusions about the efficacy and safety of treatments. This article reviews the general requirements for validating surrogate endpoints and provides a critical assessment of the use of intraocular pressure (IOP), visual fields, and structural measurements of the optic nerve as surrogate endpoints in glaucoma clinical trials. A valid surrogate endpoint must be able to predict the clinically relevant endpoint and fully capture the effect of an intervention on that endpoint. Despite its widespread use in clinical trials, no proper validation of IOP as a surrogate endpoint has ever been conducted for any class of IOP-lowering treatments. Evidence has accumulated with regard to the role of imaging measurements of optic nerve damage as surrogate endpoints in glaucoma. These measurements are predictive of functional losses in the disease and may explain, at least in part, treatment effects on clinically relevant endpoints. The use of composite endpoints in glaucoma trials may overcome weaknesses of the use of structural or functional endpoints in isolation. Unless research is dedicated to fully develop and validate suitable endpoints that can be used in glaucoma clinical trials, we run the risk of inappropriate judgments about the value of new therapies. 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.

A perfect correlate does not a surrogate make

PubMed Central

Baker, Stuart G; Kramer, Barnett S

2003-01-01

Background There is common belief among some medical researchers that if a potential surrogate endpoint is highly correlated with a true endpoint, then a positive (or negative) difference in potential surrogate endpoints between randomization groups would imply a positive (or negative) difference in unobserved true endpoints between randomization groups. We investigate this belief when the potential surrogate and unobserved true endpoints are perfectly correlated within each randomization group. Methods We use a graphical approach. The vertical axis is the unobserved true endpoint and the horizontal axis is the potential surrogate endpoint. Perfect correlation within each randomization group implies that, for each randomization group, potential surrogate and true endpoints are related by a straight line. In this scenario the investigator does not know the slopes or intercepts. We consider a plausible example where the slope of the line is higher for the experimental group than for the control group. Results In our example with unknown lines, a decrease in mean potential surrogate endpoints from control to experimental groups corresponds to an increase in mean true endpoint from control to experimental groups. Thus the potential surrogate endpoints give the wrong inference. Similar results hold for binary potential surrogate and true outcomes (although the notion of correlation does not apply). The potential surrogate endpointwould give the correct inference if either (i) the unknown lines for the two group coincided, which means that the distribution of true endpoint conditional on potential surrogate endpoint does not depend on treatment group, which is called the Prentice Criterion or (ii) if one could accurately predict the lines based on data from prior studies. Conclusion Perfect correlation between potential surrogate and unobserved true outcomes within randomized groups does not guarantee correct inference based on a potential surrogate endpoint. Even in early phase trials, investigators should not base conclusions on potential surrogate endpoints in which the only validation is high correlation with the true endpoint within a group. PMID:12962545

Endpoint-based parallel data processing in a parallel active messaging interface of a parallel computer

DOEpatents

Archer, Charles J; Blocksome, Michael E; Ratterman, Joseph D; Smith, Brian E

2014-02-11

Endpoint-based parallel data processing in a parallel active messaging interface ('PAMI') of a parallel computer, the PAMI composed of data communications endpoints, each endpoint including a specification of data communications parameters for a thread of execution on a compute node, including specifications of a client, a context, and a task, the compute nodes coupled for data communications through the PAMI, including establishing a data communications geometry, the geometry specifying, for tasks representing processes of execution of the parallel application, a set of endpoints that are used in collective operations of the PAMI including a plurality of endpoints for one of the tasks; receiving in endpoints of the geometry an instruction for a collective operation; and executing the instruction for a collective opeartion through the endpoints in dependence upon the geometry, including dividing data communications operations among the plurality of endpoints for one of the tasks.

Endpoint-based parallel data processing in a parallel active messaging interface of a parallel computer

DOEpatents

Archer, Charles J.; Blocksome, Michael A.; Ratterman, Joseph D.; Smith, Brian E.

2014-08-12

Endpoint-based parallel data processing in a parallel active messaging interface (`PAMI`) of a parallel computer, the PAMI composed of data communications endpoints, each endpoint including a specification of data communications parameters for a thread of execution on a compute node, including specifications of a client, a context, and a task, the compute nodes coupled for data communications through the PAMI, including establishing a data communications geometry, the geometry specifying, for tasks representing processes of execution of the parallel application, a set of endpoints that are used in collective operations of the PAMI including a plurality of endpoints for one of the tasks; receiving in endpoints of the geometry an instruction for a collective operation; and executing the instruction for a collective operation through the endpoints in dependence upon the geometry, including dividing data communications operations among the plurality of endpoints for one of the tasks.

Drugs' development in acute heart failure: what went wrong?

PubMed

Teneggi, Vincenzo; Sivakumar, Nithy; Chen, Deborah; Matter, Alex

2018-05-08

Acute heart failure (AHF) is a major burden disease, with a complex physiopathology, unsatisfactory diagnosis, treatment and a very poor prognosis. In the last two decades, a number of drugs have progressed from preclinical to early and late clinical development, but only a few of them have been approved and added to a stagnant pharmacological armamentarium. We have reviewed the data published on drugs developed for AHF since early 2000s, trying to recognise factors that have worked for a successful approval or for the stoppage of the program, in an attempt to delineate future trajectories for AHF drug development. Our review has identified limitations at both preclinical and clinical levels. At the preclinical level, the major shortcoming is represented by animal models looking at short-term endpoints which do not recapitulate the complexity of the human disease. At the clinical level, the main weakness is given by the disconnect between short-term endpoints assessed in the early stage of drug development, and medium-long-term endpoints requested in Phase 3 for regulatory approval. This is further amplified by the lack of validation and standardisation of short- and long-term endpoints; absence of predictive biomarkers; conduct of studies on heterogeneous populations; and use of different eligibility criteria, time of assessments, drug schedules and background therapies. Key goals remain a better understanding of AHF and the construction of a successful drug development program. A reasonable way to move forward resides in a strong collaboration between main stakeholders of therapeutic innovation: scientific community, industry and regulatory agencies.

Is automated kinetic measurement superior to end-point for advanced oxidation protein product?

PubMed

Oguz, Osman; Inal, Berrin Bercik; Emre, Turker; Ozcan, Oguzhan; Altunoglu, Esma; Oguz, Gokce; Topkaya, Cigdem; Guvenen, Guvenc

2014-01-01

Advanced oxidation protein product (AOPP) was first described as an oxidative protein marker in chronic uremic patients and measured with a semi-automatic end-point method. Subsequently, the kinetic method was introduced for AOPP assay. We aimed to compare these two methods by adapting them to a chemistry analyzer and to investigate the correlation between AOPP and fibrinogen, the key molecule responsible for human plasma AOPP reactivity, microalbumin, and HbA1c in patients with type II diabetes mellitus (DM II). The effects of EDTA and citrate-anticogulated tubes on these two methods were incorporated into the study. This study included 93 DM II patients (36 women, 57 men) with HbA1c levels > or = 7%, who were admitted to the diabetes and nephrology clinics. The samples were collected in EDTA and in citrate-anticoagulated tubes. Both methods were adapted to a chemistry analyzer and the samples were studied in parallel. In both types of samples, we found a moderate correlation between the kinetic and the endpoint methods (r = 0.611 for citrate-anticoagulated, r = 0.636 for EDTA-anticoagulated, p = 0.0001 for both). We found a moderate correlation between fibrinogen-AOPP and microalbumin-AOPP levels only in the kinetic method (r = 0.644 and 0.520 for citrate-anticoagulated; r = 0.581 and 0.490 for EDTA-anticoagulated, p = 0.0001). We conclude that adaptation of the end-point method to automation is more difficult and it has higher between-run CV% while application of the kinetic method is easier and it may be used in oxidative stress studies.

The intermediate endpoint effect in logistic and probit regression

PubMed Central

MacKinnon, DP; Lockwood, CM; Brown, CH; Wang, W; Hoffman, JM

2010-01-01

Background An intermediate endpoint is hypothesized to be in the middle of the causal sequence relating an independent variable to a dependent variable. The intermediate variable is also called a surrogate or mediating variable and the corresponding effect is called the mediated, surrogate endpoint, or intermediate endpoint effect. Clinical studies are often designed to change an intermediate or surrogate endpoint and through this intermediate change influence the ultimate endpoint. In many intermediate endpoint clinical studies the dependent variable is binary, and logistic or probit regression is used. Purpose The purpose of this study is to describe a limitation of a widely used approach to assessing intermediate endpoint effects and to propose an alternative method, based on products of coefficients, that yields more accurate results. Methods The intermediate endpoint model for a binary outcome is described for a true binary outcome and for a dichotomization of a latent continuous outcome. Plots of true values and a simulation study are used to evaluate the different methods. Results Distorted estimates of the intermediate endpoint effect and incorrect conclusions can result from the application of widely used methods to assess the intermediate endpoint effect. The same problem occurs for the proportion of an effect explained by an intermediate endpoint, which has been suggested as a useful measure for identifying intermediate endpoints. A solution to this problem is given based on the relationship between latent variable modeling and logistic or probit regression. Limitations More complicated intermediate variable models are not addressed in the study, although the methods described in the article can be extended to these more complicated models. Conclusions Researchers are encouraged to use an intermediate endpoint method based on the product of regression coefficients. A common method based on difference in coefficient methods can lead to distorted conclusions regarding the intermediate effect. PMID:17942466

Human exposure limits to hypergolic fuels

NASA Technical Reports Server (NTRS)

Garcia, H. D.; James, J. T.; Limero, T. F.

1992-01-01

Over the past four decades, many studies have been conducted on the toxicities of the rocket propellants hydrazine (HZ) and monomethylhydrazine (MH). Numerous technical challenges have made it difficult to unambiguously interpret the results of these studies, and there is considerable divergence between results obtained by different investigators on the inhalation concentrations (MAC's) for each toxic effect inducible by exposure to hypergolic fuels in spacecraft atmospheres, NASA undertook a critical review of published and unpublished investigations on the toxicities of these compounds. The current state of the art practices for similar studies. While many questions remain unanswered, MAC's were determined using the best available data for a variety of toxic endpoints for potential continuous exposure durations ranging from 1 hour to 180 days. Spacecraft MAC's (SMAC's) were set for each compound based on the most sensitive toxic endpoint at each exposure duration.

Challenge of surrogate endpoints.

PubMed

Furgerson, James L; Hannah, William N; Thompson, Jennifer C

2012-03-01

Surrogate endpoints are biomarkers that are intended to substitute for clinical endpoints. They have been used to find novel therapeutic targets, improve the statistical power and shorten the duration of clinical trials, and control the cost of conducting research studies. The more generalized use of surrogate endpoints in clinical decision making can be hazardous and should be undertaken with great caution. This article reviews prior work with surrogate endpoints and highlights caveats and lessons learned from studies using surrogate endpoints.

Surrogate and clinical endpoints for studies in peripheral artery occlusive disease: Are statistics the brakes?

PubMed

Waliszewski, Matthias W; Redlich, Ulf; Breul, Victor; Tautenhahn, Jörg

2017-04-30

The aim of this review is to present the available clinical and surrogate endpoints that may be used in future studies performed in patients with peripheral artery occlusive disease (PAOD). Importantly, we describe statistical limitations of the most commonly used endpoints and offer some guidance with respect to study design for a given sample size. The proposed endpoints may be used in studies using surgical or interventional revascularization and/or drug treatments. Considering recently published study endpoints and designs, the usefulness of these endpoints for reimbursement is evaluated. Based on these potential study endpoints and patient sample size estimates with different non-inferiority or tests for difference hypotheses, a rating relative to their corresponding reimbursement values is attempted. As regards the benefit for the patients and for the payers, walking distance and the ankle brachial index (ABI) are the most feasible endpoints in a relatively small study samples given that other non-vascular impact factors can be controlled. Angiographic endpoints such as minimal lumen diameter (MLD) do not seem useful from a reimbursement standpoint despite their intuitiveness. Other surrogate endpoints, such as transcutaneous oxygen tension measurements, have yet to be established as useful endpoints in reasonably sized studies with patients with critical limb ischemia (CLI). From a reimbursement standpoint, WD and ABI are effective endpoints for a moderate study sample size given that non-vascular confounding factors can be controlled.

Influence of Humans on Evolution and Mobilization of Environmental Antibiotic Resistome

PubMed Central

Gaze, William H.; Krone, Stephen M.; Larsson, D.G. Joakim; Li, Xian-Zhi; Robinson, Joseph A.; Simonet, Pascal; Smalla, Kornelia; Timinouni, Mohammed; Topp, Ed; Wellington, Elizabeth M.; Zhu, Yong-Guan

2013-01-01

The clinical failure of antimicrobial drugs that were previously effective in controlling infectious disease is a tragedy of increasing magnitude that gravely affects human health. This resistance by pathogens is often the endpoint of an evolutionary process that began billions of years ago in non–disease-causing microorganisms. This environmental resistome, its mobilization, and the conditions that facilitate its entry into human pathogens are at the heart of the current public health crisis in antibiotic resistance. Understanding the origins, evolution, and mechanisms of transfer of resistance elements is vital to our ability to adequately address this public health issue. PMID:23764294

In vitro acute and developmental neurotoxicity screening: an overview of cellular platforms and high-throughput technical possibilities.

PubMed

Schmidt, Béla Z; Lehmann, Martin; Gutbier, Simon; Nembo, Erastus; Noel, Sabrina; Smirnova, Lena; Forsby, Anna; Hescheler, Jürgen; Avci, Hasan X; Hartung, Thomas; Leist, Marcel; Kobolák, Julianna; Dinnyés, András

2017-01-01

Neurotoxicity and developmental neurotoxicity are important issues of chemical hazard assessment. Since the interpretation of animal data and their extrapolation to man is challenging, and the amount of substances with information gaps exceeds present animal testing capacities, there is a big demand for in vitro tests to provide initial information and to prioritize for further evaluation. During the last decade, many in vitro tests emerged. These are based on animal cells, human tumour cell lines, primary cells, immortalized cell lines, embryonic stem cells, or induced pluripotent stem cells. They differ in their read-outs and range from simple viability assays to complex functional endpoints such as neural crest cell migration. Monitoring of toxicological effects on differentiation often requires multiomics approaches, while the acute disturbance of neuronal functions may be analysed by assessing electrophysiological features. Extrapolation from in vitro data to humans requires a deep understanding of the test system biology, of the endpoints used, and of the applicability domains of the tests. Moreover, it is important that these be combined in the right way to assess toxicity. Therefore, knowledge on the advantages and disadvantages of all cellular platforms, endpoints, and analytical methods is essential when establishing in vitro test systems for different aspects of neurotoxicity. The elements of a test, and their evaluation, are discussed here in the context of comprehensive prediction of potential hazardous effects of a compound. We summarize the main cellular characteristics underlying neurotoxicity, present an overview of cellular platforms and read-out combinations assessing distinct parts of acute and developmental neurotoxicology, and highlight especially the use of stem cell-based test systems to close gaps in the available battery of tests.

Advanced topics in evidence-based urologic oncology: surrogate endpoints.

PubMed

Lavallée, Luke T; Montori, Victor M; Canfield, Stephen E; Breau, Rodney H

2011-01-01

Clinical trials often report surrogate endpoint data. A surrogate endpoint is a biological marker or clinical sign that can be substituted for a patient-important outcome. Using surrogate endpoints correctly may facilitate and expedite clinical trials and may improve medical decisions. However, rigorous criteria must be met for an endpoint to be considered a valid surrogate. The purpose of this article is to review the topic of surrogate endpoints in the context of a urologic encounter. Copyright © 2011 Elsevier Inc. All rights reserved.

Toxicity Testing in the 21st Century Beyond Environmental Chemicals

PubMed Central

Rovida, Costanza; Asakura, Shoji; Daneshian, Mardas; Hofman-Huether, Hana; Leist, Marcel; Meunier, Leo; Reif, David; Rossi, Anna; Schmutz, Markus; Valentin, Jean-Pierre; Zurlo, Joanne; Hartung, Thomas

2018-01-01

Summary After the publication of the report titled Toxicity Testing in the 21st Century – A Vision and a Strategy, many initiatives started to foster a major paradigm shift for toxicity testing – from apical endpoints in animal-based tests to mechanistic endpoints through delineation of pathways of toxicity (PoT) in human cell based systems. The US EPA has funded an important project to develop new high throughput technologies based on human cell based in vitro technologies. These methods are currently being incorporated into the chemical risk assessment process. In the pharmaceutical industry, the efficacy and toxicity of new drugs are evaluated during preclinical investigations that include drug metabolism, pharmacokinetics, pharmacodynamics and safety toxicology studies. The results of these studies are analyzed and extrapolated to predict efficacy and potential adverse effects in humans. However, due to the high failure rate of drugs during the clinical phases, a new approach for a more predictive assessment of drugs both in terms of efficacy and adverse effects is getting urgent. The food industry faces the challenge of assessing novel foods and food ingredients for the general population, while using animal safety testing for extrapolation purposes is often of limited relevance. The question is whether the latest paradigm shift proposed by the Tox21c report for chemicals may provide a useful tool to improve the risk assessment approach also for drugs and food ingredients. PMID:26168280

Idiopathic Pulmonary Fibrosis: Clinically Meaningful Primary Endpoints in Phase 3 Clinical Trials

PubMed Central

Collard, Harold R.; Anstrom, Kevin J.; Flaherty, Kevin R.; Fleming, Thomas R.; King, Talmadge E.; Martinez, Fernando J.; Brown, Kevin K.

2012-01-01

Definitive evidence of clinical efficacy in a Phase 3 trial is best shown by a beneficial impact on a clinically meaningful endpoint—that is, an endpoint that directly measures how a patient feels (symptoms), functions (the ability to perform activities in daily life), or survives. In idiopathic pulmonary fibrosis (IPF), we believe the endpoints that best meet these criteria are all-cause mortality and all-cause nonelective hospitalization. There are no validated measures of symptoms or broader constructs such as health status or funtional status in IPF. A surrogate endpoint is defined as an indirect measure that is intended to substitute for a clinically meaningful endpoint. Surrogate endpoints can be appropriate outcome measures if validated. However, validation requires substantial evidence that the effect of an intervention on a clinically meaningful endpoint is reliably predicted by the effect of an intervention on the surrogate endpoint. For patients with IPF, there are currently no validated surrogate endpoints. PMID:22505745

Computer Simulation of Embryonic Systems: What can a virtual embryo teach us about developmental toxicity? Microcephaly: Computational and organotypic modeling of a complex human birth defect (seminar and lecture - Thomas Jefferson University, Philadelphia, PA)

EPA Science Inventory

(1) Standard practice for assessing developmental toxicity is the observation of apical endpoints (intrauterine death, fetal growth retardation, structural malformations) in pregnant rats/rabbits following exposure during organogenesis. EPA’s computational toxicology research pro...

Effects Of Combinations of Ozone and Diesel Exhaust Exposures On Blood, Cardiac, And Lung Endpoints

EPA Science Inventory

Human subjects were exposed to combinations of 300 ppb ozone (03) and 300 ug/m3 diesel exhaust (DE) to examine if synergistic effects were observed. Subjects received either filtered air (FA), 03, DE, or DE+03 on Day 1, followed by only 03 exposures on Day 2, and a follow-up on D...

Human Health Safety Evaluation of Halon Replacement Candidates

DTIC Science & Technology

2000-05-01

neurotoxicity, developmental neurotoxicity, immunotoxicity, and endocrine disruptor tests may be considered if there is reason to suspect alterations in...conclusion of the study), gross necropsy, and select organ weight measurements (e.g., liver, lungs, kidneys, adrenals, testes, brain) "* Preserve ...and evaluated in the study. The biological endpoints of a 90-day study include daily clinical observations; measurements of body weight, food

Maternal exposure to a mixture of persistent organic pollutants (POPs) affects testis histology, epididymal sperm count and induces sperm DNA fragmentation in mice.

PubMed

Khezri, Abdolrahman; Lindeman, Birgitte; Krogenæs, Anette K; Berntsen, Hanne F; Zimmer, Karin E; Ropstad, Erik

2017-08-15

Persistent organic pollutants (POPs) are widespread throughout the environment and some are suspected to induce reproductive toxicity. As animals and humans are exposed to complex mixtures of POPs, it is reasonable to assess how such mixtures could interact with the reproductive system. Our aim is to investigate how maternal exposure to a mixture of 29 different persistent organic pollutants, formulated to mimic the relative POP levels in the food basket of the Scandinavian population, could alter reproductive endpoints. Female mice were exposed via feed from weaning, during pregnancy and lactation in 3 exposure groups (control (C), low (L) and high (H)). Testicular morphometric endpoints, epididymal sperm concentration and sperm DNA integrity were assessed in adult male offspring. We found that the number of tubules, proportion of tubule compartments and epididymal sperm concentration significantly decreased in both POP exposed groups. Epididymal sperm from both POP exposed groups showed increased DNA fragmentation. It is concluded that maternal exposure to a defined POP mixture relevant to human exposure can affect testicular development, sperm production and sperm chromatin integrity. Copyright © 2017 Elsevier Inc. All rights reserved.

Surrogate endpoints and emerging surrogate endpoints for risk reduction of cardiovascular disease.

PubMed

Rasnake, Crystal M; Trumbo, Paula R; Heinonen, Therese M

2008-02-01

This article reviews surrogate endpoints and emerging biomarkers that were discussed at the annual "Cardiovascular Biomarkers and Surrogate Endpoints" symposium cosponsored by the US Food and Drug Administration (FDA) and the Montreal Heart Institute. The FDA's Center for Food Safety and Applied Nutrition (CFSAN) uses surrogate endpoints in its scientific review of a substance/disease relationship for a health claim. CFSAN currently recognizes three validated surrogate endpoints: blood pressure, blood total cholesterol, and blood low-density lipoprotein (LDL) concentration in its review of a health claim for cardiovascular disease (CVD). Numerous potential surrogate endpoints of CVD are being evaluated as the pathophysiology of heart disease is becoming better understood. However, these emerging biomarkers need to be validated as surrogate endpoints before they are used by CFSAN in the evaluation of a CVD health claim.

Data communications in a parallel active messaging interface of a parallel computer

DOEpatents

Archer, Charles J; Blocksome, Michael A; Ratterman, Joseph D; Smith, Brian E

2013-10-29

Data communications in a parallel active messaging interface (`PAMI`) of a parallel computer, the parallel computer including a plurality of compute nodes that execute a parallel application, the PAMI composed of data communications endpoints, each endpoint including a specification of data communications parameters for a thread of execution on a compute node, including specifications of a client, a context, and a task, the compute nodes and the endpoints coupled for data communications through the PAMI and through data communications resources, including receiving in an origin endpoint of the PAMI a data communications instruction, the instruction characterized by an instruction type, the instruction specifying a transmission of transfer data from the origin endpoint to a target endpoint and transmitting, in accordance with the instruction type, the transfer data from the origin endpoint to the target endpoint.

Sample size determination for equivalence assessment with multiple endpoints.

PubMed

Sun, Anna; Dong, Xiaoyu; Tsong, Yi

2014-01-01

Equivalence assessment between a reference and test treatment is often conducted by two one-sided tests (TOST). The corresponding power function and sample size determination can be derived from a joint distribution of the sample mean and sample variance. When an equivalence trial is designed with multiple endpoints, it often involves several sets of two one-sided tests. A naive approach for sample size determination in this case would select the largest sample size required for each endpoint. However, such a method ignores the correlation among endpoints. With the objective to reject all endpoints and when the endpoints are uncorrelated, the power function is the production of all power functions for individual endpoints. With correlated endpoints, the sample size and power should be adjusted for such a correlation. In this article, we propose the exact power function for the equivalence test with multiple endpoints adjusted for correlation under both crossover and parallel designs. We further discuss the differences in sample size for the naive method without and with correlation adjusted methods and illustrate with an in vivo bioequivalence crossover study with area under the curve (AUC) and maximum concentration (Cmax) as the two endpoints.

Dose response models and a quantitative microbial risk assessment framework for the Mycobacterium avium complex that account for recent developments in molecular biology, taxonomy, and epidemiology.

PubMed

Hamilton, Kerry A; Weir, Mark H; Haas, Charles N

2017-02-01

Mycobacterium avium complex (MAC) is a group of environmentally-transmitted pathogens of great public health importance. This group is known to be harbored, amplified, and selected for more human-virulent characteristics by amoeba species in aquatic biofilms. However, a quantitative microbial risk assessment (QMRA) has not been performed due to the lack of dose response models resulting from significant heterogeneity within even a single species or subspecies of MAC, as well as the range of human susceptibilities to mycobacterial disease. The primary human-relevant species and subspecies responsible for the majority of the human disease burden and present in drinking water, biofilms, and soil are M. avium subsp. hominissuis, M. intracellulare, and M. chimaera. A critical review of the published literature identified important health endpoints, exposure routes, and susceptible populations for MAC risk assessment. In addition, data sets for quantitative dose-response functions were extracted from published in vivo animal dosing experiments. As a result, seven new exponential dose response models for human-relevant species of MAC with endpoints of lung lesions, death, disseminated infection, liver infection, and lymph node lesions are proposed. Although current physical and biochemical tests used in clinical settings do not differentiate between M. avium and M. intracellulare, differentiating between environmental species and subspecies of the MAC can aid in the assessment of health risks and control of MAC sources. A framework is proposed for incorporating the proposed dose response models into susceptible population- and exposure route-specific QMRA models. Copyright © 2016 Elsevier Ltd. All rights reserved.

A comparison of water quality criteria for the Great Lakes based on human and wildlife health

USGS Publications Warehouse

Ludwig, James P.; Giesy, John P.; Summer, Cheryl L.; Bowerman, William; Aulerich, Richard J.; Bursian, Steven J.; Auman, Heidi J.; Jones, Paul D.; Williams, Lisa L.; Tillitt, Donald E.; Gilbertson, Michael

1993-01-01

Water quality criteria (WQC) can be derived in several ways. The usual techniques involve hazard and risk assessment procedures. For non-persistent, non-biomagnified compounds and elements, WQC are experimentally derived from their acute and chronic toxicity to aquatic organisms. For those persistent chlorinated hydrocarbons (PCHs) that are bioaccumulated and biomagnified, these traditional techniques have not been effective, partly because effects higher in the food web were not considered. Polychlorinated biphenyls (PCBs) are the bioaccumulative synthetic chemicals of primary toxicological significance to the Great Lakes biota which have caused widespread injury to wildlife. In the Laurentian Great Lakes, the primary emphasis of hazard assessments has been on the potential for adverse effects in humans who eat fish. The primary regulatory endpoint of traditional hazard and risk assessments underlying current WQC are the probabilities of additional cancers occurring in the human population. The analysis presented here indicates that this is not adequate to restore sensitive wildlife species that are highly exposed to PCBs, especially those that have suffered serious population declines. Because WQC are legal instruments, the methods of deriving WQC have large implications for remediation, litigation, and damage assessments. Here WQC are derived for six species based on the responses of wildlife in the field or produced by feeding fish to surrogate species, rather than projecting a potential of increased cancer rates in humans. If the most sensitive wildlife species are restored and protected for very sensitive reproductive endpoints, then all components of the ecosystem, including human health, should be more adequately protected. The management of Great Lakes wildlife requires an understanding of the injury and causal relationships to persistent toxic substances.

Potential pre-cataractous markers induced by low-dose radiation effects in cultured human lens cells

NASA Astrophysics Data System (ADS)

Blakely, E.; McNamara, M.; Bjornstad, K.; Chang, P.

The human lens is one of the most radiosensitive organs of the body. Cataract, the opacification of the lens, is a late-appearing response to radiation damage. Recent evidence indicates that exposure to relatively low doses of space radiation are associated with an increased incidence and early appearance of human cataracts (Cucinotta et al., Radiat. Res. 156:460-466, 2001). Basic research in this area is needed to integrate the early responses of various late-responding tissues into our understanding and estimation of radiation risk for space travel. In addition, these studies may contribute to the development of countermeasures for the early lenticular changes, in order to prevent the late sequelae. Radiation damage to the lens is not life threatening but, if severe, can affect vision unless surgically corrected with synthetic lens replacement. The lens, however, may be a sensitive detector of radiation effects for other cells of ectodermal origin in the body for which there are not currently clear endpoints of low-dose radiation effects. We have investigated the dose-dependent expression of several radiation-responsive endpoints using our in vitro model of differentiating human lens epithelial cells (Blakely et al., Investigative Ophthalmology &Visual Sciences, 41(12):3898-3907, 2000). We have investigated radiation effects on several gene families that include, or relate to, DNA damage, cytokines, cell-cycle regulators, cell adhesion molecules, cell cytoskeletal function and apoptotic cell death. In this paper we will summarize some of our dose-dependent data from several radiation types, and describe the model of molecular and cellular events that we believe may be associated with precataractous events in the human lens after radiation exposure. This work was supported by NASA Grant #T-965W.

An Evaluation of Automotive Interior Packages Based on Human Ocular and Joint Motor Properties

NASA Astrophysics Data System (ADS)

Tanaka, Yoshiyuki; Rakumatsu, Takeshi; Horiue, Masayoshi; Miyazaki, Tooru; Nishikawa, Kazuo; Nouzawa, Takahide; Tsuji, Toshio

This paper proposes a new evaluation method of an automotive interior package based on human oculomotor and joint-motor properties. Assuming the long-term driving situation in the express high way, the three evaluation indices were designed on i) the ratio of head motion at gazing the driving items; ii) the load torque for maintaining the standard driving posture; and iii) the human force manipulability at the end-point of human extremities. Experiments were carried out for two different interior packages with four subjects who have the special knowledge on the automobile development. Evaluation results demonstrate that the proposed method can quantitatively analyze the driving interior in good agreement with the generally accepted subjective opinion in the automobile industry.

Data communications for a collective operation in a parallel active messaging interface of a parallel computer

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

Faraj, Daniel A.

Algorithm selection for data communications in a parallel active messaging interface (`PAMI`) of a parallel computer, the PAMI composed of data communications endpoints, each endpoint including specifications of a client, a context, and a task, endpoints coupled for data communications through the PAMI, including associating in the PAMI data communications algorithms and bit masks; receiving in an origin endpoint of the PAMI a collective instruction, the instruction specifying transmission of a data communications message from the origin endpoint to a target endpoint; constructing a bit mask for the received collective instruction; selecting, from among the associated algorithms and bit masks,more » a data communications algorithm in dependence upon the constructed bit mask; and executing the collective instruction, transmitting, according to the selected data communications algorithm from the origin endpoint to the target endpoint, the data communications message.« less

Data communications in a parallel active messaging interface of a parallel computer

DOEpatents

Davis, Kristan D.; Faraj, Daniel A.

2014-07-22

Algorithm selection for data communications in a parallel active messaging interface (`PAMI`) of a parallel computer, the PAMI composed of data communications endpoints, each endpoint including specifications of a client, a context, and a task, endpoints coupled for data communications through the PAMI, including associating in the PAMI data communications algorithms and ranges of message sizes so that each algorithm is associated with a separate range of message sizes; receiving in an origin endpoint of the PAMI a data communications instruction, the instruction specifying transmission of a data communications message from the origin endpoint to a target endpoint, the data communications message characterized by a message size; selecting, from among the associated algorithms and ranges, a data communications algorithm in dependence upon the message size; and transmitting, according to the selected data communications algorithm from the origin endpoint to the target endpoint, the data communications message.

Data communications in a parallel active messaging interface of a parallel computer

DOEpatents

Davis, Kristan D; Faraj, Daniel A

2013-07-09

Algorithm selection for data communications in a parallel active messaging interface (`PAMI`) of a parallel computer, the PAMI composed of data communications endpoints, each endpoint including specifications of a client, a context, and a task, endpoints coupled for data communications through the PAMI, including associating in the PAMI data communications algorithms and ranges of message sizes so that each algorithm is associated with a separate range of message sizes; receiving in an origin endpoint of the PAMI a data communications instruction, the instruction specifying transmission of a data communications message from the origin endpoint to a target endpoint, the data communications message characterized by a message size; selecting, from among the associated algorithms and ranges, a data communications algorithm in dependence upon the message size; and transmitting, according to the selected data communications algorithm from the origin endpoint to the target endpoint, the data communications message.

Data communications for a collective operation in a parallel active messaging interface of a parallel computer

DOEpatents

Faraj, Daniel A

2013-07-16

Algorithm selection for data communications in a parallel active messaging interface (`PAMI`) of a parallel computer, the PAMI composed of data communications endpoints, each endpoint including specifications of a client, a context, and a task, endpoints coupled for data communications through the PAMI, including associating in the PAMI data communications algorithms and bit masks; receiving in an origin endpoint of the PAMI a collective instruction, the instruction specifying transmission of a data communications message from the origin endpoint to a target endpoint; constructing a bit mask for the received collective instruction; selecting, from among the associated algorithms and bit masks, a data communications algorithm in dependence upon the constructed bit mask; and executing the collective instruction, transmitting, according to the selected data communications algorithm from the origin endpoint to the target endpoint, the data communications message.

Screening level risk assessment model for chemical fate and effects in the environment.

PubMed

Arnot, Jon A; Mackay, Don; Webster, Eva; Southwood, Jeanette M

2006-04-01

A screening level risk assessment model is developed and described to assess and prioritize chemicals by estimating environmental fate and transport, bioaccumulation, and exposure to humans and wildlife for a unit emission rate. The most sensitive risk endpoint is identified and a critical emission rate is then calculated as a result of that endpoint being reached. Finally, this estimated critical emission rate is compared with the estimated actual emission rate as a risk assessment factor. This "back-tracking" process avoids the use of highly uncertain emission rate data as model input. The application of the model is demonstrated in detail for three diverse chemicals and in less detail for a group of 70 chemicals drawn from the Canadian Domestic Substances List. The simple Level II and the more complex Level III fate calculations are used to "bin" substances into categories of similar probable risk. The essential role of the model is to synthesize information on chemical and environmental properties within a consistent mass balance framework to yield an overall estimate of screening level risk with respect to the defined endpoint. The approach may be useful to identify and prioritize those chemicals of commerce that are of greatest potential concern and require more comprehensive modeling and monitoring evaluations in actual regional environments and food webs.

QSAR models to predict mutagenicity of acrylates, methacrylates and alpha,beta-unsaturated carbonyl compounds.

PubMed

Pérez-Garrido, Alfonso; Helguera, Aliuska Morales; Rodríguez, Francisco Girón; Cordeiro, M Natália D S

2010-05-01

The purpose of this study is to develop a quantitative structure-activity relationship (QSAR) model that can distinguish mutagenic from non-mutagenic species with alpha,beta-unsaturated carbonyl moiety using two endpoints for this activity - Ames test and mammalian cell gene mutation test - and also to gather information about the molecular features that most contribute to eliminate the mutagenic effects of these chemicals. Two data sets were used for modeling the two mutagenicity endpoints: (1) Ames test and (2) mammalian cells mutagenesis. The first one comprised 220 molecules, while the second one 48 substances, ranging from acrylates, methacrylates to alpha,beta-unsaturated carbonyl compounds. The QSAR models were developed by applying linear discriminant analysis (LDA) along with different sets of descriptors computed using the DRAGON software. For both endpoints, there was a concordance of 89% in the prediction and 97% confidentiality by combining the three models for the Ames test mutagenicity. We have also identified several structural alerts to assist the design of new monomers. These individual models and especially their combination are attractive from the point of view of molecular modeling and could be used for the prediction and design of new monomers that do not pose a human health risk. 2010 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

Persistent high-risk human papillomavirus (HPV) infections as surrogate endpoints of progressive cervical disease. Potential new endpoint for efficacy studies with new-generation (non-HPV 16/18) prophylactic HPV vaccines.

PubMed

Syrjänen, K

2011-01-01

Recent data indicate that persistent HR-HPV infections represent a significantly increased risk of developing incident high-grade CIN and cervical cancer. Accordingly, 6-month (6M+) or 12-month (12M+) type-specific persistence of HR-HPV have been proposed as powerful surrogates of progressive disease. Because of substantial practical impact in future HPV vaccine trials using non-HPV 16/18 vaccines, studies on HR-HPV persistence as a surrogate endpoint of progressive CIN have been subject to a comprehensive meta-analyses recently. The present communication was solicited to bring this important and timely topic to the awareness of the readers, in a format consisting of a review of the recent literature, supplemented with the author's own experience from different studies. Based on a large number of relevant studies, there remains little doubt that persistence of HR-HPV for 6+ or 12+ months is associated with a significantly increased risk of developing incident high-grade CIN. However, some data also disclosed several important issues that need to be carefully considered and/or adequately resolved before adopting 6M+ or 12M+ HR-HPV persistence as a surrogate of progressive disease. These include i) definitions of HPV persistence, ii) HPV detection techniques and iii) testing intervals and iv) length of follow-up, as well as v) diagnosis of the surrogate endpoints, and vi) other study characteristics, including vii) the type of reference category used in calculating the risk estimates. All these issues are critically discussed in the present communication. Of major impact seems to be the reference category used to calculate these risk estimates, as evident from the NIS-LAMS cohort. Taken together, it is suggested that in all future studies using the 6M+ or 12M+ HR-HPV persistence as a surrogate endpoint of progressive disease, a "gold standard" should be used in calculating the risk estimates. In addition to deciding, 1) whether to use 6M+ or 12M+ persistence criteria, and 2) cytological, histological or combined surrogate endpoints (SIL, CIN1, CIN2, CIN/SIL), one should 3) use exclusively the HPV negative reference group in calculating the risk estimates for viral persistence endpoints. This is supported by the data from the recent meta-analysis as well as from the author's combined NIS-LAMS cohort, both implicating that the most consistent association to progressive disease is obtained when women with persistent HR-HPV are compared with HPV-negative women. It is the conviction of this author that the two other reference categories (HPV transient and HPV mixed outcome) are far too heterogeneous and subject to potential misclassifications to give consistent and reproducible risk estimates for HR-HPV persistence as a surrogate endpoint of progressive CIN.

Observations on Three Endpoint Properties and Their Relationship to Regulatory Outcomes of European Oncology Marketing Applications

PubMed Central

Stolk, Pieter; McAuslane, James Neil; Schellens, Jan; Breckenridge, Alasdair M.; Leufkens, Hubert

2015-01-01

Background. Guidance and exploratory evidence indicate that the type of endpoints and the magnitude of their outcome can define a therapy’s clinical activity; however, little empirical evidence relates specific endpoint properties with regulatory outcomes. Materials and Methods. We explored the relationship of 3 endpoint properties to regulatory outcomes by assessing 50 oncology marketing authorization applications (MAAs; reviewed from 2009 to 2013). Results. Overall, 16 (32%) had a negative outcome. The most commonly used hard endpoints were overall survival (OS) and the duration of response or stable disease. OS was a component of 91% approved and 63% failed MAAs. The most commonly used surrogate endpoints were progression-free survival (PFS), response rate, and health-related quality of life assessments. There was no difference (p = .3801) between the approved and failed MAA cohorts in the proportion of hard endpoints used. A mean of slightly more than four surrogate endpoints were used per approved MAA compared with slightly more than two for failed MAAs. Longer OS and PFS duration outcomes were generally associated with approvals, often when not statistically significant. The approved cohort was associated with a preponderance of statistically significant (p < .05) improvements in primary endpoints (p < .0001 difference between the approved and failed groups). Conclusion. Three key endpoint properties (type of endpoint [hard/surrogate], magnitude of an endpoint outcome, and its statistical significance) are consistent with the European Medicines Agency guidance and, notwithstanding the contribution of unique disease-specific circumstances, are associated with a predictable positive outcome for oncology MAAs. Implications for Practice: Regulatory decisions made by the European Medicines Agency determine which new medicines will be available to European prescribers and for which therapeutic indications. Regulatory success or failure can be influenced by many factors. This study assessed three key properties of endpoints used in preauthorization trials (type of endpoint [hard/surrogate], magnitude of endpoint outcome, and its statistical significance) and whether they are associated with a positive regulatory outcome. Clinicians can use these properties, which are described in the publicly available European public assessment reports, to help guide their understanding of the clinical effect of new oncologic therapies. PMID:25948678

Observations on Three Endpoint Properties and Their Relationship to Regulatory Outcomes of European Oncology Marketing Applications.

PubMed

Liberti, Lawrence; Stolk, Pieter; McAuslane, James Neil; Schellens, Jan; Breckenridge, Alasdair M; Leufkens, Hubert

2015-06-01

Guidance and exploratory evidence indicate that the type of endpoints and the magnitude of their outcome can define a therapy's clinical activity; however, little empirical evidence relates specific endpoint properties with regulatory outcomes. We explored the relationship of 3 endpoint properties to regulatory outcomes by assessing 50 oncology marketing authorization applications (MAAs; reviewed from 2009 to 2013). Overall, 16 (32%) had a negative outcome. The most commonly used hard endpoints were overall survival (OS) and the duration of response or stable disease. OS was a component of 91% approved and 63% failed MAAs. The most commonly used surrogate endpoints were progression-free survival (PFS), response rate, and health-related quality of life assessments. There was no difference (p = .3801) between the approved and failed MAA cohorts in the proportion of hard endpoints used. A mean of slightly more than four surrogate endpoints were used per approved MAA compared with slightly more than two for failed MAAs. Longer OS and PFS duration outcomes were generally associated with approvals, often when not statistically significant. The approved cohort was associated with a preponderance of statistically significant (p < .05) improvements in primary endpoints (p < .0001 difference between the approved and failed groups). Three key endpoint properties (type of endpoint [hard/surrogate], magnitude of an endpoint outcome, and its statistical significance) are consistent with the European Medicines Agency guidance and, notwithstanding the contribution of unique disease-specific circumstances, are associated with a predictable positive outcome for oncology MAAs. Regulatory decisions made by the European Medicines Agency determine which new medicines will be available to European prescribers and for which therapeutic indications. Regulatory success or failure can be influenced by many factors. This study assessed three key properties of endpoints used in preauthorization trials (type of endpoint [hard/surrogate], magnitude of endpoint outcome, and its statistical significance) and whether they are associated with a positive regulatory outcome. Clinicians can use these properties, which are described in the publicly available European public assessment reports, to help guide their understanding of the clinical effect of new oncologic therapies. ©AlphaMed Press.

SpEnD: Linked Data SPARQL Endpoints Discovery Using Search Engines

NASA Astrophysics Data System (ADS)

Yumusak, Semih; Dogdu, Erdogan; Kodaz, Halife; Kamilaris, Andreas; Vandenbussche, Pierre-Yves

In this study, a novel metacrawling method is proposed for discovering and monitoring linked data sources on the Web. We implemented the method in a prototype system, named SPARQL Endpoints Discovery (SpEnD). SpEnD starts with a "search keyword" discovery process for finding relevant keywords for the linked data domain and specifically SPARQL endpoints. Then, these search keywords are utilized to find linked data sources via popular search engines (Google, Bing, Yahoo, Yandex). By using this method, most of the currently listed SPARQL endpoints in existing endpoint repositories, as well as a significant number of new SPARQL endpoints, have been discovered. Finally, we have developed a new SPARQL endpoint crawler (SpEC) for crawling and link analysis.

Compensatory mortality in a recovering top carnivore: wolves in Wisconsin, USA (1979-2013).

PubMed

Stenglein, Jennifer L; Wydeven, Adrian P; Van Deelen, Timothy R

2018-05-01

Populations of large terrestrial carnivores are in various stages of recovery worldwide and the question of whether there is compensation in mortality sources is relevant to conservation. Here, we show variation in Wisconsin wolf survival from 1979 to 2013 by jointly estimating the hazard of wolves' radio-telemetry ending (endpoint) and endpoint cause. In previous analyses, wolves lost to radio-telemetry follow-up (collar loss) were censored from analysis, thereby assuming collar loss was unconfounded with mortality. Our approach allowed us to explicitly estimate hazard due to collar loss and did not require censoring these records from analysis. We found mean annual survival was 76% and mean annual causes of mortality were illegal killing (9.4%), natural and unknown causes (9.5%), and other human-caused mortality such as hunting, vehicle collisions and lethal control (5.1%). Illegal killing and natural mortality were highest during winter, causing wolf survival to decrease relative to summer. Mortality was highest during early recovery and lowest during a period of sustained population growth. Wolves again experienced higher risk of human-caused mortality relative to natural mortality as wolves expanded into areas with more human activity. We detected partial compensation in human- and natural-caused mortality since 2004 as the population saturated more available habitat. Prior to 2004, we detected additivity in mortality sources. Assessments of wolf survival and cause of mortality rates and the finding of partial compensation in mortality sources will inform wolf conservation and management efforts by identifying sources and sinks, finding areas of conservation need, and assessing management zone delineation.

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics.

PubMed

Liu, Jianfang; Lichtenberg, Tara; Hoadley, Katherine A; Poisson, Laila M; Lazar, Alexander J; Cherniack, Andrew D; Kovatich, Albert J; Benz, Christopher C; Levine, Douglas A; Lee, Adrian V; Omberg, Larsson; Wolf, Denise M; Shriver, Craig D; Thorsson, Vesteinn; Hu, Hai

2018-04-05

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Copyright © 2018 Elsevier Inc. All rights reserved.

When is a soil remediated? Comparison of biopiled and windrowed soils contaminated with bunker-fuel in a full-scale trial.

PubMed

Coulon, Frédéric; Al Awadi, Mohammed; Cowie, William; Mardlin, David; Pollard, Simon; Cunningham, Colin; Risdon, Graeme; Arthur, Paul; Semple, Kirk T; Paton, Graeme I

2010-10-01

A six month field scale study was carried out to compare windrow turning and biopile techniques for the remediation of soil contaminated with bunker C fuel oil. End-point clean-up targets were defined by human risk assessment and ecotoxicological hazard assessment approaches. Replicate windrows and biopiles were amended with either nutrients and inocula, nutrients alone or no amendment. In addition to fractionated hydrocarbon analysis, culturable microbial characterisation and soil ecotoxicological assays were performed. This particular soil, heavy in texture and historically contaminated with bunker fuel was more effectively remediated by windrowing, but coarser textures may be more amendable to biopiling. This trial reveals the benefit of developing risk and hazard based approaches in defining end-point bioremediation of heavy hydrocarbons when engineered biopile or windrow are proposed as treatment option. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Genotoxicity studies in groundwater, surface waters, and contaminated soil.

PubMed

Verschaeve, Luc

2002-05-08

It is at present considered important to include biological tests in measuring programmes of environmental samples to supplement the chemical and physical parameters that are currently used. A battery of tests is therefore necessary, also within a given "endpoint" (e.g., genotoxicity), because one single test will not give all the answers to our questions. As it is not possible to include all available tests in routine screening programmes, a selection of tests should be made. According to comparative investigations, the bacterial Ames test remains very important. When no preconcentration step is involved, other bacterial tests (e.g., the umu-C and VITOTOX tests) may be recommended. The comet assay may be used in Daphnia or human white blood cells. Further validations, comparisons, mechanistic investigations, etc. remain necessary as differences are often found between the tests that are not solely explained by differences in genetic endpoint and that therefore should further be investigated and understood.

Investigation of the effects of magnetic field exposure on human melatonin. Interim report

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

Graham, C.; Cook, M.R.; Cohen, H.D.

Several rodent studies have suggested that magnetic field exposure may alter the daily pattern of melatonin secretion. This study investigated melatonin levels in mean exposed overnight to magnetic fields of 10 mG and 200 mG. The study also assessed the potential effects of exposure on a number of performance and self-reported endpoints in the subjects. Investigation of this area is important, as altered diurnal melatonin cycles have been linked to a variety of endpoints, including reproductive outcome, neurobehavioral function, and carcinogenesis. The results of this investigation did not support the a priori hypothesis that exposure to 60-Hz magnetic fields ofmore » 10 mG and 200 mG alters nighttime melatonin levels in a population of adult males. However, the data suggested the possibility of differential sensitivity to magnetic fields based on an individual`s baseline melatonin level.« less

The Role of Ecological Endpoints in Watershed Management

EPA Science Inventory

Landscape change and pollution in watersheds affect ecological endpoints in receiving water bodies. Therefore, these endpoints are useful in watershed management. Fish and benthic macro invertebrates are often used as endpoints, since they are easily measured in the field and int...

USE OF SCALE INVARIANCE IN EVALUATING JUDGEMENT INDICATORS

EPA Science Inventory

Indicators are used to draw conclusions about ecological endpoints when these endpoints cannot be measured directly. In many cases, inference about an endpoint are only possible because assumptions have been made about the relationship between indicator and endpoint; we refer to ...

21 CFR 314.510 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Approval based on a surrogate endpoint or on an... Serious or Life-Threatening Illnesses § 314.510 Approval based on a surrogate endpoint or on an effect on... the drug product has an effect on a surrogate endpoint that is reasonably likely, based on...

21 CFR 314.510 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Approval based on a surrogate endpoint or on an... Serious or Life-Threatening Illnesses § 314.510 Approval based on a surrogate endpoint or on an effect on... the drug product has an effect on a surrogate endpoint that is reasonably likely, based on...

21 CFR 314.510 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Approval based on a surrogate endpoint or on an... Serious or Life-Threatening Illnesses § 314.510 Approval based on a surrogate endpoint or on an effect on... the drug product has an effect on a surrogate endpoint that is reasonably likely, based on...

21 CFR 314.510 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Approval based on a surrogate endpoint or on an... Serious or Life-Threatening Illnesses § 314.510 Approval based on a surrogate endpoint or on an effect on... the drug product has an effect on a surrogate endpoint that is reasonably likely, based on...

21 CFR 314.510 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity. 314.510 Section 314.510 Food... Serious or Life-Threatening Illnesses § 314.510 Approval based on a surrogate endpoint or on an effect on...

Ultrasound and radiology surrogate endpoints in pharmacological studies.

PubMed

Agewall, S; DeGroot, E; Marcos-Alberca, P; Zamorano, J L; Barrero, A A; Badano, L P; Perrone-Filardi, P

2012-09-01

Cardiovascular studies investigating therapeutic intervention with clinical endpoints are costly due to the need for considerable duration and large number of patients, or both. Therefore, for evaluation of novel cardiovascular drug efficacy, surrogate endpoints are used. Cardiovascular imaging endpoints have proven their worth. Sometimes the relevance of imaging is questioned and other methods are suggested instead. There is also some confusion about the strengths of imaging endpoints. The aim of the present paper is to review ultrasound and radiology imaging techniques as surrogate endpoints in pharmacological trials. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Vedolizumab: a review of its use in adult patients with moderately to severely active ulcerative colitis or Crohn's disease.

PubMed

Garnock-Jones, K P

2015-02-01

Vedolizumab (Entyvio™) is a humanized monoclonal antibody α4β7 integrin-receptor antagonist indicated for the treatment of adult patients with moderately to severely active ulcerative colitis or Crohn's disease. This article reviews the pharmacological properties of intravenous infusions of vedolizumab and its clinical efficacy in adult patients with these diseases. In phase III clinical trials, patients with ulcerative colitis had significantly higher rates of clinical response and clinical remission when treated with vedolizumab than when receiving placebo at both 6 and 52 weeks. However, outcomes with vedolizumab in patients with Crohn's disease were mixed. In a study that evaluated both clinical remission rate and CDAI-100 response rate as primary endpoints, only the clinical remission rate at 6 weeks was significantly higher with vedolizumab than placebo. In another trial, there was no significant between-group difference in the clinical remission rate in TNF-antagonist failure patients at 6 weeks (primary endpoint), although there was a significant difference at 10 weeks. In the Crohn's disease study that included maintenance treatment, vedolizumab was significantly more effective at 52 weeks than placebo in both endpoints (clinical remission was the only primary endpoint in the maintenance study). Vedolizumab was generally well tolerated in these trials. As vedolizumab is a specific α4β7 integrin antagonist, with gut-specific effects, it is unlikely to be associated with the development of progressive multifocal leukoencephalopathy, a risk observed with the less selective α4β7/α4β1 integrin antagonist natalizumab. Vedolizumab is a useful addition to the treatment options available for patients with moderately to severely active ulcerative colitis and Crohn's disease.

Efficacy of spironolactone on survival in dogs with naturally occurring mitral regurgitation caused by myxomatous mitral valve disease.

PubMed

Bernay, F; Bland, J M; Häggström, J; Baduel, L; Combes, B; Lopez, A; Kaltsatos, V

2010-01-01

Spironolactone, an aldosterone antagonist, has been demonstrated to decrease mortality in human patients when added to other cardiac therapies. Spironolactone in addition to conventional therapy increases survival compared with conventional therapy in dogs with naturally occurring myxomatous mitral valve disease (MMVD). Between February 2003 and March 2005, 221 dogs were recruited in Europe. Nine dogs were excluded from analysis, leaving 212 dogs with moderate to severe mitral regurgitation (MR) caused by MMVD (International Small Animal Cardiac Health Council classification classes II [n = 190] and III [n = 21]). Double-blinded, field study conducted with dogs randomized to receive either spironolactone (2 mg/kg once a day) or placebo in addition to conventional therapy (angiotensin converting enzyme inhibitor, plus furosemide and digoxin if needed). Primary endpoint was a composite of cardiac-related death, euthanasia, or severe worsening of MR. Primary endpoint reached by 11/102 dogs (10.8%) in the spironolactone group (6 deaths, 5 worsening) versus 28/110 (25.5%) in control group (14 deaths, 8 euthanasia, 6 worsening). Risk of reaching the composite endpoint significantly decreased by 55% (hazard ratio [HR] = 0.45; 95% confidence limits [CL], 0.22-0.90; log rank test, P = .017). Risk of cardiac-related death or euthanasia significantly reduced by 69% (HR = 0.31; 95% CL, 0.13-0.76; P = .0071). Number of dogs not completing the study for cardiac and other miscellaneous reasons similar in spironolactone (67/102) and control groups (66/110). Spironolactone added to conventional cardiac therapy decreases the risk of reaching the primary endpoint (ie, cardiac-related death, euthanasia, or severe worsening) in dogs with moderate to severe MR caused by MMVD.

A phase III randomized trial of gantenerumab in prodromal Alzheimer's disease.

PubMed

Ostrowitzki, Susanne; Lasser, Robert A; Dorflinger, Ernest; Scheltens, Philip; Barkhof, Frederik; Nikolcheva, Tania; Ashford, Elizabeth; Retout, Sylvie; Hofmann, Carsten; Delmar, Paul; Klein, Gregory; Andjelkovic, Mirjana; Dubois, Bruno; Boada, Mercè; Blennow, Kaj; Santarelli, Luca; Fontoura, Paulo

2017-12-08

Gantenerumab is a fully human monoclonal antibody that binds aggregated amyloid-β (Aβ) and removes Aβ plaques by Fc receptor-mediated phagocytosis. In the SCarlet RoAD trial, we assessed the efficacy and safety of gantenerumab in prodromal Alzheimer's disease (AD). In this randomized, double-blind, placebo-controlled phase III study, we investigated gantenerumab over 2 years. Patients were randomized to gantenerumab 105 mg or 225 mg or placebo every 4 weeks by subcutaneous injection. The primary endpoint was the change from baseline to week 104 in Clinical Dementia Rating Sum of Boxes (CDR-SB) score. We evaluated treatment effects on cerebrospinal fluid biomarkers (all patients) and amyloid positron emission tomography (substudy). A futility analysis was performed once 50% of patients completed 2 years of treatment. Safety was assessed in patients who received at least one dose. Of the 3089 patients screened, 797 were randomized. The study was halted early for futility; dosing was discontinued; and the study was unblinded. No differences between groups in the primary (least squares mean [95% CI] CDR-SB change from baseline 1.60 [1.28, 1.91], 1.69 [1.37, 2.01], and 1.73 [1.42, 2.04] for placebo, gantenerumab 105 mg, and gantenerumab 225 mg, respectively) or secondary clinical endpoints were observed. The incidence of generally asymptomatic amyloid-related imaging abnormalities increased in a dose- and APOE ε4 genotype-dependent manner. Exploratory analyses suggested a dose-dependent drug effect on clinical and biomarker endpoints. The study was stopped early for futility, but dose-dependent effects observed in exploratory analyses on select clinical and biomarker endpoints suggest that higher dosing with gantenerumab may be necessary to achieve clinical efficacy. ClinicalTrials.gov, NCT01224106 . Registered on October 14, 2010.

Surrogate endpoints in randomized cardiovascular clinical trials.

PubMed

Domanski, Michael; Pocock, Stuart; Bernaud, Corine; Borer, Jeffrey; Geller, Nancy; Revkin, James; Zannad, Faiez

2011-08-01

Surrogate endpoints predict the occurrence and timing of a clinical endpoint of interest (CEI). Substitution of a surrogate endpoint for a CEI can dramatically reduce the time and cost necessary to complete a Phase III clinical trial. However, assurance that use of a surrogate endpoint will result in a correct conclusion regarding treatment effect on a CEI requires prior rigorous validation of the surrogate. Surrogate endpoints can also be of substantial use in Phase I and II studies to assess whether the intended therapeutic pathway is operative, thus providing assurance regarding the reasonableness of proceeding to a Phase III trial. This paper discusses the uses and validation of surrogate endpoints. © 2010 The Authors Fundamental and Clinical Pharmacology © 2010 Société Française de Pharmacologie et de Thérapeutique.

Perfluorooctanoic acid (PFOA), an emerging drinking water contaminant: a critical review of recent literature.

PubMed

Post, Gloria B; Cohn, Perry D; Cooper, Keith R

2012-07-01

Perfluorooctanoic acid (PFOA) is an anthropogenic contaminant that differs in several ways from most other well-studied organic chemicals found in drinking water. PFOA is extremely resistant to environmental degradation processes and thus persists indefinitely. Unlike most other persistent and bioaccumulative organic pollutants, PFOA is water-soluble, does not bind well to soil or sediments, and bioaccumulates in serum rather than in fat. It has been detected in finished drinking water and drinking water sources impacted by releases from industrial facilities and waste water treatment plants, as well as in waters with no known point sources. However, the overall occurrence and population exposure from drinking water is not known. PFOA persists in humans with a half-life of several years and is found in the serum of almost all U.S. residents and in populations worldwide. Exposure sources include food, food packaging, consumer products, house dust, and drinking water. Continued exposure to even relatively low concentrations in drinking water can substantially increase total human exposure, with a serum:drinking water ratio of about 100:1. For example, ongoing exposures to drinking water concentrations of 10 ng/L, 40 ng/L, 100 ng/L, or 400 ng/L are expected to increase mean serum levels by about 25%, 100%, 250%, and 1000%, respectively, from the general population background serum level of about 4 ng/mL. Infants are potentially a sensitive subpopulation for PFOA's developmental effects, and their exposure through breast milk from mothers who use contaminated drinking water and/or from formula prepared with contaminated drinking water is higher than in adults exposed to the same drinking water concentration. Numerous health endpoints are associated with human PFOA exposure in the general population, communities with contaminated drinking water, and workers. As is the case for most such epidemiology studies, causality for these effects is not proven. Unlike most other well-studied drinking water contaminants, the human dose-response curve for several effects appears to be steepest at the lower exposure levels, including the general population range, with no apparent threshold for some endpoints. There is concordance in animals and humans for some effects, while humans and animals appear to react differently for other effects such as lipid metabolism. PFOA was classified as "likely to be carcinogenic in humans" by the USEPA Science Advisory Board. In animal studies, developmental effects have been identified as more sensitive endpoints for toxicity than carcinogenicity or the long-established hepatic effects. Notably, exposure to an environmentally relevant drinking water concentration caused adverse effects on mammary gland development in mice. This paper reviews current information relevant to the assessment of PFOA as an emerging drinking water contaminant. This information suggests that continued human exposure to even relatively low concentrations of PFOA in drinking water results in elevated body burdens that may increase the risk of health effects. Copyright © 2012 Elsevier Inc. All rights reserved.

Branched Nerve Allografts to Improve Outcomes in Facial Composite Tissue Transplantation

DTIC Science & Technology

2017-12-01

Ethicon, Inc. Somervile, N.J.). Postoperatively, animals were recovered per standard protocol in the animal care facility.  Experimental Design ...official Department of the Army position, policy or decision unless so designated by other documentation. REPORT DOCUMENTATION PAGE Form Approved OMB No...a human xenograft with or without oral Tacrolimus. Electrophysiologic assessments were performed pre -operatively and at the study endpoint (24 weeks

Dose-Rate Dependence of High-Dose Health Effects in Humans from Photon Radiation with Application to Radiological Terrorism

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

Strom, Daniel J.

2005-01-14

In 1981, as part of a symposium entitled ''The Control of Exposure of the Public to Ionizing Radiation in the Event of Accident or Attack,'' Lushbaugh, H?bner, and Fry published a paper examining ''radiation tolerance'' of various human health endpoints as a function of dose rate. This paper may not have received the notice it warrants. The health endpoints examined by Lushbaugh et al. were the lethal dose that will kill 50% of people within 60 days of exposure without medical care (LD50/60); severe bone marrow damage in healthy men; severe bone marrow damage in leukemia patients; temporary sterility (azoospermia);more » reduced male fertility; and late effects such as cancer. Their analysis was grounded in extensive clinical experience and anchored to a few selected data points, and based on the 1968 dose-rate dependence theory of J.L. Bateman. The Lushbaugh et al. paper did not give predictive equations for the relationships, although they were implied in the text, and the relationships were presented in a non-intuitive way. This work derives the parameters needed in Bateman's equation for each health endpoint, tabulates the results, and plots them in a more conventional manner on logarithmic scales. The results give a quantitative indication of how the human organism can tolerate more radiation dose when it is delivered at lower dose rates. For example, the LD50/60 increases from about 3 grays (300 rads) when given at very high dose rates to over 10 grays (1,000 rads) when given at much lower dose rates over periods of several months. The latter figure is borne out by the case of an individual who survived for at least 19 years after receiving doses in the range of 9 to 17 grays (900-1700 rads) over 106 days. The Lushbaugh et al. work shows the importance of sheltering when confronted with long-term exposure to radiological contamination such as would be expected from a radiological dispersion event, reactor accident, or ground-level nuclear explosion.« less

Useful pharmacodynamic endpoints in children: selection, measurement, and next steps

PubMed Central

Kelly, Lauren E; Sinha, Yashwant; Barker, Charlotte I S; Standing, Joseph F; Offringa, Martin

2018-01-01

Pharmacodynamic (PD) endpoints are essential for establishing the benefit-to-risk ratio for therapeutic interventions in children and neonates. This article discusses the selection of an appropriate measure of response, the PD endpoint, which is a critical methodological step in designing pediatric efficacy and safety studies. We provide an overview of existing guidance on the choice of PD endpoints in pediatric clinical research. We identified several considerations relevant to the selection and measurement of PD endpoints in pediatric clinical trials, including the use of biomarkers, modeling, compliance, scoring systems, and validated measurement tools. To be useful, PD endpoints in children need to be clinically relevant, responsive to both treatment and/or disease progression, reproducible, and reliable. In most pediatric disease areas, this requires significant validation efforts. We propose a minimal set of criteria for useful PD endpoint selection and measurement. We conclude that, given the current heterogeneity of pediatric PD endpoint definitions and measurements, both across and within defined disease areas, there is an acute need for internationally agreed, validated, and condition-specific pediatric PD endpoints that consider the needs of all stakeholders, including healthcare providers, policy makers, patients, and families. PMID:29667952

Improvement in latent variable indirect response joint modeling of a continuous and a categorical clinical endpoint in rheumatoid arthritis.

PubMed

Hu, Chuanpu; Zhou, Honghui

2016-02-01

Improving the quality of exposure-response modeling is important in clinical drug development. The general joint modeling of multiple endpoints is made possible in part by recent progress on the latent variable indirect response (IDR) modeling for ordered categorical endpoints. This manuscript aims to investigate, when modeling a continuous and a categorical clinical endpoint, the level of improvement achievable by joint modeling in the latent variable IDR modeling framework through the sharing of model parameters for the individual endpoints, guided by the appropriate representation of drug and placebo mechanism. This was illustrated with data from two phase III clinical trials of intravenously administered mAb X for the treatment of rheumatoid arthritis, with the 28-joint disease activity score (DAS28) and 20, 50, and 70% improvement in the American College of Rheumatology (ACR20, ACR50, and ACR70) disease severity criteria were used as efficacy endpoints. The joint modeling framework led to a parsimonious final model with reasonable performance, evaluated by visual predictive check. The results showed that, compared with the more common approach of separately modeling the endpoints, it is possible for the joint model to be more parsimonious and yet better describe the individual endpoints. In particular, the joint model may better describe one endpoint through subject-specific random effects that would not have been estimable from data of this endpoint alone.

Equilibrium-Based Movement Endpoints Elicited from Primary Motor Cortex Using Repetitive Microstimulation

PubMed Central

Van Acker, Gustaf M.; Amundsen, Sommer L.; Messamore, William G.; Zhang, Hongyu Y.; Luchies, Carl W.

2014-01-01

High-frequency, long-duration intracortical microstimulation (HFLD-ICMS) is increasingly being used to deduce how the brain encodes coordinated muscle activity and movement. However, the full movement repertoire that can be elicited from the forelimb representation of primary motor cortex (M1) using this method has not been systematically determined. Our goal was to acquire a comprehensive M1 forelimb representational map of movement endpoints elicited with HFLD-ICMS, using stimulus parameters optimal for evoking stable forelimb spatial endpoints. The data reveal a 3D forelimb movement endpoint workspace that is represented in a patchwork fashion on the 2D M1 cortical surface. Although cortical maps of movement endpoints appear quite disorderly with respect to movement space, we show that the endpoint locations in the workspace evoked with HFLD-ICMS of two adjacent cortical points are closer together than would be expected if the organization were random. Although there were few obvious consistencies in the endpoint maps across the two monkeys tested, one notable exception was endpoints bringing the hand to the mouth, which was located at the boundary between the hand and face representation. Endpoints at the extremes of the monkey's workspace and locations above the head were largely absent. Our movement endpoints are best explained as resulting from coactivation of agonist and antagonist muscles driving the joints toward equilibrium positions determined by the length–tension relationships of the muscles. PMID:25411500

Impact of weighted composite compared to traditional composite endpoints for the design of randomized controlled trials.

PubMed

Bakal, Jeffrey A; Westerhout, Cynthia M; Armstrong, Paul W

2015-12-01

Composite endpoints are commonly used in cardiovascular clinical trials. When using a composite endpoint a subject is considered to have an event when the first component endpoint has occurred. The use of composite endpoints offers the ability to incorporate several clinically important endpoint events thereby augmenting the event rate and increasing statistical power for a given sample size. One assumption of the composite is that all component events are of equal clinical importance. This assumption is rarely achieved given the diversity of component endpoints included. One means of adjusting for this diversity is to adjust the outcomes using severity weights determined a priori. The use of a weighted endpoint also allows for the incorporation of multiple endpoints per patient. Although weighting the outcomes lowers the effective number of events, it offers additional information that reduces the variance of the estimate. We created a series of simulation studies to examine the effect on power as the individual components of a typical composite were changed. In one study, we noted that the weighted composite was able to offer discriminative power when the component outcomes were altered, while the traditional method was not. In the other study, we noted that the weighted composite offered a similar level of power to the traditional composite when the change was driven by the more severe endpoints. © The Author(s) 2011.

A Family with Severe Insulin Resistance and Diabetes Mellitus due to a Missense Mutation in AKT2

PubMed Central

George, Stella; Rochford, Justin J.; Wolfrum, Christian; Gray, Sarah L.; Schinner, Sven; Wilson, Jenny C.; Soos, Maria A.; Murgatroyd, Peter R.; Williams, Rachel M.; Acerini, Carlo L.; Dunger, David B.; Barford, David; Umpleby, A. Margot; Wareham, Nicholas J.; Davies, Huw Alban; Schafer, Alan J.; Stoffel, Markus; O’Rahilly, Stephen; Barroso, Ines

2008-01-01

Inherited defects in signaling pathways downstream of the insulin receptor have long been suggested to contribute to human Type 2 diabetes mellitus. Here we describe a mutation in the gene encoding the protein kinase AKT2/PKBβ in a family that shows autosomal dominant inheritance of severe insulin resistance and diabetes mellitus. Expression of the mutant kinase in cultured cells disrupted insulin signaling to metabolic end-points and inhibited the function of co-expressed, wild type AKT. These findings demonstrate the central importance of AKT signaling to insulin sensitivity in humans. PMID:15166380

A rank test for bivariate time-to-event outcomes when one event is a surrogate

PubMed Central

Shaw, Pamela A.; Fay, Michael P.

2016-01-01

In many clinical settings, improving patient survival is of interest but a practical surrogate, such as time to disease progression, is instead used as a clinical trial’s primary endpoint. A time-to-first endpoint (e.g. death or disease progression) is commonly analyzed but may not be adequate to summarize patient outcomes if a subsequent event contains important additional information. We consider a surrogate outcome very generally, as one correlated with the true endpoint of interest. Settings of interest include those where the surrogate indicates a beneficial outcome so that the usual time-to-first endpoint of death or surrogate event is nonsensical. We present a new two-sample test for bivariate, interval-censored time-to-event data, where one endpoint is a surrogate for the second, less frequently observed endpoint of true interest. This test examines whether patient groups have equal clinical severity. If the true endpoint rarely occurs, the proposed test acts like a weighted logrank test on the surrogate; if it occurs for most individuals, then our test acts like a weighted logrank test on the true endpoint. If the surrogate is a useful statistical surrogate, our test can have better power than tests based on the surrogate that naively handle the true endpoint. In settings where the surrogate is not valid (treatment affects the surrogate but not the true endpoint), our test incorporates the information regarding the lack of treatment effect from the observed true endpoints and hence is expected to have a dampened treatment effect compared to tests based on the surrogate alone. PMID:27059817

Evaluation of neural reflex activation as a mode of action for the acute respiratory effects of ozone.

PubMed

Prueitt, Robyn L; Goodman, Julie E

2016-09-01

Exposure to elevated levels of ozone has been associated with a variety of respiratory-related health endpoints in both epidemiology and controlled human exposure studies, including lung function decrements and airway inflammation. A mode of action (MoA) for these effects has not been established, but it has been proposed that they may occur through ozone-induced activation of neural reflexes. We critically reviewed experimental studies of ozone exposure and neural reflex activation and applied the International Programme on Chemical Safety (IPCS) mode-of-action/human relevance framework to evaluate the biological plausibility and human relevance of this proposed MoA. Based on the currently available experimental data, we found that the proposed MoA of neural reflex activation is biologically plausible for the endpoint of ozone-induced lung function decrements at high ozone exposures, but further studies are needed to fill important data gaps regarding the relevance of this MoA at lower exposures. A role for the proposed MoA in ozone-induced airway inflammation is less plausible, as the evidence is conflicting and is also of unclear relevance given the lack of studies conducted at lower exposures. The evidence suggests a different MoA for ozone-induced inflammation that may still be linked to the key events in the proposed MoA, such that neural reflex activation may have some degree of involvement in modulating ozone-induced neutrophil influx, even if it is not a direct role.

Efficacy and safety of subcutaneous tabalumab, a monoclonal antibody to B-cell activating factor, in patients with systemic lupus erythematosus: results from ILLUMINATE-2, a 52-week, phase III, multicentre, randomised, double-blind, placebo-controlled study.

PubMed

Merrill, J T; van Vollenhoven, R F; Buyon, J P; Furie, R A; Stohl, W; Morgan-Cox, M; Dickson, C; Anderson, P W; Lee, C; Berclaz, P-Y; Dörner, T

2016-02-01

To evaluate the efficacy and safety of tabalumab, a human IgG4 monoclonal antibody that neutralises membrane and soluble B-cell activating factor (BAFF). This randomised, placebo-controlled study enrolled 1124 patients with moderate-to-severe systemic lupus erythematosus (SLE) (Safety of Estrogens in Lupus Erythematosus National Assessment- SLE Disease Activity Index ≥6 at baseline). Patients received standard of care plus subcutaneous study drug, starting with a loading dose (240 mg) at week 0 and followed by 120 mg every 2 weeks (120 Q2W), 120 mg every 4 weeks (120 Q4W) or placebo. Primary endpoint was proportion achieving SLE Responder Index 5 (SRI-5) improvement at week 52. Clinical characteristics were balanced across groups. The primary endpoint was met with 120 Q2W (38.4% vs 27.7%, placebo; p=0.002), but not with the less frequent 120 Q4W regimen (34.8%, p=0.051). Although key secondary endpoints (time to severe flare, corticosteroid sparing and fatigue) were not met, patients treated with tabalumab had greater SRI-5 response rates in a serologically active subset and improvements in more stringent SRI cut-offs, SELENA-SLEDAI, Physician's Global Assessment, anti-double-stranded DNA antibodies, complement, total B cells and immunoglobulins. The incidences of deaths, serious adverse events (AEs), and treatment-emergent AEs were similar in the 120 Q2W, 120 Q4W and placebo groups, but depression and suicidal ideation, albeit rare events, were more commonly reported with tabalumab. SRI-5 was met with 120 Q2W and although key secondary endpoints were not met, numerous other secondary endpoints significantly improved in addition to pharmacodynamic evidence of BAFF pathway blockade. The safety profile for tabalumab was similar to placebo, except for depression and suicidality, which were uncommon. NCT01205438. 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/

Development of a loop-mediated isothermal amplification (LAMP) assay for rapid screening of ticks and fleas for spotted fever group rickettsia

PubMed Central

Martin, Jaclyn; Carrillo, Yisel; Talley, Justin L.; Ochoa-Corona, Francisco M.

2018-01-01

Background The importance of tick and flea-borne rickettsia infections is increasingly recognized worldwide. While increased focus has shifted in recent years to the development of point-of-care diagnostics for various vector-borne diseases in humans and animals, little research effort has been devoted to their integration into vector surveillance and control programs, particularly in resource-challenged countries. One technology which may be helpful for large scale vector surveillance initiatives is loop-mediated isothermal amplification (LAMP). The aim of this study was to develop a LAMP assay to detect spotted fever group (SFG) rickettsia DNA from field-collected ticks and fleas and compare with published end-point PCR results. Methodology/Principal findings A Spotted Fever Group rickettsia-specific loop-mediated isothermal amplification (SFGR-LAMP) assay was developed using primers based on a region of the R. rickettsii 17kDa protein gene. The sensitivity, specificity, and reproducibility of the assay were evaluated. The assay was then compared with the results of end-point PCR assays for pooled tick and flea samples obtained from field-based surveillance studies. The sensitivity of the SFGR-LAMP assay was 0.00001 ng/μl (25μl volume) which was 10 times more sensitive than the 17kDa protein gene end-point PCR used as the reference method. The assay only recognized gDNA from SFG and transitional group (TRG) rickettsia species tested but did not detect gDNA from typhus group (TG) rickettsia species or closely or distantly related bacterial species. The SFGR-LAMP assay detected the same positives from a set of pooled tick and flea samples detected by end-point PCR in addition to two pooled flea samples not detected by end-point PCR. Conclusions/significance To our knowledge, this is the first study to develop a functional LAMP assay to initially screen for SFG and TRG rickettsia pathogens in field-collected ticks and fleas. With a high sensitivity and specificity, the results indicate the potential use as a field-based surveillance tool for tick and flea-borne rickettsial pathogens in resource-challenged countries. PMID:29390021

Development of a loop-mediated isothermal amplification (LAMP) assay for rapid screening of ticks and fleas for spotted fever group rickettsia.

PubMed

Noden, Bruce H; Martin, Jaclyn; Carrillo, Yisel; Talley, Justin L; Ochoa-Corona, Francisco M

2018-01-01

The importance of tick and flea-borne rickettsia infections is increasingly recognized worldwide. While increased focus has shifted in recent years to the development of point-of-care diagnostics for various vector-borne diseases in humans and animals, little research effort has been devoted to their integration into vector surveillance and control programs, particularly in resource-challenged countries. One technology which may be helpful for large scale vector surveillance initiatives is loop-mediated isothermal amplification (LAMP). The aim of this study was to develop a LAMP assay to detect spotted fever group (SFG) rickettsia DNA from field-collected ticks and fleas and compare with published end-point PCR results. A Spotted Fever Group rickettsia-specific loop-mediated isothermal amplification (SFGR-LAMP) assay was developed using primers based on a region of the R. rickettsii 17kDa protein gene. The sensitivity, specificity, and reproducibility of the assay were evaluated. The assay was then compared with the results of end-point PCR assays for pooled tick and flea samples obtained from field-based surveillance studies. The sensitivity of the SFGR-LAMP assay was 0.00001 ng/μl (25μl volume) which was 10 times more sensitive than the 17kDa protein gene end-point PCR used as the reference method. The assay only recognized gDNA from SFG and transitional group (TRG) rickettsia species tested but did not detect gDNA from typhus group (TG) rickettsia species or closely or distantly related bacterial species. The SFGR-LAMP assay detected the same positives from a set of pooled tick and flea samples detected by end-point PCR in addition to two pooled flea samples not detected by end-point PCR. To our knowledge, this is the first study to develop a functional LAMP assay to initially screen for SFG and TRG rickettsia pathogens in field-collected ticks and fleas. With a high sensitivity and specificity, the results indicate the potential use as a field-based surveillance tool for tick and flea-borne rickettsial pathogens in resource-challenged countries.

[Immunological surrogate endpoints to evaluate vaccine efficacy].

PubMed

Jin, Pengfei; Li, Jingxin; Zhou, Yang; Zhu, Fengcai

2015-12-01

An immunological surrogate endpoints is a vaccine-induced immune response (either humoral or cellular immune) that predicts protection against clinical endpoints (infection or disease), and can be used to evaluate vaccine efficacy in clinical vaccine trials. Compared with field efficacy trials observing clinical endpoints, immunological vaccine trials could reduce the sample size or shorten the duration of a trial, which promote the license and development of new candidate vaccines. For these reasons, establishing immunological surrogate endpoints is one of 14 Grand Challenges of Global Health of the National Institutes of Health (NIH) and the Bill and Melinda Gates Foundation. From two parts of definition and statistical methods for evaluation of surrogate endpoints, this review provides a more comprehensive description.

Data communications in a parallel active messaging interface of a parallel computer

DOEpatents

Archer, Charles J; Blocksome, Michael A; Ratterman, Joseph D; Smith, Brian E

2014-02-11

Data communications in a parallel active messaging interface ('PAMI') or a parallel computer, the parallel computer including a plurality of compute nodes that execute a parallel application, the PAMI composed of data communications endpoints, each endpoint including a specification of data communications parameters for a thread of execution of a compute node, including specification of a client, a context, and a task, the compute nodes and the endpoints coupled for data communications instruction, the instruction characterized by instruction type, the instruction specifying a transmission of transfer data from the origin endpoint to a target endpoint and transmitting, in accordance witht the instruction type, the transfer data from the origin endpoin to the target endpoint.

Health-related quality-of-life as co-primary endpoint in randomized clinical trials in oncology.

PubMed

Fiteni, Frédéric; Pam, Alhousseiny; Anota, Amélie; Vernerey, Dewi; Paget-Bailly, Sophie; Westeel, Virginie; Bonnetain, Franck

2015-01-01

Overall survival (OS) has been considered as the most relevant primary endpoint but trials using OS often require large numbers of patients and long-term follow-up. Therefore composite endpoints, which are assessed earlier, are frequently used as primary endpoint but suffer from important limitations specially a lack of validation as surrogate of OS. Therefore, Health-related quality of life (HRQoL) could be considered as an outcome to judge efficacy of a treatment. An alternative approach would be to combine HRQoL with composite endpoints as co-primary endpoint to ensure a clinical benefit for patients of a new therapy. The decision rules of such design, the procedure to control the Type I error and the determination of sample size remain questions to debate. Here, we discusses HRQoL as co-primary endpoints in randomized clinical trials in oncology and provide some solutions to promote such design.

Biomarkers and surrogate endpoints in clinical trials.

PubMed

Fleming, Thomas R; Powers, John H

2012-11-10

One of the most important considerations in designing clinical trials is the choice of outcome measures. These outcome measures could be clinically meaningful endpoints that are direct measures of how patients feel, function, and survive. Alternatively, indirect measures, such as biomarkers that include physical signs of disease, laboratory measures, and radiological tests, often are considered as replacement endpoints or 'surrogates' for clinically meaningful endpoints. We discuss the definitions of clinically meaningful endpoints and surrogate endpoints, and provide examples from recent clinical trials. We provide insight into why indirect measures such as biomarkers may fail to provide reliable evidence about the benefit-to-risk profile of interventions. We also discuss the nature of evidence that is important in assessing whether treatment effects on a biomarker reliably predict effects on a clinically meaningful endpoint, and provide insights into why this reliability is specific to the context of use of the biomarker. Copyright © 2012 John Wiley & Sons, Ltd.

Biomarkers and Surrogate Endpoints In Clinical Trials

PubMed Central

Fleming, Thomas R.; Powers, John H

2012-01-01

One of the most important considerations in designing clinical trials is the choice of outcome measures. These outcome measures could be clinically meaningful endpoints that are direct measures of how patients feel, function and survive. Alternatively, indirect measures, such as biomarkers that include physical signs of disease, laboratory measures and radiological tests, often are considered as replacement endpoints or “surrogates” for clinically meaningful endpoints. We discuss the definitions of clinically meaningful endpoints and surrogate endpoints, and provide examples from recent clinical trials. We provide insight into why indirect measures such as biomarkers may fail to provide reliable evidence about the benefit-to-risk profile of interventions. We also discuss the nature of evidence that is important in assessing whether treatment effects on a biomarker reliably predict effects on a clinically meaningful endpoint, and provide insights into why this reliability is specific to the context of use of the biomarker. . PMID:22711298

Endpoint-based parallel data processing with non-blocking collective instructions in a parallel active messaging interface of a parallel computer

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

Archer, Charles J; Blocksome, Michael A; Cernohous, Bob R

Endpoint-based parallel data processing with non-blocking collective instructions in a PAMI of a parallel computer is disclosed. The PAMI is composed of data communications endpoints, each including a specification of data communications parameters for a thread of execution on a compute node, including specifications of a client, a context, and a task. The compute nodes are coupled for data communications through the PAMI. The parallel application establishes a data communications geometry specifying a set of endpoints that are used in collective operations of the PAMI by associating with the geometry a list of collective algorithms valid for use with themore » endpoints of the geometry; registering in each endpoint in the geometry a dispatch callback function for a collective operation; and executing without blocking, through a single one of the endpoints in the geometry, an instruction for the collective operation.« less

Utilization of optical emission endpoint in photomask dry etch processing

NASA Astrophysics Data System (ADS)

Faure, Thomas B.; Huynh, Cuc; Lercel, Michael J.; Smith, Adam; Wagner, Thomas

2002-03-01

Use of accurate and repeatable endpoint detection during dry etch processing of photomask is very important for obtaining good mask mean-to-target and CD uniformity performance. It was found that the typical laser reflectivity endpoint detecting system used on photomask dry etch systems had several key limitations that caused unnecessary scrap and non-optimum image size performance. Consequently, work to develop and implement use of a more robust optical emission endpoint detection system for chrome dry etch processing of photomask was performed. Initial feasibility studies showed that the emission technique was sensitive enough to monitor pattern loadings on contact and via level masks down to 3 percent pattern coverage. Additional work was performed to further improve this to 1 percent pattern coverage by optimizing the endpoint detection parameters. Comparison studies of mask mean-to-target performance and CD uniformity were performed with the use of optical emission endpoint versus laser endpoint for masks built using TOK IP3600 and ZEP 7000 resist systems. It was found that an improvement in mean-to-target performance and CD uniformity was realized on several types of production masks. In addition, part-to-part endpoint time repeatability was found to be significantly improved with the use of optical emission endpoint.

[Structural endpoints for glaucoma studies].

PubMed

Popa-Cherechenau, A; Schmidl, D; Garhöfer, G; Schmetterer, L

2018-03-06

Structural endpoints have been discussed as surrogate endpoints for the approval of neuroprotective drugs in glaucoma. Is the evidence strong enough to establish structural endpoints as surrogate endpoints? Review of current understanding between structure and function in glaucoma. The introduction of optical coherence tomography has revolutionized imaging in glaucoma patients. Clinically either the nerve fiber layer thickness can be measured along a circle centered in the optic nerve head or the ganglion cell layer thickness can be assessed in the macular region, the latter being quantified in combination with other inner retinal layers. On a microscopic level there is a strong correlation between structural and functional loss but this relation can only partially be described with currently available clinical methods. This is particularly true for longitudinal course of the disease in glaucoma patients. Novel imaging techniques that are not yet used clinically may have the potential to increase our understanding between structure and function in glaucoma but further research in this field is required. The current evidence does not allow the establishment of structural endpoints as surrogate endpoints for phase 3 studies in glaucoma. Neuroprotective drugs have to be approved on the basis of visual field data because this is the patient-relevant endpoint. Structural endpoints can, however, play an important role in phase 2 and proof of concept studies.

Equilibrium-based movement endpoints elicited from primary motor cortex using repetitive microstimulation.

PubMed

Van Acker, Gustaf M; Amundsen, Sommer L; Messamore, William G; Zhang, Hongyu Y; Luchies, Carl W; Cheney, Paul D

2014-11-19

High-frequency, long-duration intracortical microstimulation (HFLD-ICMS) is increasingly being used to deduce how the brain encodes coordinated muscle activity and movement. However, the full movement repertoire that can be elicited from the forelimb representation of primary motor cortex (M1) using this method has not been systematically determined. Our goal was to acquire a comprehensive M1 forelimb representational map of movement endpoints elicited with HFLD-ICMS, using stimulus parameters optimal for evoking stable forelimb spatial endpoints. The data reveal a 3D forelimb movement endpoint workspace that is represented in a patchwork fashion on the 2D M1 cortical surface. Although cortical maps of movement endpoints appear quite disorderly with respect to movement space, we show that the endpoint locations in the workspace evoked with HFLD-ICMS of two adjacent cortical points are closer together than would be expected if the organization were random. Although there were few obvious consistencies in the endpoint maps across the two monkeys tested, one notable exception was endpoints bringing the hand to the mouth, which was located at the boundary between the hand and face representation. Endpoints at the extremes of the monkey's workspace and locations above the head were largely absent. Our movement endpoints are best explained as resulting from coactivation of agonist and antagonist muscles driving the joints toward equilibrium positions determined by the length-tension relationships of the muscles. Copyright © 2014 the authors 0270-6474/14/3415722-13$15.00/0.

Considerations in choosing a primary endpoint that measures durability of virological suppression in an antiretroviral trial.

PubMed

Gilbert, P B; Ribaudo, H J; Greenberg, L; Yu, G; Bosch, R J; Tierney, C; Kuritzkes, D R

2000-09-08

At present, many clinical trials of anti-HIV-1 therapies compare treatments by a primary endpoint that measures the durability of suppression of HIV-1 replication. Several durability endpoints are compared. Endpoints are compared by their implicit assumptions regarding surrogacy for clinical outcomes, sample size requirements, and accommodations for inter-patient differences in baseline plasma HIV-1-RNA levels and in initial treatment response. Virological failure is defined by the non-suppression of virus levels at a prespecified follow-up time T(early virological failure), or by relapse. A binary virological failure endpoint is compared with three time-to-virological failure endpoints: time from (i) randomization that assigns early failures a failure time of T weeks; (ii) randomization that extends the early failure time T for slowly responding subjects; and (iii) virological response that assigns non-responders a failure time of 0 weeks. Endpoint differences are illustrated with Agouron's trial 511. In comparing high with low-dose nelfinavir (NFV) regimens in Agouron 511, the difference in Kaplan-Meier estimates of the proportion not failing by 24 weeks is 16.7% (P = 0.048), 6.5% (P = 0.29) and 22.9% (P = 0.0030) for endpoints (i), (ii) and (iii), respectively. The results differ because NFV suppresses virus more quickly at the higher dose, and the endpoints weigh this treatment difference differently. This illustrates that careful consideration needs to be given to choosing a primary endpoint that will detect treatment differences of interest. A time from randomization endpoint is usually recommended because of its advantages in flexibility and sample size, especially at interim analyses, and for its interpretation for patient management.

The relevance of dietary sodium in hemodialysis

PubMed Central

Mc Causland, Finnian R.; Waikar, Sushrut S.; Brunelli, Steven M.

2013-01-01

Since the earliest days of hemodialysis, dietary sodium restriction has been recommended as a therapeutic means to mitigate problems of extracellular volume overload, hypertension and inter-dialytic weight gain. Recently, there has been a proliferation of human subjects' research examining the potential effects of dietary sodium curtailment. Herein we examine the available evidence with respect to the effects of dietary sodium restriction on clinically relevant endpoints among hemodialysis patients. PMID:23129821

The Endpoint Hypothesis: A Topological-Cognitive Assessment of Geographic Scale Movement Patterns

NASA Astrophysics Data System (ADS)

Klippel, Alexander; Li, Rui

Movement patterns of individual entities at the geographic scale are becoming a prominent research focus in spatial sciences. One pertinent question is how cognitive and formal characterizations of movement patterns relate. In other words, are (mostly qualitative) formal characterizations cognitively adequate? This article experimentally evaluates movement patterns that can be characterized as paths through a conceptual neighborhood graph, that is, two extended spatial entities changing their topological relationship gradually. The central questions addressed are: (a) Do humans naturally use topology to create cognitive equivalent classes, that is, is topology the basis for categorizing movement patterns spatially? (b) Are ‘all’ topological relations equally salient, and (c) does language influence categorization. The first two questions are addressed using a modification of the endpoint hypothesis stating that: movement patterns are distinguished by the topological relation they end in. The third question addresses whether language has an influence on the classification of movement patterns, that is, whether there is a difference between linguistic and non-linguistic category construction. In contrast to our previous findings we were able to document the importance of topology for conceptualizing movement patterns but also reveal differences in the cognitive saliency of topological relations. The latter aspect calls for a weighted conceptual neighborhood graph to cognitively adequately model human conceptualization processes.

Bioanalytical evidence that chemicals in tattoo ink can induce adaptive stress responses.

PubMed

Neale, Peta A; Stalter, Daniel; Tang, Janet Y M; Escher, Beate I

2015-10-15

Tattooing is becoming increasingly popular, particularly amongst young people. However, tattoo inks contain a complex mixture of chemical impurities that may pose a long-term risk for human health. As a first step towards the risk assessment of these complex mixtures we propose to assess the toxicological hazard potential of tattoo ink chemicals with cell-based bioassays. Targeted modes of toxic action and cellular endpoints included cytotoxicity, genotoxicity and adaptive stress response pathways. The studied tattoo inks, which were extracted with hexane as a proxy for the bioavailable fraction, caused effects in all bioassays, with the red and yellow tattoo inks having the greatest response, particularly inducing genotoxicity and oxidative stress response endpoints. Chemical analysis revealed the presence of polycyclic aromatic hydrocarbons in the tested black tattoo ink at concentrations twice the recommended level. The detected polycyclic aromatic hydrocarbons only explained 0.06% of the oxidative stress response of the black tattoo ink, thus the majority of the effect was caused by unidentified components. The study indicates that currently available tattoo inks contain components that induce adaptive stress response pathways, but to evaluate the risk to human health further work is required to understand the toxicokinetics of tattoo ink chemicals in the body. Copyright © 2015 Elsevier B.V. All rights reserved.

It's All Relative: A Validation of Radiation Quality Comparison Metrics

NASA Technical Reports Server (NTRS)

Chappell, Lori J.; Milder, Caitlin M.; Elgart, S. Robin; Semones, Edward J.

2017-01-01

The difference between high-LET and low-LET radiation is quantified by a measure called relative biological effectiveness (RBE). RBE is defined as the ratio of the dose of a reference radiation to that of a test radiation to achieve the same effect level, and thus, is described either as an iso-effector dose-to-dose ratio. A single dose point is not sufficient to calculate an RBE value; therefore, studies with only one dose point usually calculate an effect-to-effect ratio. While not formally used in radiation protection, these iso-dose values may still be informative. Shuryak, et al 2017 investigated the use of an iso-dose metric termed "radiation effects ratio" (RER) and used both RBE and RER to estimate high-LET risks. To apply RBE or RER to risk prediction, the selected metric must be uniquely defined. That is, the calculated value must be consistent within a model given a constant set of constraints and assumptions, regardless of how effects are defined using statistical transformations from raw endpoint data. We first test the RBE and the RER to determine whether they are uniquely defined using transformations applied to raw data. Then, we test whether both metrics can predict heavy ion response data after simulated effect size scaling between human populations or when converting animal to human endpoints.

Targeted Metabolomics Identifies Pharmacodynamic Biomarkers for BIO 300 Mitigation of Radiation-Induced Lung Injury.

PubMed

Jones, Jace W; Jackson, Isabel L; Vujaskovic, Zeljko; Kaytor, Michael D; Kane, Maureen A

2017-12-01

Biomarkers serve a number of purposes during drug development including defining the natural history of injury/disease, serving as a secondary endpoint or trigger for intervention, and/or aiding in the selection of an effective dose in humans. BIO 300 is a patent-protected pharmaceutical formulation of nanoparticles of synthetic genistein being developed by Humanetics Corporation. The primary goal of this metabolomic discovery experiment was to identify biomarkers that correlate with radiation-induced lung injury and BIO 300 efficacy for mitigating tissue damage based upon the primary endpoint of survival. High-throughput targeted metabolomics of lung tissue from male C57L/J mice exposed to 12.5 Gy whole thorax lung irradiation, treated daily with 400 mg/kg BIO 300 for either 2 weeks or 6 weeks starting 24 h post radiation exposure, were assayed at 180 d post-radiation to identify potential biomarkers. A panel of lung metabolites that are responsive to radiation and able to distinguish an efficacious treatment schedule of BIO 300 from a non-efficacious treatment schedule in terms of 180 d survival were identified. These metabolites represent potential biomarkers that could be further validated for use in drug development of BIO 300 and in the translation of dose from animal to human.

Cognitive Invariants of Geographic Event Conceptualization: What Matters and What Refines?

NASA Astrophysics Data System (ADS)

Klippel, Alexander; Li, Rui; Hardisty, Frank; Weaver, Chris

Behavioral experiments addressing the conceptualization of geographic events are few and far between. Our research seeks to address this deficiency by developing an experimental framework on the conceptualization of movement patterns. In this paper, we report on a critical experiment that is designed to shed light on the question of cognitively salient invariants in such conceptualization. Invariants have been identified as being critical to human information processing, particularly for the processing of dynamic information. In our experiment, we systematically address cognitive invariants of one class of geographic events: single entity movement patterns. To this end, we designed 72 animated icons that depict the movement patterns of hurricanes around two invariants: size difference and topological equivalence class movement patterns endpoints. While the endpoint hypothesis, put forth by Regier (2007), claims a particular focus of human cognition to ending relations of events, other research suggests that simplicity principles guide categorization and, additionally, that static information is easier to process than dynamic information. Our experiments show a clear picture: Size matters. Nonetheless, we also find categorization behaviors consistent with experiments in both the spatial and temporal domain, namely that topology refines these behaviors and that topological equivalence classes are categorized consistently. These results are critical steppingstones in validating spatial formalism from a cognitive perspective and cognitively grounding work on ontologies.

Tafenoquine is not neurotoxic following supertherapeutic dosing in rats.

PubMed

Dow, Geoffrey S; Brown, Tracey; Reid, Mark; Smith, Bryan; Toovey, Stephen

Tafenoquine is a new drug for malaria prevention. The goal of the present work was to conduct a specific neurobehavioral study in rats with histopathological assessment of the brain. The clinical, hematological, behavioral, motor activity, and neurohistopathologic changes induced by different dose levels of tafenoquine were evaluated following single super-therapeutic dose administration. Toxicokinetic data were generated to allow extrapolation to clinical exposures. At the highest dose (500 mg/kg), two animals (of 12) died. Surviving animals showed clinical signs of toxicity and had reduced body weight 7-8 days after dosing. Decreases in motor activity were observed on more than one occasion at doses > 9-fold higher than the clinical exposure. No statistically significant changes were observed for other behavioral endpoints. No neurohistopathological changes were noted. Changes in hematological and clinical pathology endpoints were observed at the lowest dose level (125 mg/kg). For context, the human dosing regimen is a 10 mg/kg load followed by 3.3 mg/kg weekly (in a 60 kg person). As in humans, adverse events other than neurotoxicity were dose-limiting for tafenoquine in rats. This raises the prospect that a new weekly prophylactic, without neurologic liability, may become available in the near future. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Human adipose stem cell and ASC-derived cardiac progenitor cellular therapy improves outcomes in a murine model of myocardial infarction

PubMed Central

Davy, Philip MC; Lye, Kevin D; Mathews, Juanita; Owens, Jesse B; Chow, Alice Y; Wong, Livingston; Moisyadi, Stefan; Allsopp, Richard C

2015-01-01

Background Adipose tissue is an abundant and potent source of adult stem cells for transplant therapy. In this study, we present our findings on the potential application of adipose-derived stem cells (ASCs) as well as induced cardiac-like progenitors (iCPs) derived from ASCs for the treatment of myocardial infarction. Methods and results Human bone marrow (BM)-derived stem cells, ASCs, and iCPs generated from ASCs using three defined cardiac lineage transcription factors were assessed in an immune-compromised mouse myocardial infarction model. Analysis of iCP prior to transplant confirmed changes in gene and protein expression consistent with a cardiac phenotype. Endpoint analysis was performed 1 month posttransplant. Significantly increased endpoint fractional shortening, as well as reduction in the infarct area at risk, was observed in recipients of iCPs as compared to the other recipient cohorts. Both recipients of iCPs and ASCs presented higher myocardial capillary densities than either recipients of BM-derived stem cells or the control cohort. Furthermore, mice receiving iCPs had a significantly higher cardiac retention of transplanted cells than all other groups. Conclusion Overall, iCPs generated from ASCs outperform BM-derived stem cells and ASCs in facilitating recovery from induced myocardial infarction in mice. PMID:26604802

Ultrasensitive detection in optically dense physiological media: applications to fast reliable biological assays

NASA Astrophysics Data System (ADS)

Matveeva, Evgenia G.; Gryczynski, Ignacy; Berndt, Klaus W.; Lakowicz, Joseph R.; Goldys, Ewa; Gryczynski, Zygmunt

2006-02-01

We present a novel approach for performing fluorescence immunoassay in serum and whole blood using fluorescently labeled anti-rabbit IgG. This approach, which is based on Surface Plasmon-Coupled Emission (SPCE), provides increased sensitivity and substantial background reduction due to exclusive selection of the signal from the fluorophores located near a bio-affinity surface. Effective coupling range for SPCE is only couple of hundred nanometers from the metallic surface. Excited fluorophores outside the coupling layer do not contribute to SPCE, and their free-space emission is not transmitted through the opaque metallic film into the glass substrate. An antigen (rabbit IgG) was adsorbed to a slide covered with a thin silver metal layer, and the SPCE signal from the fluorophore-labeled anti-rabbit antibody, binding to the immobilized antigen, was detected. The effect of the sample matrix (buffer, human serum, or human whole blood) on the end-point immunoassay SPCE signal is discussed. The kinetics of binding could be monitored directly in whole blood or serum. The results showed that human serum and human whole blood attenuate the SPCE end-point signal and the immunoassay kinetic signal only approximately 2- and 3-fold, respectively (compared to buffer), resulting in signals that are easily detectable even in whole blood. The high optical absorption of the hemoglobin can be tolerated because only fluorophores within a couple of hundred nanometers from the metallic film contribute to SPCE. Both glass and plastic slides can be used for SPCE-based assays. We believe that SPCE has the potential of becoming a powerful approach for performing immunoassays based on surface-bound analytes or antibodies for many biomarkers directly in dense samples such as whole blood, without any need for washing steps.

Toward a multi-country monitoring system of reproductive health in the context of endocrine disrupting chemical exposure.

PubMed

Le Moal, Joëlle; Sharpe, Richard M; Jϕrgensen, Niels; Levine, Hagai; Jurewicz, Joanna; Mendiola, Jaime; Swan, Shanna H; Virtanen, Helena; Christin-Maître, Sophie; Cordier, Sylvaine; Toppari, Jorma; Hanke, Wojciech

2016-02-01

Worrying trends regarding human reproductive endpoints (e.g. semen quality, reproductive cancers) have been reported and there is growing circumstantial evidence for a possible causal link between these trends and exposure to endocrine disrupting chemicals (EDCs). However, there is a striking lack of human data to fill the current knowledge gaps. To answer the crucial questions raised on human reproductive health, there is an urgent need for a reproductive surveillance system to be shared across countries. A multidisciplinary network named HUman Reproductive health and Global ENvironment Network (HURGENT) was created aiming at designing a European monitoring system for reproductive health indicators. Collaborative work allowed setting up the available knowledge to design such a system. Furthermore we conducted an overview of 23 potential indicators, based upon a weight of evidence (WoE) approach according to their potential relation with EDC exposure. The framework and purposes of the surveillance system are settled as well as the approach to select suitable reproductive indicators. The indicators found with the highest scores according to the WoE approach are prostate and breast cancer incidence, sex ratio, endometriosis and uterine fibroid incidence, indicators related to the testicular dysgenesis syndrome, precocious puberty incidence and reproductive hormone levels. Not only sentinel health endpoints, but also diseases with high burdens in public health are highlighted as prior indicators in the context of EDC exposure. Our work can serve as a basis to construct, as soon as possible, the first multi-country reproductive monitoring system. © The Author 2015. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.

A Unified Probabilistic Framework for Dose-Response Assessment of Human Health Effects.

PubMed

Chiu, Weihsueh A; Slob, Wout

2015-12-01

When chemical health hazards have been identified, probabilistic dose-response assessment ("hazard characterization") quantifies uncertainty and/or variability in toxicity as a function of human exposure. Existing probabilistic approaches differ for different types of endpoints or modes-of-action, lacking a unifying framework. We developed a unified framework for probabilistic dose-response assessment. We established a framework based on four principles: a) individual and population dose responses are distinct; b) dose-response relationships for all (including quantal) endpoints can be recast as relating to an underlying continuous measure of response at the individual level; c) for effects relevant to humans, "effect metrics" can be specified to define "toxicologically equivalent" sizes for this underlying individual response; and d) dose-response assessment requires making adjustments and accounting for uncertainty and variability. We then derived a step-by-step probabilistic approach for dose-response assessment of animal toxicology data similar to how nonprobabilistic reference doses are derived, illustrating the approach with example non-cancer and cancer datasets. Probabilistically derived exposure limits are based on estimating a "target human dose" (HDMI), which requires risk management-informed choices for the magnitude (M) of individual effect being protected against, the remaining incidence (I) of individuals with effects ≥ M in the population, and the percent confidence. In the example datasets, probabilistically derived 90% confidence intervals for HDMI values span a 40- to 60-fold range, where I = 1% of the population experiences ≥ M = 1%-10% effect sizes. Although some implementation challenges remain, this unified probabilistic framework can provide substantially more complete and transparent characterization of chemical hazards and support better-informed risk management decisions.

IsomiR expression profiles in human lymphoblastoid cell lines exhibit population and gender dependencies

PubMed Central

Loher, Phillipe; Londin, Eric R.; Rigoutsos, Isidore

2014-01-01

For many years it was believed that each mature microRNA (miRNA) existed as a single entity with fixed endpoints and a ‘static’ and unchangeable primary sequence. However, recent evidence suggests that mature miRNAs are more ‘dynamic’ and that each miRNA precursor arm gives rise to multiple isoforms, the isomiRs. Here we report on our identification of numerous and abundant isomiRs in the lymphoblastoid cell lines (LCLs) of 452 men and women from five different population groups. Unexpectedly, we find that these isomiRs exhibit an expression profile that is population-dependent and gender-dependent. This is important as it indicates that the LCLs of each gender/population combination have their own unique collection of mature miRNA transcripts. Moreover, each identified isomiR has its own characteristic abundance that remains consistent across biological replicates indicating that these are not degradation products. The primary sequences of identified isomiRs differ from the known miRBase miRNA either at their 5´-endpoint (leads to a different ‘seed’ sequence and suggests a different targetome), their 3´-endpoint, or both simultaneously. Our analysis of Argonaute PAR-CLIP data from LCLs supports the association of many of these newly identified isomiRs with the Argonaute silencing complex and thus their functional roles through participation in the RNA interference pathway. PMID:25229428

Letrozole combined with low dose highly purified HMG for ovulation induction in clomiphene citrate-resistant infertile Chinese women with polycystic ovary syndrome: a prospective study.

PubMed

Zhao, Yue; Ruan, Xiangyan; Mueck, Alfred O

2017-06-01

There are still open questions about ovulation induction in clomiphene citrate-(CC)-resistant infertile women. Especially little is known about efficacy and safety of letrozole (LTZ) combined with low-dose highly purified human menopausal gonadotropin (Hp-HMG) in women with polycystic ovary syndrome (PCOS). Prospective, single-arm single-center trial in 200 infertile PCOS patients refractory for at least three CC-treatment cycles. Women with hyperandrogenism took Diane-35 for at least 3 months. All patients got LTZ on day 3 for 5 d in combination with Hp-HMG, starting with 75 IU from cycle day 7 and maintained for up to 3 d. The maximum dose was 150 IU. Primary end-points were ongoing and clinical pregnancy rate, secondary end-points mono-follicular development, ovulation rate, OHSS, multiple pregnancy and early pregnancy loss. Major safety end-point was the incidence of adverse events. Within 395 cycles the ongoing pregnancy rate was 28.24%, for cycles 35.23%, for patients 68%. The rate of ovulation per cycle was 97.7%, percentage of mono-follicular development 70.9%. No severe OHSS, multiple pregnancy, local or systemic side effects were seen. LTZ combined with low-dose Hp-HMG is an effective and safe choice for reducing hyperstimulation and increasing pregnancy rate in CC-resistant women with PCOS.

IsomiR expression profiles in human lymphoblastoid cell lines exhibit population and gender dependencies.

PubMed

Loher, Phillipe; Londin, Eric R; Rigoutsos, Isidore

2014-09-30

For many years it was believed that each mature microRNA (miRNA) existed as a single entity with fixed endpoints and a 'static' and unchangeable primary sequence. However, recent evidence suggests that mature miRNAs are more 'dynamic' and that each miRNA precursor arm gives rise to multiple isoforms, the isomiRs. Here we report on our identification of numerous and abundant isomiRs in the lymphoblastoid cell lines (LCLs) of 452 men and women from five different population groups. Unexpectedly, we find that these isomiRs exhibit an expression profile that is population-dependent and gender-dependent. This is important as it indicates that the LCLs of each gender/population combination have their own unique collection of mature miRNA transcripts. Moreover, each identified isomiR has its own characteristic abundance that remains consistent across biological replicates indicating that these are not degradation products. The primary sequences of identified isomiRs differ from the known miRBase miRNA either at their 5´-endpoint (leads to a different 'seed' sequence and suggests a different targetome), their 3´-endpoint, or both simultaneously. Our analysis of Argonaute PAR-CLIP data from LCLs supports the association of many of these newly identified isomiRs with the Argonaute silencing complex and thus their functional roles through participation in the RNA interference pathway.

Challenges to the Therapeutic Pipeline for Irritable Bowel Syndrome: Endpoints and Regulatory Hurdles

PubMed Central

Camilleri, Michael; Chang, Lin

2008-01-01

Recent advances in our understanding of basic neuroenteric mechanisms and the role of effectors and transmitters in the brain-gut axis have provided opportunities to develop new therapeutic agents for irritable bowel syndrome (IBS). Furthermore, human pharmacodynamic studies utilizing transit, colonic or rectal sensitivity, and brain imaging have been useful in determining therapeutic efficacy (particularly for drugs that act on motor function). This review provides an overview of medications that have not yet been approved for treatment of patients with IBS, yet have shown promise in phase IIB trials. These include drugs that act on the serotonin receptor and transporter system, antidepressants, norepinephrine reuptake inhibitors, opioids, cholecystokinin antagonists, neurokinin-antagonists, chloride channel activators, guanylate cyclase C agonists, atypical benzodiazepines, probiotics and antibiotics. The changing landscape in the regulatory approval process has impacted the development of IBS drugs. Guidance documents from regulatory agencies in Europe and the United States have focused on patients’ reported outcomes and associated quality of life. After a decade of experience with different endpoints that have generated some data on psychometric validation and unprecedented information about responsiveness of the binary or global endpoints to drug therapy, it is necessary to pursue further validation studies before or during pivotal phase IIB or III trials. The hope of providing relief to patients should galvanize all parties to achieve these goals. PMID:18848833

Bayesian Adaptive Trial Design for a Newly Validated Surrogate Endpoint

PubMed Central

Renfro, Lindsay A.; Carlin, Bradley P.; Sargent, Daniel J.

2011-01-01

Summary The evaluation of surrogate endpoints for primary use in future clinical trials is an increasingly important research area, due to demands for more efficient trials coupled with recent regulatory acceptance of some surrogates as ‘valid.’ However, little consideration has been given to how a trial which utilizes a newly-validated surrogate endpoint as its primary endpoint might be appropriately designed. We propose a novel Bayesian adaptive trial design that allows the new surrogate endpoint to play a dominant role in assessing the effect of an intervention, while remaining realistically cautious about its use. By incorporating multi-trial historical information on the validated relationship between the surrogate and clinical endpoints, then subsequently evaluating accumulating data against this relationship as the new trial progresses, we adaptively guard against an erroneous assessment of treatment based upon a truly invalid surrogate. When the joint outcomes in the new trial seem plausible given similar historical trials, we proceed with the surrogate endpoint as the primary endpoint, and do so adaptively–perhaps stopping the trial for early success or inferiority of the experimental treatment, or for futility. Otherwise, we discard the surrogate and switch adaptive determinations to the original primary endpoint. We use simulation to test the operating characteristics of this new design compared to a standard O’Brien-Fleming approach, as well as the ability of our design to discriminate trustworthy from untrustworthy surrogates in hypothetical future trials. Furthermore, we investigate possible benefits using patient-level data from 18 adjuvant therapy trials in colon cancer, where disease-free survival is considered a newly-validated surrogate endpoint for overall survival. PMID:21838811

Determining the Primary Endpoint for a Stimulant Abuse Trial: Lessons Learned from STRIDE (CTN 0037)

PubMed Central

Trivedi, Madhukar H.; Greer, Tracy L.; Potter, Jennifer Sharpe; Grannemann, Bruce D.; Nunes, Edward V.; Rethorst, Chad; Warden, Diane; Ring, Kolette M.; Somoza, Eugene

2012-01-01

Background No consensus is available for identifying the best primary outcome for substance abuse trials. While abstinence is the most desirable outcome for substance use interventions, a wide variety of other endpoints have been used to evaluate efficacy trials. Objectives This report provides a framework for determining an optimal primary endpoint and the relevant measurement approach for substance use disorder treatment trials. The framework was developed based on a trial for stimulant abuse using exercise as an augmentation treatment, delivered within the NIDA Clinical Trials Network. The use of a common primary endpoint across trials will facilitate comparisons of treatment efficacy. Methods Primary endpoint options in existing substance abuse studies were evaluated. This evaluation included surveys of the literature for endpoints and measurement approaches, followed by assessment of endpoint choices against study design issues, population characteristics, tests of sensitivity and tests of clinical meaningfulness. Conclusion We concluded that the best current choice for a primary endpoint is percent days abstinent, as measured by the Time Line Follow Back (TLFB) interview conducted three times a week with recall aided by a take-home Substance Use Diary. To further improve the accuracy of the self-reported drug use, an algorithm will be applied to reconcile the results from the TLFB with the results of qualitative urine drug screens. Scientific Significance There is a need for a standardized endpoint in this field to allow for comparison across treatment studies, and we suggest that the recommended endpoint be considered for use in this field. PMID:21854276

Neuroretinal Rim Area Change in Glaucoma Patients With Visual Field Progression Endpoints and Intraocular Pressure Reduction. The Canadian Glaucoma Study: 4.

PubMed

Malik, Rizwan; O'Leary, Neil; Mikelberg, Frederick S; Balazsi, A Gordon; LeBlanc, Raymond P; Lesk, Mark R; Nicolela, Marcelo T; Trope, Graham E; Chauhan, Balwantray C

2016-03-01

To compare rim area rates in patients with and without the visual field (VF) progression endpoint in the Canadian Glaucoma Study and determine whether intraocular pressure (IOP) reduction following the endpoint altered rim area rate. Prospective multicenter cohort study. setting: University hospitals. Two hundred and six patients with open-angle glaucoma were examined at 4-month intervals with standard automated perimetry and confocal scanning laser tomography. After the endpoint, IOP was reduced by ≥20%. Univariate analysis for change in rim area rate and multivariable analysis to adjust for independent covariates (eg, age, sex, and IOP). Patients with an endpoint (n = 59) had a worse rim area rate prior to the endpoint compared to those without (n = 147; median [interquartile range]: -14 [-32, 11] × 10(-3) mm(2)/y and -5 [-14, 5] × 10(-3) mm(2)/y, respectively, P = .02). In univariate analysis, there was no difference in rim area rate before and after the endpoint (median difference [95% CI], 8 (-10, 24) × 10(-3) mm(2)/y), but the muItivariate analysis showed that IOP reduction >2 mm Hg after the endpoint was strongly linked to a reduction in rim area rate decline (8 × 10(-3) mm(2)/y for each additional 1 mm Hg reduction). Patients with a VF endpoint had a median rim area rate that was nearly 3 times worse than those without an endpoint. Lower mean follow-up IOP was independently associated with a slower decline in rim area. Copyright © 2016 Elsevier Inc. All rights reserved.

Surrogate endpoints for clinical trials in primary sclerosing cholangitis: Review and results from an International PSC Study Group consensus process.

PubMed

Ponsioen, Cyriel Y; Chapman, Roger W; Chazouillères, Olivier; Hirschfield, Gideon M; Karlsen, Tom H; Lohse, Ansgar W; Pinzani, Massimo; Schrumpf, Erik; Trauner, Michael; Gores, Gregory J

2016-04-01

Primary sclerosing cholangitis (PSC) is a rare, but serious, cholestatic disease for which, to date, no effective therapy exists to halt disease progression toward end-stage liver disease. Clinical trial design to study drugs that improve prognosis is hampered by the relatively low event rate of clinically relevant endpoints. To overcome this shortcoming, there is an urgent need to identify appropriate surrogate endpoints. At present, there are no established surrogate endpoints. This article provides a critical review and describes the results of a consensus process initiated by the International PSC Study Group to delineate appropriate candidate surrogate endpoints at present for clinical trials in this frequently dismal disease. The consensus process resulted in a shortlist of five candidates as surrogate endpoints for measuring disease progression: alkaline phosphatase (ALP); transient elastography (TE); histology; combination of ALP+histology; and bilirubin. Of these, histology, ALP, and TE came out as the most promising. However, the expert panel concluded that no biomarker currently exceeds level 3 validation. Combining multiple endpoints is advisable. At present, there are insufficient data to support level 2 validation for any surrogate endpoint in PSC. Concerted efforts by all stakeholders are highly needed. Novel, promising noninvasive biomarkers are under study and should be incorporated as exploratory endpoints in clinical trials. © 2015 by the American Association for the Study of Liver Diseases.

Statistical evaluation of surrogate endpoints with examples from cancer clinical trials.

PubMed

Buyse, Marc; Molenberghs, Geert; Paoletti, Xavier; Oba, Koji; Alonso, Ariel; Van der Elst, Wim; Burzykowski, Tomasz

2016-01-01

A surrogate endpoint is intended to replace a clinical endpoint for the evaluation of new treatments when it can be measured more cheaply, more conveniently, more frequently, or earlier than that clinical endpoint. A surrogate endpoint is expected to predict clinical benefit, harm, or lack of these. Besides the biological plausibility of a surrogate, a quantitative assessment of the strength of evidence for surrogacy requires the demonstration of the prognostic value of the surrogate for the clinical outcome, and evidence that treatment effects on the surrogate reliably predict treatment effects on the clinical outcome. We focus on these two conditions, and outline the statistical approaches that have been proposed to assess the extent to which these conditions are fulfilled. When data are available from a single trial, one can assess the "individual level association" between the surrogate and the true endpoint. When data are available from several trials, one can additionally assess the "trial level association" between the treatment effect on the surrogate and the treatment effect on the true endpoint. In the latter case, the "surrogate threshold effect" can be estimated as the minimum effect on the surrogate endpoint that predicts a statistically significant effect on the clinical endpoint. All these concepts are discussed in the context of randomized clinical trials in oncology, and illustrated with two meta-analyses in gastric cancer. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

76 FR 35450 - Draft Guidance for Industry on Clinical Trial Endpoints for the Approval of Non-Small Cell Lung...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-17

...] Draft Guidance for Industry on Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer... entitled ``Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer Drugs and Biologics... draft guidance for industry entitled ``Clinical Trial Endpoints for the Approval of Non-Small Cell Lung...

Post hoc analyses: after the facts.

PubMed

Srinivas, Titte R; Ho, Bing; Kang, Joseph; Kaplan, Bruce

2015-01-01

Prospective clinical trials are constructed with high levels of internal validity. Sample size and power considerations usually address primary endpoints. Primary endpoints have traditionally included events that are becoming increasingly less common and thus have led to growing use of composite endpoints and noninferiority trial designs in transplantation. This approach may mask real clinical benefit in one or the other domain with regard to either clinically relevant secondary endpoints or other unexpected findings. In addition, endpoints solely chosen based on power considerations are prone to misjudgment of actual treatment effect size as well as consistency of that effect. In the instances where treatment effects may have been underestimated, valuable information may be lost if buried within a composite endpoint. In all these cases, analyses and post hoc analyses of data become relevant in informing practitioners about clinical benefits or safety signals that may not be captured by the primary endpoint. On the other hand, there are many pitfalls in using post hoc determined endpoints. This short review is meant to allow readers to appreciate post hoc analysis not as an entity with a single approach, but rather as an analysis with unique limitations and strengths that often raise new questions to be addressed in further inquiries.

Feline Hypertrophic Cardiomyopathy: A Spontaneous Large Animal Model of Human HCM

PubMed Central

Freeman, Lisa M.; Rush, John E.; Stern, Joshua A.; Huggins, Gordon S.; Maron, Martin S.

2017-01-01

Hypertrophic cardiomyopathy (HCM) is a common disease in pet cats, affecting 10-15% of the pet cat population. The similarity to human HCM, the rapid progression of disease, and the defined and readily determined endpoints of feline HCM make it an excellent natural model that is genotypically and phenotypically similar to human HCM. The Maine Coon and Ragdoll cats are particularly valuable models of HCM because of myosin binding protein-C mutations and even higher disease incidence compared to the overall feline population. The cat overcomes many of the limitations of rodent HCM models, and can provide enhanced translation of information from in vitro and induced small animal models to human clinical trials. Physicians and veterinarians working together in a collaborative and interdisciplinary approach can accelerate the discovery of more effective treatments for this and other cardiovascular diseases affecting human and veterinary patients. PMID:28868097

Environmental pollutants and dysregulation of male puberty--a comparison among species.

PubMed

Magnusson, Ulf; Ljungvall, Karl

2014-04-01

The scientific literature on altered onset of puberty predominantly involves studies on females. This paper reviews current knowledge on the role of environmental pollutants in dysregulation of male puberty in humans, laboratory rodents and farm animals. The methods used to determine the onset of puberty are well developed in humans and farm animals, and standardized across studies in humans. In laboratory rodents standardized external morphological endpoints are used. There is an increasing weight of evidence from epidemiological studies in humans, as well as from experiments in animals, indicating that environmental pollutants dysregulate puberty in males. Most data are from studies on "classical" persistent environmental pollutants. Assessing the effect of multichemical environmental pollution on dysregulation of puberty in humans is more challenging; further solid epidemiological data would likely contribute most to our understanding, especially if combined with systematically collected field-data from selected wildlife. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Biomarkers and surrogate endpoints in kidney disease.

PubMed

Hartung, Erum A

2016-03-01

Kidney disease and its related comorbidities impose a large public health burden. Despite this, the number of clinical trials in nephrology lags behind many other fields. An important factor contributing to the relatively slow pace of nephrology trials is that existing clinical endpoints have significant limitations. "Hard" endpoints for chronic kidney disease, such as progression to end-stage renal disease, may not be reached for decades. Traditional biomarkers, such as serum creatinine in acute kidney injury, may lack sensitivity and predictive value. Finding new biomarkers to serve as surrogate endpoints is therefore an important priority in kidney disease research and may help to accelerate nephrology clinical trials. In this paper, I first review key concepts related to the selection of clinical trial endpoints and discuss statistical and regulatory considerations related to the evaluation of biomarkers as surrogate endpoints. This is followed by a discussion of the challenges and opportunities in developing novel biomarkers and surrogate endpoints in three major areas of nephrology research: acute kidney injury, chronic kidney disease, and autosomal dominant polycystic kidney disease.

Clinical Trial Principles and Endpoint Definitions for Paravalvular Leaks in Surgical Prosthesis: An Expert Statement.

PubMed

Ruiz, Carlos E; Hahn, Rebecca T; Berrebi, Alain; Borer, Jeffrey S; Cutlip, Donald E; Fontana, Greg; Gerosa, Gino; Ibrahim, Reda; Jelnin, Vladimir; Jilaihawi, Hasan; Jolicoeur, E Marc; Kliger, Chad; Kronzon, Itzhak; Leipsic, Jonathon; Maisano, Francesco; Millan, Xavier; Nataf, Patrick; O'Gara, Patrick T; Pibarot, Philippe; Ramee, Stephen R; Rihal, Charanjit S; Rodes-Cabau, Josep; Sorajja, Paul; Suri, Rakesh; Swain, Julie A; Turi, Zoltan G; Tuzcu, E Murat; Weissman, Neil J; Zamorano, Jose L; Serruys, Patrick W; Leon, Martin B

2017-04-25

The VARC (Valve Academic Research Consortium) for transcatheter aortic valve replacement set the standard for selecting appropriate clinical endpoints reflecting safety and effectiveness of transcatheter devices, and defining single and composite clinical endpoints for clinical trials. No such standardization exists for circumferentially sutured surgical valve paravalvular leak (PVL) closure. This document seeks to provide core principles, appropriate clinical endpoints, and endpoint definitions to be used in clinical trials of PVL closure devices. The PVL Academic Research Consortium met to review evidence and make recommendations for assessment of disease severity, data collection, and updated endpoint definitions. A 5-class grading scheme to evaluate PVL was developed in concordance with VARC recommendations. Unresolved issues in the field are outlined. The current PVL Academic Research Consortium provides recommendations for assessment of disease severity, data collection, and endpoint definitions. Future research in the field is warranted. Copyright © 2017 American College of Cardiology Foundation and European Society of Cardiology. Published by Elsevier Inc. All rights reserved.

Human Abuse Potential of an Abuse-Deterrent (AD), Extended-Release (ER) Morphine Product Candidate (Morphine-ADER Injection-Molded Tablets) versus Extended-Release Morphine Administered Orally in Nondependent Recreational Opioid Users

PubMed Central

Webster, Lynn R.; Lawler, John; Lindhardt, Karsten; Dayno, Jeffrey M.

2017-01-01

Objective. To compare the relative human abuse potential of intact and manipulated morphine abuse-deterrent, extended-release injection-molded tablets (morphine-ADER-IMT) with that of marketed morphine sulfate ER tablets Methods. This randomized, double-blind, triple-dummy, active- and placebo-controlled, 4-way crossover, single-center study included adult volunteers who were experienced, nondependent, recreational opioid users. Participants were randomized 1:1:1:1 to placebo, morphine-ADER-IMT (60 mg, intact), morphine-ADER-IMT (60 mg, manipulated), and morphine ER (60 mg, manipulated) and received 1 dose of each oral agent in crossover fashion, separated by ≥5 days. Pharmacodynamic and pharmacokinetic endpoints were assessed, including the primary endpoint of peak effect of Drug Liking (Emax) via Drug Liking Visual Analog Scale (VAS) score and the secondary endpoints of time to Emax (TEmax) and mean abuse quotient (AQ; a pharmacokinetic parameter associated with drug liking). Results. Thirty-eight participants completed the study. Median Drug Liking VAS Emax was significantly lower after treatment with manipulated morphine-ADER-IMT (67) compared with manipulated morphine ER (74; P = 0.007). TEmax was significantly shorter after treatment with manipulated morphine ER compared with intact (P < 0.0001) or manipulated (P = 0.004) morphine-ADER-IMT. Mean AQ was lower after treatment with intact (5.7) or manipulated (16.4) morphine-ADER-IMT compared with manipulated morphine ER (45.9). Conclusions. Manipulated morphine-ADER-IMT demonstrated significantly lower Drug Liking Emax compared with manipulated morphine ER when administered orally. Morphine-ADER-IMT would be an important new AD, ER morphine product with lower potential for unintentional misuse by chewing or intentional manipulation for oral abuse than currently available non-AD morphine ER products. PMID:27633773

The SABRE Trial (Sirolimus Angioplasty Balloon for Coronary In-Stent Restenosis): Angiographic Results and 1-Year Clinical Outcomes.

PubMed

Verheye, Stefan; Vrolix, Mathias; Kumsars, Indulis; Erglis, Andrejs; Sondore, Dace; Agostoni, Pierfrancesco; Cornelis, Kristoff; Janssens, Luc; Maeng, Michael; Slagboom, Ton; Amoroso, Giovanni; Jensen, Lisette Okkels; Granada, Juan F; Stella, Pieter

2017-10-23

The aim of this first-in-human study was to assess the safety and effectiveness of the Virtue sirolimus-eluting balloon in a cohort of patients with in-stent restenosis (ISR). Angioplasty balloons coated with the cytotoxic drug paclitaxel have been widely used for ISR treatment. The Virtue angioplasty balloon (Caliber Therapeutics, New Hope, Pennsylvania) delivers sirolimus in a nanoencapsulated liquid formulation. This clinical trial is the first to examine a sirolimus-eluting balloon for ISR. In this prospective, single-arm feasibility study at 9 European centers, 50 ISR patients were treated with the Virtue balloon. Angiographic measurements at 6 months are reported, along with 12-month clinical follow-up. Procedural success in the intention-to-treat population was 100%. The primary safety endpoint was target lesion failure (TLF) (cardiac death, target vessel myocardial infarction, and clinically driven target lesion revascularization) assessed at 30 days (0%, n = 50). The primary performance endpoint was in-segment late lumen loss (LLL) at 6 months (0.31 ± 0.52 mm; n = 47). Secondary 6-month endpoints include binary restenosis (19.1%), diameter stenosis (30.3 ± 19.9%), and major adverse cardiac events (MACE) (10.2%, n = 49). In the 36-patient per-protocol population (excluding major protocol violations and previously stented ISR), LLL was 0.12 ± 0.33 mm at 6 months. Clinical outcomes at 1 year for the intention-to-treat group were 12.2% TLF and 14.3% MACE and for the per-protocol population were 2.8% TLF and 2.8% MACE. This first-in-human study showed excellent procedural success for the Virtue sirolimus-eluting angioplasty balloon, 6-month LLL rates in line with current stent-free ISR treatment options, and clinical outcomes that warrant further evaluation in dedicated randomized studies. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Endpoint-based parallel data processing with non-blocking collective instructions in a parallel active messaging interface of a parallel computer

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

Archer, Charles J; Blocksome, Michael A; Cernohous, Bob R

Methods, apparatuses, and computer program products for endpoint-based parallel data processing with non-blocking collective instructions in a parallel active messaging interface (`PAMI`) of a parallel computer are provided. Embodiments include establishing by a parallel application a data communications geometry, the geometry specifying a set of endpoints that are used in collective operations of the PAMI, including associating with the geometry a list of collective algorithms valid for use with the endpoints of the geometry. Embodiments also include registering in each endpoint in the geometry a dispatch callback function for a collective operation and executing without blocking, through a single onemore » of the endpoints in the geometry, an instruction for the collective operation.« less

Earlier Endpoints Are Required for Hemorrhagic Shock Trials among Severely Injured Patients

PubMed Central

Fox, Erin E.; Holcomb, John B.; Wade, Charles E.; Bulger, Eileen M.; Tilley, Barbara C.

2016-01-01

Background Choosing the appropriate endpoint for a trauma hemorrhage control trial can determine the likelihood of its success. Recent Phase 3 trials and observational studies have used 24-hour and/or 30-day all-cause mortality as the primary endpoint and some have not used exception from informed consent (EFIC), resulting in multiple failed trials. Five recent high-quality prospective studies among 4,064 hemorrhaging trauma patients provide new evidence to support earlier primary endpoints. Methods The goal of this project was to determine the optimal endpoint for hemorrhage control trials using existing literature and new analyses of previously published data. Results Recent studies among bleeding trauma patients show that hemorrhagic deaths occur rapidly, at a high rate, and in a consistent pattern. Early preventable deaths among trauma patients are largely due to hemorrhage and the median time to hemorrhagic death from admission is 2.0-2.6 hours. Approximately 85% of hemorrhagic deaths occur within 6 hours. The hourly mortality rate due to traumatic injury decreases rapidly after enrollment from 4.6% per hour at 1 hour post-enrollment to 1% per hour at 6 hours to <0.1% per hour by 9 hours and thereafter. Early primary endpoints (within 6 hours) have critically important benefits for hemorrhage control trials, including being congruent with the median time to hemorrhagic death, biologic plausibility, and enabling the use of all-cause mortality, which is definitive and objective. Conclusions Primary endpoints should be congruent with the timing of the disease process. Therefore, if a resuscitation/hemorrhage control intervention is under study, a primary endpoint of all-cause mortality evaluated within the first 6 hours is appropriate. Before choosing the timing of the primary endpoint for a large multicenter trial, we recommend performing a Phase 2 trial under EFIC to better understand the effects of the hemorrhage control intervention and distribution of time to death. When early primary endpoints are used, patients should be monitored for multiple subsequent secondary safety endpoints, including 24 hour and 30 day all-cause mortality as well as the customary safety endpoints. PMID:28207628

Surrogate and clinical endpoints in interventional cardiology: are statistics the brakes?

PubMed

Waliszewski, Matthias; Rittger, Harald

2016-10-01

Randomized controlled trials are the gold standard for demonstrating safety and efficacy of coronary devices with or without accompanying drug treatments in interventional cardiology. With the advent of last-generation drug-eluting stents having enhanced technical attributes and long-term clinical benefits, the proof of incremental angiographic or long-term clinical efficacy becomes more challenging. The purpose of this review is to provide an overview of the most common and alternative study endpoints in interventional cardiology and their potential reimbursement value. Moreover, we intend to describe the statistical limitations in order to demonstrate differences between potential treatment groups. Furthermore, careful endpoint recommendations for a given patient number are offered for future study designs. The number of patients per treatment group was estimated for various study designs such as noninferiority test hypotheses with hard clinical endpoints and various surrogate endpoints. To test for differences in various surrogate endpoint scenarios, the corresponding patient group sizes were explored. To evaluate these endpoints in terms of their reimbursement impact, preferred endpoints for technical appraisals in interventional cardiology at the National Institute of Health and Care Excellence (NICE) were used. Even with the most stringent experimental control to reduce bias-introducing factors, studies with hard primary clinical endpoints such as the occurrence of major adverse cardiac events (MACE) or target-lesion revascularization (TLR) rates remain the gold standard, with numbers reaching into the 300-700 patient range per group. Study designs using loss in fractional-flow reserve (FFR) or stent-strut-coverage rates can be statistically formulated; however, the clinical ramifications for the patient remain to be discussed. Nonrandomized study designs with intrapatient angiographic controls in nontarget vessels may merit further thoughts and explorations. From a reimbursement impact, the primary endpoints MACE and TLR are the best choices for a moderately sized study population of 500 patients per group. Angiographic endpoints, in particular minimal lumen diameter (MLD), are not useful in this context. The emerging endpoints such as loss in FFR or stent coverage require smaller patient populations. However, their impact on reimbursement-related decisions is limited. © The Author(s), 2016.

Surrogate and clinical endpoints in interventional cardiology: are statistics the brakes?

PubMed Central

Waliszewski, Matthias; Rittger, Harald

2016-01-01

Background: Randomized controlled trials are the gold standard for demonstrating safety and efficacy of coronary devices with or without accompanying drug treatments in interventional cardiology. With the advent of last-generation drug-eluting stents having enhanced technical attributes and long-term clinical benefits, the proof of incremental angiographic or long-term clinical efficacy becomes more challenging. The purpose of this review is to provide an overview of the most common and alternative study endpoints in interventional cardiology and their potential reimbursement value. Moreover, we intend to describe the statistical limitations in order to demonstrate differences between potential treatment groups. Furthermore, careful endpoint recommendations for a given patient number are offered for future study designs. Methods: The number of patients per treatment group was estimated for various study designs such as noninferiority test hypotheses with hard clinical endpoints and various surrogate endpoints. To test for differences in various surrogate endpoint scenarios, the corresponding patient group sizes were explored. To evaluate these endpoints in terms of their reimbursement impact, preferred endpoints for technical appraisals in interventional cardiology at the National Institute of Health and Care Excellence (NICE) were used. Results: Even with the most stringent experimental control to reduce bias-introducing factors, studies with hard primary clinical endpoints such as the occurrence of major adverse cardiac events (MACE) or target-lesion revascularization (TLR) rates remain the gold standard, with numbers reaching into the 300–700 patient range per group. Study designs using loss in fractional-flow reserve (FFR) or stent-strut-coverage rates can be statistically formulated; however, the clinical ramifications for the patient remain to be discussed. Nonrandomized study designs with intrapatient angiographic controls in nontarget vessels may merit further thoughts and explorations. Conclusions: From a reimbursement impact, the primary endpoints MACE and TLR are the best choices for a moderately sized study population of 500 patients per group. Angiographic endpoints, in particular minimal lumen diameter (MLD), are not useful in this context. The emerging endpoints such as loss in FFR or stent coverage require smaller patient populations. However, their impact on reimbursement-related decisions is limited. PMID:27378486

Experimental cancer cachexia: Evolving strategies for getting closer to the human scenario.

PubMed

Penna, Fabio; Busquets, Sílvia; Argilés, Josep M

2016-06-01

Cancer cachexia is a frequent syndrome that dramatically affects patient quality of life, anti-cancer treatment effectiveness, and overall survival. To date, no effective treatment is available and most of the studies are performed in experimental models in order to uncover the underlying mechanisms and to design prospective therapeutic strategies. This review summarizes the most relevant information regarding the use of animal models for studying cancer cachexia. Technical limitations and degree of recapitulation of the features of human cachexia are highlighted, in order to help investigators choose the most suitable model according to study-specific endpoints. Copyright © 2015 Elsevier Ltd. All rights reserved.

Developmental Toxicity of Drinking Water Disinfection By-Products to Embryos of the African Clawed Frog (Xenopus laevis)

DTIC Science & Technology

2005-06-10

and as representatives of byproducts of different disinfection processes . Endpoints measured included embryo mortality (LC50), embryo malformation...chemicals were selected for testing based on their potential for human harm and as representatives of byproducts of different disinfection processes ...highest frequency include notochord maldevelopment, craniofacial defects, and cardiac edema. The EC50 for BDCM malformations (62-72 mg/L) was at a much

Naval Medical Research and Development News. Volume 8, Issue 1, January 2016

DTIC Science & Technology

2016-01-01

you are active or reserve, civilian, contractor , or volunteer - your reach spans the globe and you are an important part of fulfilling that trust...human health risk assessment rely on determination of biologically-effective concentrations in suites of in vitro high throughput screening ( HTS ...Dashboard (http:// actor.epa.gov/dashboard/) provides access to the results of more than 800 HTS in vitro assay endpoints for over 1800 chemicals

An investigation into the two-stage meta-analytic copula modelling approach for evaluating time-to-event surrogate endpoints which comprise of one or more events of interest.

PubMed

Dimier, Natalie; Todd, Susan

2017-09-01

Clinical trials of experimental treatments must be designed with primary endpoints that directly measure clinical benefit for patients. In many disease areas, the recognised gold standard primary endpoint can take many years to mature, leading to challenges in the conduct and quality of clinical studies. There is increasing interest in using shorter-term surrogate endpoints as substitutes for costly long-term clinical trial endpoints; such surrogates need to be selected according to biological plausibility, as well as the ability to reliably predict the unobserved treatment effect on the long-term endpoint. A number of statistical methods to evaluate this prediction have been proposed; this paper uses a simulation study to explore one such method in the context of time-to-event surrogates for a time-to-event true endpoint. This two-stage meta-analytic copula method has been extensively studied for time-to-event surrogate endpoints with one event of interest, but thus far has not been explored for the assessment of surrogates which have multiple events of interest, such as those incorporating information directly from the true clinical endpoint. We assess the sensitivity of the method to various factors including strength of association between endpoints, the quantity of data available, and the effect of censoring. In particular, we consider scenarios where there exist very little data on which to assess surrogacy. Results show that the two-stage meta-analytic copula method performs well under certain circumstances and could be considered useful in practice, but demonstrates limitations that may prevent universal use. Copyright © 2017 John Wiley & Sons, Ltd.

Reliability of a Manual Procedure for Marking the EZ Endpoint Location in Patients with Retinitis Pigmentosa

PubMed Central

Ramachandran, Rithambara; Cai, Cindy X.; Lee, Dongwon; Epstein, Benjamin C.; Locke, Kirsten G.; Birch, David G.; Hood, Donald C.

2016-01-01

Purpose We developed and evaluated a training procedure for marking the endpoints of the ellipsoid zone (EZ), also known as the inner segment/outer segment (IS/OS) border, on frequency domain optical coherence tomography (fdOCT) scans from patients with retinitis pigmentosa (RP). Methods A manual for marking EZ endpoints was developed and used to train 2 inexperienced graders. After training, an experienced grader and the 2 trained graders marked the endpoints on fdOCT horizontal line scans through the macula from 45 patients with RP. They marked the endpoints on these same scans again 1 month later. Results Intragrader agreement was excellent. The intraclass correlation coefficient (ICC) was 0.99, the average difference of endpoint locations (19.6 μm) was close to 0 μm, and the 95% limits were between −284 and 323 μm, approximately ±1.1°. Intergrader agreement also was excellent. The ICC values were 0.98 (time 1) and 0.97 (time 2), the average difference among graders was close to zero, and the 95% limits of these differences was less than 350 μm, approximately 1.2°, for both test times. Conclusions While automated algorithms are becoming increasingly accurate, EZ endpoints still have to be verified manually and corrected when necessary. With training, the inter- and intragrader agreement of manually marked endpoints is excellent. Translational Relevance For clinical studies, the EZ endpoints can be marked by hand if a training procedure, including a manual, is used. The endpoint confidence intervals, well under ±2.0°, are considerably smaller than the 6° spacing for the typically used static visual field. PMID:27226930

Biomarkers and Surrogate Endpoints: Lessons Learned From Glaucoma

PubMed Central

Medeiros, Felipe A.

2017-01-01

With the recent progress in imaging technologies for assessment of structural damage in glaucoma, a debate has emerged on whether these measurements can be used as valid surrogate endpoints in clinical trials evaluating new therapies for the disease. A discussion of surrogates should be grounded on knowledge acquired from their use in other areas of medicine as well as regulatory requirements. This article reviews the conditions for valid surrogacy in the context of glaucoma clinical trials and critically evaluates the role of biomarkers such as IOP and imaging measurements as potential surrogates for clinically relevant outcomes. Valid surrogate endpoints must be able to predict a clinically relevant endpoint, such as loss of vision or decrease in quality of life. In addition, the effect of a proposed treatment on the surrogate must capture the effect of the treatment on the clinically relevant endpoint. Despite its widespread use in clinical trials, no proper validation of IOP as a surrogate endpoint has yet been conducted for any class of IOP-lowering treatments. Although strong evidence has accumulated about imaging measurements as predictors of relevant functional outcomes in glaucoma, there is still insufficient evidence to support their use as valid surrogate endpoints. However, imaging biomarkers could potentially be used as part of composite endpoints in glaucoma trials, overcoming weaknesses of the use of structural or functional endpoints in isolation. Efforts should be taken to properly design and conduct studies that can provide proper validation of potential biomarkers in glaucoma clinical trials. PMID:28475699

Biomarkers and Surrogate Endpoints: Lessons Learned From Glaucoma.

PubMed

Medeiros, Felipe A

2017-05-01

With the recent progress in imaging technologies for assessment of structural damage in glaucoma, a debate has emerged on whether these measurements can be used as valid surrogate endpoints in clinical trials evaluating new therapies for the disease. A discussion of surrogates should be grounded on knowledge acquired from their use in other areas of medicine as well as regulatory requirements. This article reviews the conditions for valid surrogacy in the context of glaucoma clinical trials and critically evaluates the role of biomarkers such as IOP and imaging measurements as potential surrogates for clinically relevant outcomes. Valid surrogate endpoints must be able to predict a clinically relevant endpoint, such as loss of vision or decrease in quality of life. In addition, the effect of a proposed treatment on the surrogate must capture the effect of the treatment on the clinically relevant endpoint. Despite its widespread use in clinical trials, no proper validation of IOP as a surrogate endpoint has yet been conducted for any class of IOP-lowering treatments. Although strong evidence has accumulated about imaging measurements as predictors of relevant functional outcomes in glaucoma, there is still insufficient evidence to support their use as valid surrogate endpoints. However, imaging biomarkers could potentially be used as part of composite endpoints in glaucoma trials, overcoming weaknesses of the use of structural or functional endpoints in isolation. Efforts should be taken to properly design and conduct studies that can provide proper validation of potential biomarkers in glaucoma clinical trials.

The influence of non-DNA-targeted effects on carbon ion–induced low-dose hyper-radiosensitivity in MRC-5 cells

PubMed Central

Ye, Fei; Ning, Jing; Liu, Xinguo; Jin, Xiaodong; Wang, Tieshan; Li, Qiang

2016-01-01

Low-dose hyper-radiosensitivity (LDHRS) is a hot topic in normal tissue radiation protection. However, the primary causes for LDHRS still remain unclear. In this study, the impact of non-DNA-targeted effects (NTEs) on high-LET radiation–induced LDHRS was investigated. Human normal lung fibroblast MRC-5 cells were irradiated with high-LET carbon ions, and low-dose biological effects (in terms of various bio-endpoints, including colony formation, DNA damage and micronuclei formation) were detected under conditions with and without gap junctional intercellular communication (GJIC) inhibition. LDHRS was observed when the radiation dose was <0.2 Gy for all bio-endpoints under investigation, but vanished when the GJIC was suppressed. Based on the probability of cells being hit and micro-dose per cell calculation, we deduced that the LDHRS phenomenon came from the combined action of direct hits and NTEs. We concluded that GJIC definitely plays an important role in cytotoxic substance spreading in high-LET carbon ion–induced LDHRS. PMID:26559335

[HTA-Perspective: Challenges in the early assessment of new oncological drugs].

PubMed

Wild, Claudia; Nachtnebel, Anna

2013-01-01

Oncologic drug therapies have gained wide attention in the context of health policy priority setting for serious and socially significant diseases with high human and monetary costs. Due to uncertainties and scepticism about the actual therapeutic importance of newly approved oncology products, an early assessment programme was already established in Austria in 2007. The assessment of new oncology products is thereby faced with special challenges, since study populations are frequently not representative or the study design is laid out in such a manner that a definitive assessment of patient-relevant endpoints is not possible (cross-overs after interim assessments, surrogate parameters as primary endpoints, uncontrolled studies or those with unrealistic comparators, invalidated post-hoc identified biomarkers). On account of these major uncertainties, even the European Medicines Agency (EMA) is already contemplating multi-stage, "adaptive" approvals, and national reimbursement institutions are increasingly working with outcome-oriented, conditional reimbursement. (As supplied by publisher). Copyright © 2013. Published by Elsevier GmbH.

Body temperature measurement in mice during acute illness: implantable temperature transponder versus surface infrared thermometry.

PubMed

Mei, Jie; Riedel, Nico; Grittner, Ulrike; Endres, Matthias; Banneke, Stefanie; Emmrich, Julius Valentin

2018-02-23

Body temperature is a valuable parameter in determining the wellbeing of laboratory animals. However, using body temperature to refine humane endpoints during acute illness generally lacks comprehensiveness and exposes to inter-observer bias. Here we compared two methods to assess body temperature in mice, namely implanted radio frequency identification (RFID) temperature transponders (method 1) to non-contact infrared thermometry (method 2) in 435 mice for up to 7 days during normothermia and lipopolysaccharide (LPS) endotoxin-induced hypothermia. There was excellent agreement between core and surface temperature as determined by method 1 and 2, respectively, whereas the intra- and inter-subject variation was higher for method 2. Nevertheless, using machine learning algorithms to determine temperature-based endpoints both methods had excellent accuracy in predicting death as an outcome event. Therefore, less expensive and cumbersome non-contact infrared thermometry can serve as a reliable alternative for implantable transponder-based systems for hypothermic responses, although requiring standardization between experimenters.

A Unified Probabilistic Framework for Dose–Response Assessment of Human Health Effects

PubMed Central

Slob, Wout

2015-01-01

Background When chemical health hazards have been identified, probabilistic dose–response assessment (“hazard characterization”) quantifies uncertainty and/or variability in toxicity as a function of human exposure. Existing probabilistic approaches differ for different types of endpoints or modes-of-action, lacking a unifying framework. Objectives We developed a unified framework for probabilistic dose–response assessment. Methods We established a framework based on four principles: a) individual and population dose responses are distinct; b) dose–response relationships for all (including quantal) endpoints can be recast as relating to an underlying continuous measure of response at the individual level; c) for effects relevant to humans, “effect metrics” can be specified to define “toxicologically equivalent” sizes for this underlying individual response; and d) dose–response assessment requires making adjustments and accounting for uncertainty and variability. We then derived a step-by-step probabilistic approach for dose–response assessment of animal toxicology data similar to how nonprobabilistic reference doses are derived, illustrating the approach with example non-cancer and cancer datasets. Results Probabilistically derived exposure limits are based on estimating a “target human dose” (HDMI), which requires risk management–informed choices for the magnitude (M) of individual effect being protected against, the remaining incidence (I) of individuals with effects ≥ M in the population, and the percent confidence. In the example datasets, probabilistically derived 90% confidence intervals for HDMI values span a 40- to 60-fold range, where I = 1% of the population experiences ≥ M = 1%–10% effect sizes. Conclusions Although some implementation challenges remain, this unified probabilistic framework can provide substantially more complete and transparent characterization of chemical hazards and support better-informed risk management decisions. Citation Chiu WA, Slob W. 2015. A unified probabilistic framework for dose–response assessment of human health effects. Environ Health Perspect 123:1241–1254; http://dx.doi.org/10.1289/ehp.1409385 PMID:26006063

Determining significant endpoints for ecological risk analyses. 1998 annual progress report

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

Hinton, T.G.; Congdon, J.; Scott, D.

1998-06-01

'The goal of this report is to establish a protocol for assessing risks to non-human populations exposed to environmental stresses typically found on many DOE sites. The authors think that they can achieve this by using novel biological dosimeters in controlled, manipulative dose/effects experiments, and by coupling changes in metabolic rates and energy allocation patterns to meaningful population response variables (such as age-specific survivorship, reproductive output, age at maturity and longevity). This research is needed to determine the relevancy of sublethal cellular damage to the performance of individuals and populations exposed to chronic, low-level radiation, and radiation with concomitant exposuremore » to chemicals. They believe that a scientifically defensible endpoint for measuring ecological risks can only be determined once its understood the extent to which molecular damage from contaminant exposure is detrimental at the individual and population levels of biological organization. The experimental facility will allow them to develop a credible assessment tool for appraising ecological risks, and to evaluate the effects of radionuclide/chemical synergisms on non-human species. This report summarizes work completed midway of a 3-year project that began in November 1996. Emphasis to date has centered on three areas: (1) developing a molecular probe to measure stable chromosomal aberrations known as reciprocal translocations, (2) constructing an irradiation facility where the statistical power inherent in replicated mesocosms can be used to address the response of non-human organisms to exposures from low levels of radiation and metal contaminants, and (3) quantifying responses of organisms living in contaminated mesocosms and field sites.'« less

Life cycle assessment of municipal solid waste management scenarios on the small island of Mauritius.

PubMed

Rajcoomar, Avinash; Ramjeawon, Toolseeram

2017-03-01

The aim of this study was to use the life cycle assessment tool to assess, from an environmental point of view, the different possible municipal solid waste (MSW) management scenarios for the island of Mauritius. The scenarios include landfilling with energy recovery (S1), incineration with energy recovery (S2), composting, incineration and landfilling (S3) and finally composting, recycling, incineration and landfilling (S4). The MSW generated in 2010 was selected as the functional unit. Foreground data were collected through surveys and literature. Background data were obtained from ecoinvent data in SimaPro 8 libraries. The scenarios were compared both through the CML-IA baseline-midpoint method and the ReCiPe end-point method. From the midpoint method, the results obtained indicates that landfilling (S1) has the greatest impact in all the analyzed impact categories except ozone layer depletion and human toxicity, while incineration (S2) has the least impact on almost all the analyzed damage categories except in global warming potential and human toxicity. The collection and transportation of waste has a significant impact on the environment. From the end-point method, S4 reduces the damage impact categories on Human Health, Ecosystems and Resources due to the recycling process. S3 is not favorable due to the impact caused by the composting process. However, it is also very important to emphasize that for incineration, the best available technology with energy recovery shall be considered. It is recommended that S2 and S4 are considered for strategic planning.

Omnisphero: a high-content image analysis (HCA) approach for phenotypic developmental neurotoxicity (DNT) screenings of organoid neurosphere cultures in vitro.

PubMed

Schmuck, Martin R; Temme, Thomas; Dach, Katharina; de Boer, Denise; Barenys, Marta; Bendt, Farina; Mosig, Axel; Fritsche, Ellen

2017-04-01

Current developmental neurotoxicity (DNT) testing in animals faces major limitations, such as high cost and time demands as well as uncertainties in their methodology, evaluation and regulation. Therefore, the use of human-based 3D in vitro systems in combination with high-content image analysis (HCA) might contribute to DNT testing with lower costs, increased throughput and enhanced predictivity for human hazard identification. Human neural progenitor cells (hNPCs) grown as 3D neurospheres mimic basic processes of brain development including hNPC migration and differentiation and are therefore useful for DNT hazard identification. HCA of migrated neurospheres creates new challenges for automated evaluations because it encompasses variable cell densities, inconsistent z-layers and heterogeneous cell populations. We tackle those challenges with our Omnisphero software, which assesses multiple endpoints of the 'Neurosphere Assay.' For neuronal identification, Omnisphero reaches a true positive rate (TPR) of 83.8 % and a false discovery rate (FDR) of 11.4 %, thus being comparable to the interindividual difference among two researchers (TPR = 94.3, FDR = 11.0 %) and largely improving the results obtained by an existing HCA approach, whose TPR does not exceed 50 % at a FDR above 50 %. The high FDR of existing methods results in incorrect measurements of neuronal morphological features accompanied by an overestimation of compound effects. Omnisphero additionally includes novel algorithms to assess 'neurosphere-specific' endpoints like radial migration and neuronal density distribution within the migration area. Furthermore, a user-assisted parameter optimization procedure makes Omnisphero accessible to non-expert end users.

A quantitative analysis of statistical power identifies obesity endpoints for improved in vivo preclinical study design

PubMed Central

Selimkhanov, Jangir; Thompson, W. Clayton; Guo, Juen; Hall, Kevin D.; Musante, Cynthia J.

2017-01-01

The design of well-powered in vivo preclinical studies is a key element in building knowledge of disease physiology for the purpose of identifying and effectively testing potential anti-obesity drug targets. However, as a result of the complexity of the obese phenotype, there is limited understanding of the variability within and between study animals of macroscopic endpoints such as food intake and body composition. This, combined with limitations inherent in the measurement of certain endpoints, presents challenges to study design that can have significant consequences for an anti-obesity program. Here, we analyze a large, longitudinal study of mouse food intake and body composition during diet perturbation to quantify the variability and interaction of key metabolic endpoints. To demonstrate how conclusions can change as a function of study size, we show that a simulated pre-clinical study properly powered for one endpoint may lead to false conclusions based on secondary endpoints. We then propose guidelines for endpoint selection and study size estimation under different conditions to facilitate proper power calculation for a more successful in vivo study design. PMID:28392555

Biomarkers and surrogate endpoints in kidney disease

PubMed Central

2015-01-01

Kidney disease and its related comorbidities impose a large public health burden. Despite this, the number of clinical trials in nephrology lags behind many other fields. An important factor contributing to the relatively slow pace of nephrology trials is that existing clinical endpoints have significant limitations. “Hard” endpoints for chronic kidney disease, such as progression to end-stage renal disease, may not be reached for decades. Traditional biomarkers, such as serum creatinine in acute kidney injury, may lack sensitivity and predictive value. Finding new biomarkers to serve as surrogate endpoints is therefore an important priority in kidney disease research and may help to accelerate nephrology clinical trials. In this paper, I first review key concepts related to the selection of clinical trial endpoints and discuss statistical and regulatory considerations related to the evaluation of biomarkers as surrogate endpoints. This is followed by a discussion of the challenges and opportunities in developing novel biomarkers and surrogate endpoints in three major areas of nephrology research: acute kidney injury, chronic kidney disease, and autosomal dominant polycystic kidney disease. PMID:25980469

Biomarkers and Surrogate Endpoints in Drug Development: A European Regulatory View.

PubMed

Wickström, Kerstin; Moseley, Jane

2017-05-01

To give a European regulatory overview of the requirements on and the use of biomarkers or surrogate endpoints in the development of drugs for ocular disease. Definitions, methods to validate new markers, and circumstances where surrogate endpoints can be appropriate are summarized. The key endpoints that have been used in registration studies so far are based on visual acuity, signs, and symptoms, or on surrogate endpoints. In some ocular conditions, established outcome measures such as those based on visual acuity or visual field are not feasible (as with slowly progressing diseases), or lack relevance (e.g., when central visual acuity may be preserved even though the patient is legally blind owing to a severely restricted visual field, or vice versa). There are several ocular conditions for which there is an unmet medical need. In some of these conditions, surrogate endpoints as well as new clinical endpoints are needed to help speed up patient access to new medicines. Interaction with European regulators through the pathway specific for the development of biomarkers or novel methods is encouraged.

Anatomy of an experimental two-link flexible manipulator under end-point control

NASA Technical Reports Server (NTRS)

Oakley, Celia M.; Cannon, Robert H., Jr.

1990-01-01

The design and experimental implementation of an end-point controller for two-link flexible manipulators are presented. The end-point controller is based on linear quadratic Gaussian (LQG) theory and is shown to exhibit significant improvements in trajectory tracking over a conventional controller design. To understand the behavior of the manipulator structure under end-point control, a strobe sequence illustrating the link deflections during a typical slew maneuver is included.

Efficient estimation of the distribution of time to composite endpoint when some endpoints are only partially observed

PubMed Central

Daniel, Rhian M.; Tsiatis, Anastasios A.

2014-01-01

Two common features of clinical trials, and other longitudinal studies, are (1) a primary interest in composite endpoints, and (2) the problem of subjects withdrawing prematurely from the study. In some settings, withdrawal may only affect observation of some components of the composite endpoint, for example when another component is death, information on which may be available from a national registry. In this paper, we use the theory of augmented inverse probability weighted estimating equations to show how such partial information on the composite endpoint for subjects who withdraw from the study can be incorporated in a principled way into the estimation of the distribution of time to composite endpoint, typically leading to increased efficiency without relying on additional assumptions above those that would be made by standard approaches. We describe our proposed approach theoretically, and demonstrate its properties in a simulation study. PMID:23722304

Data communications in a parallel active messaging interface of a parallel computer

DOEpatents

Blocksome, Michael A.; Ratterman, Joseph D.; Smith, Brian E.

2014-09-02

Eager send data communications in a parallel active messaging interface (`PAMI`) of a parallel computer, the PAMI composed of data communications endpoints that specify a client, a context, and a task, including receiving an eager send data communications instruction with transfer data disposed in a send buffer characterized by a read/write send buffer memory address in a read/write virtual address space of the origin endpoint; determining for the send buffer a read-only send buffer memory address in a read-only virtual address space, the read-only virtual address space shared by both the origin endpoint and the target endpoint, with all frames of physical memory mapped to pages of virtual memory in the read-only virtual address space; and communicating by the origin endpoint to the target endpoint an eager send message header that includes the read-only send buffer memory address.

Data communications in a parallel active messaging interface of a parallel computer

DOEpatents

Blocksome, Michael A.; Ratterman, Joseph D.; Smith, Brian E.

2014-09-16

Eager send data communications in a parallel active messaging interface (`PAMI`) of a parallel computer, the PAMI composed of data communications endpoints that specify a client, a context, and a task, including receiving an eager send data communications instruction with transfer data disposed in a send buffer characterized by a read/write send buffer memory address in a read/write virtual address space of the origin endpoint; determining for the send buffer a read-only send buffer memory address in a read-only virtual address space, the read-only virtual address space shared by both the origin endpoint and the target endpoint, with all frames of physical memory mapped to pages of virtual memory in the read-only virtual address space; and communicating by the origin endpoint to the target endpoint an eager send message header that includes the read-only send buffer memory address.

Endpoints and cutpoints in head and neck oncology trials: methodical background, challenges, current practice and perspectives.

PubMed

Hezel, Marcus; von Usslar, Kathrin; Kurzweg, Thiemo; Lörincz, Balazs B; Knecht, Rainald

2016-04-01

This article reviews the methodical and statistical basics of designing a trial, with a special focus on the process of defining and choosing endpoints and cutpoints as the foundations of clinical research, and ultimately that of evidence-based medicine. There has been a significant progress in the treatment of head and neck cancer in the past few decades. Currently available treatment options can have a variety of different goals, depending e.g. on tumor stage, among other factors. The outcome of a specific treatment in clinical trials is measured using endpoints. Besides classical endpoints, such as overall survival or organ preservation, other endpoints like quality of life are becoming increasingly important in designing and conducting a trial. The present work is based on electronic research and focuses on the solid methodical and statistical basics of a clinical trial, on the structure of study designs and on the presentation of various endpoints.

Effects of Chronic Social Defeat Stress on Sleep and Circadian Rhythms Are Mitigated by Kappa-Opioid Receptor Antagonism

PubMed Central

Wells, Audrey M.; Ridener, Elysia; Kim, Woori; Carroll, F. Ivy; Cohen, Bruce M.

2017-01-01

Stress plays a critical role in the neurobiology of mood and anxiety disorders. Sleep and circadian rhythms are affected in many of these conditions. Here we examined the effects of chronic social defeat stress (CSDS), an ethological form of stress, on sleep and circadian rhythms. We exposed male mice implanted with wireless telemetry transmitters to a 10 day CSDS regimen known to produce anhedonia (a depressive-like effect) and social avoidance (an anxiety-like effect). EEG, EMG, body temperature, and locomotor activity data were collected continuously during the CSDS regimen and a 5 day recovery period. CSDS affected numerous endpoints, including paradoxical sleep (PS) and slow-wave sleep (SWS), as well as the circadian rhythmicity of body temperature and locomotor activity. The magnitude of the effects increased with repeated stress, and some changes (PS bouts, SWS time, body temperature, locomotor activity) persisted after the CSDS regimen had ended. CSDS also altered mRNA levels of the circadian rhythm-related gene mPer2 within brain areas that regulate motivation and emotion. Administration of the κ-opioid receptor (KOR) antagonist JDTic (30 mg/kg, i.p.) before CSDS reduced stress effects on both sleep and circadian rhythms, or hastened their recovery, and attenuated changes in mPer2. Our findings show that CSDS produces persistent disruptions in sleep and circadian rhythmicity, mimicking attributes of stress-related conditions as they appear in humans. The ability of KOR antagonists to mitigate these disruptions is consistent with previously reported antistress effects. Studying homologous endpoints across species may facilitate the development of improved treatments for psychiatric illness. SIGNIFICANCE STATEMENT Stress plays a critical role in the neurobiology of mood and anxiety disorders. We show that chronic social defeat stress in mice produces progressive alterations in sleep and circadian rhythms that resemble features of depression as it appears in humans. Whereas some of these alterations recover quickly upon cessation of stress, others persist. Administration of a kappa-opioid receptor (KOR) antagonist reduced stress effects or hastened recovery, consistent with the previously reported antistress effects of this class of agents. Use of endpoints, such as sleep and circadian rhythm, that are homologous across species will facilitate the implementation of translational studies that better predict clinical outcomes in humans, improve the success of clinical trials, and facilitate the development of more effective therapeutics. PMID:28674176

B cell increases and ex vivo IL-2 production as secondary endpoints for the detection of sensitizers in non-radioisotopic local lymph node assay using flow cytometry.

PubMed

Jung, Kyoung-Mi; Jang, Won-Hee; Lee, Yong-Kyoung; Yum, Young Na; Sohn, Soojung; Kim, Bae-Hwan; Chung, Jin-Ho; Park, Young-Ho; Lim, Kyung-Min

2012-03-25

Non-radioisotopic local lymph node assay (LLNA) using 5-bromo-2'-deoxyuridine (BrdU) with flow cytometry (FCM) is gaining attention since it is free from the regulatory issues in traditional LLNA (tLLNA) accompanying in vivo uses of radioisotope, (3)H-thymidine. However, there is also concern over compromised performance of non-radioisotopic LLNA, raising needs for additional endpoints to improve the accuracy. With the full 22 reference substances enlisted in OECD Test Guideline No. 429, we evaluated the performance of LLNA:BrdU-FCM along with the concomitant measurements of B/T cell ratio and ex vivo cytokine production from isolated lymph node cells (LNCs) to examine the utility of these markers as secondary endpoints. Mice (Balb/c, female) were topically treated with substances on both ears for 3 days and then, BrdU was intraperitoneally injected on day 5. After a day, lymph nodes were isolated and undergone FCM to determine BrdU incorporation and B/T cell sub-typing with B220+ and CD3e+. Ex vivo cytokine production by LNCs was measured such as IL-2, IL-4, IL-6, IL-12, IFN-γ, MCP-1, GM-CSF and TNFα. Mice treated with sensitizers showed preferential increases in B cell population and the selective production of IL-2, which matched well with the increases in BrdU incorporation. When compared with guinea pig or human data, BrdU incorporation, B cell increase and IL-2 production ex vivo could successfully identify sensitizers with the accuracy comparable to tLLNA, suggesting that these markers may be useful for improving the accuracy of LLNA:BrdU-FCM or as stand-alone non-radioisotopic endpoints. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Polycyclic aromatic hydrocarbon-induced signaling events relevant to inflammation and tumorigenesis in lung cells are dependent on molecular structure.

PubMed

Osgood, Ross S; Upham, Brad L; Hill, Thomas; Helms, Katherine L; Velmurugan, Kalpana; Babica, Pavel; Bauer, Alison K

2014-01-01

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental and occupational toxicants, which are a major human health concern in the U.S. and abroad. Previous research has focused on the genotoxic events caused by high molecular weight PAHs, but not on non-genotoxic events elicited by low molecular weight PAHs. We used an isomeric pair of low molecular weight PAHs, namely 1-Methylanthracene (1-MeA) and 2-Methylanthracene (2-MeA), in which only 1-MeA possessed a bay-like region, and hypothesized that 1-MeA, but not 2-MeA, would affect non-genotoxic endpoints relevant to tumor promotion in murine C10 lung cells, a non-tumorigenic type II alveolar pneumocyte and progenitor cell type of lung adenocarcinoma. The non-genotoxic endpoints assessed were dysregulation of gap junction intercellular communication function and changes in the major pulmonary connexin protein, connexin 43, using fluorescent redistribution and immunoblots, activation of mitogen activated protein kinases (MAPK) using phosphospecific MAPK antibodies for immunoblots, and induction of inflammatory genes using quantitative RT-PCR. 2-MeA had no effect on any of the endpoints, but 1-MeA dysregulated gap junctional communication in a dose and time dependent manner, reduced connexin 43 protein expression, and altered membrane localization. 1-MeA also activated ERK1/2 and p38 MAP kinases. Inflammatory genes, such as cyclooxygenase 2, and chemokine ligand 2 (macrophage chemoattractant 2), were also upregulated in response to 1-MeA only. These results indicate a possible structure-activity relationship of these low molecular weight PAHs relevant to non-genotoxic endpoints of the promoting aspects of cancer. Therefore, our novel findings may improve the ability to predict outcomes for future studies with additional toxicants and mixtures, identify novel targets for biomarkers and chemotherapeutics, and have possible implications for future risk assessment for these PAHs.

Reducing indoor air pollution by air conditioning is associated with improvements in cardiovascular health among the general population.

PubMed

Lin, Lian-Yu; Chuang, Hsiao-Chi; Liu, I-Jung; Chen, Hua-Wei; Chuang, Kai-Jen

2013-10-01

Indoor air pollution is associated with cardiovascular effects, however, little is known about the effects of improving indoor air quality on cardiovascular health. The aim of this study was to explore whether improving indoor air quality through air conditioning can improve cardiovascular health in human subjects. We recruited a panel of 300 healthy subjects from Taipei, aged 20 and over, to participate in six home visits each, to measure a variety of cardiovascular endpoints, including high sensitivity-C-reactive protein (hs-CRP), 8-hydroxy-2'-deoxyguanosine (8-OHdG), fibrinogen in plasma and heart rate variability (HRV). Indoor particles and total volatile organic compounds (VOCs) were measured simultaneously at the participant's home during each visit. Three exposure conditions were investigated in this study: participants were requested to keep their windows open during the first two visits, close their windows during the next two visits, and close the windows and turn on their air conditioners during the last two visits. We used linear mixed-effects models to associate the cardiovascular endpoints with individual indoor air pollutants. The results showed that increases in hs-CRP, 8-OHdG and fibrinogen, and decreases in HRV indices were associated with increased levels of indoor particles and total VOCs in single-pollutant and two-pollutant models. The effects of indoor particles and total VOCs on cardiovascular endpoints were greatest during visits with the windows open. During visits with the air conditioners turned on, no significant changes in cardiovascular endpoints were observed. In conclusion, indoor air pollution is associated with inflammation, oxidative stress, blood coagulation and autonomic dysfunction. Reductions in indoor air pollution and subsequent improvements in cardiovascular health can be achieved by closing windows and turning on air conditioners at home. Copyright © 2013 Elsevier B.V. All rights reserved.

Clinical evidence for orphan medicinal products-a cause for concern?

PubMed

Picavet, Eline; Cassiman, David; Hollak, Carla E; Maertens, Johan A; Simoens, Steven

2013-10-16

The difficulties associated with organising clinical studies for orphan medicinal products (OMPs) are plentiful. Recent debate on the long-term effectiveness of some OMPs, led us to question whether the initial standards for clinical evidence for OMPs, set by the European Medicines Agency (EMA) at the time of marketing authorization, are too low. Therefore, the aim of this study was to quantitatively evaluate the characteristics and quality of clinical evidence that is presented for OMPs to obtain marketing authorization in Europe, using the new and validated COMPASS tool. We quantitatively assessed the characteristics and quality of clinical evidence of the pivotal studies of 64 OMPs as described in the European Public Assessment Report and/or the Scientific Discussion document prepared by the Committee for Human Medicinal Products of the EMA. The 64 OMPs were altogether authorized for 78 orphan indications, for which 117 studies were identified as 'pivotal' or 'main' studies. In approximately two thirds of the studies, the allocation was randomized (64.8%) and a control arm was used (68.5%). Half of the studies applied some type of blinding. Only a minority (26.9%) of the studies included a Quality-of-Life (QoL) related endpoint, of which a third claim an improvement in QoL. Upon analyzing the quality of reporting, we found that some aspects (i.e. the endpoints, the sampling criteria, and the interventions) are well described, whereas other items (i.e. a description of the patients and of potential biases) are not reported for all studies. In conclusion, the pivotal studies that are the basis for marketing authorization of OMPs are a cause for concern, as they exhibit methodological flaws i.e. the lack of QoL-related endpoints as outcome, lack of blinding in the study design and the use of surrogate endpoints. Additionally, there are shortcomings in the reporting of those studies that complicate the interpretation. A more demanding regulatory process for OMPs is needed to guide evidence-based clinical decision-making.

Analysis of operational comfort in manual tasks using human force manipulability measure.

PubMed

Tanaka, Yoshiyuki; Nishikawa, Kazuo; Yamada, Naoki; Tsuji, Toshio

2015-01-01

This paper proposes a scheme for human force manipulability (HFM) based on the use of isometric joint torque properties to simulate the spatial characteristics of human operation forces at an end-point of a limb with feasible magnitudes for a specified limb posture. This is also applied to the evaluation/prediction of operational comfort (OC) when manually operating a human-machine interface. The effectiveness of HFM is investigated through two experiments and computer simulations of humans generating forces by using their upper extremities. Operation force generation with maximum isometric effort can be roughly estimated with an HFM measure computed from information on the arm posture during a maintained posture. The layout of a human-machine interface is then discussed based on the results of operational experiments using an electric gear-shifting system originally developed for robotic devices. The results indicate a strong relationship between the spatial characteristics of the HFM and OC levels when shifting, and the OC is predicted by using a multiple regression model with HFM measures.

The art and science of choosing efficacy endpoints for rare disease clinical trials.

PubMed

Cox, Gerald F

2018-04-01

An important challenge in rare disease clinical trials is to demonstrate a clinically meaningful and statistically significant response to treatment. Selecting the most appropriate and sensitive efficacy endpoints for a treatment trial is part art and part science. The types of endpoints should align with the stage of development (e.g., proof of concept vs. confirmation of clinical efficacy). The patient characteristics and disease stage should reflect the treatment goal of improving disease manifestations or preventing disease progression. For rare diseases, regulatory approval requires demonstration of clinical benefit, defined as how a patient, feels, functions, or survives, in at least one adequate and well-controlled pivotal study conducted according to Good Clinical Practice. In some cases, full regulatory approval can occur using a validated surrogate biomarker, while accelerated, or provisional, approval can occur using a biomarker that is likely to predict clinical benefit. Rare disease studies are small by necessity and require the use of endpoints with large effect sizes to demonstrate statistical significance. Understanding the quantitative factors that determine effect size and its impact on powering the study with an adequate sample size is key to the successful choice of endpoints. Interpreting the clinical meaningfulness of an observed change in an efficacy endpoint can be justified by statistical methods, regulatory precedence, and clinical context. Heterogeneous diseases that affect multiple organ systems may be better accommodated by endpoints that assess mean change across multiple endpoints within the same patient rather than mean change in an individual endpoint across all patients. © 2018 Wiley Periodicals, Inc.

SEMICONDUCTOR TECHNOLOGY A signal processing method for the friction-based endpoint detection system of a CMP process

NASA Astrophysics Data System (ADS)

Chi, Xu; Dongming, Guo; Zhuji, Jin; Renke, Kang

2010-12-01

A signal processing method for the friction-based endpoint detection system of a chemical mechanical polishing (CMP) process is presented. The signal process method uses the wavelet threshold denoising method to reduce the noise contained in the measured original signal, extracts the Kalman filter innovation from the denoised signal as the feature signal, and judges the CMP endpoint based on the feature of the Kalman filter innovation sequence during the CMP process. Applying the signal processing method, the endpoint detection experiments of the Cu CMP process were carried out. The results show that the signal processing method can judge the endpoint of the Cu CMP process.

Hermes III endpoint energy calculation from photonuclear activation of 197Au and 58Ni foils

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

Parzyck, Christopher Thomas

2014-09-01

A new process has been developed to characterize the endpoint energy of HERMES III on a shot-to-shot basis using standard dosimetry tools from the Sandia Radiation Measurements Laboratory. Photonuclear activation readings from nickel and gold foils are used in conjunction with calcium fluoride thermoluminescent dosimeters to derive estimated electron endpoint energies for a series of HERMES shots. The results are reasonably consistent with the expected endpoint voltages on those shots.

Individual and Composite Study Endpoints: Separating the Wheat from the Chaff

PubMed Central

Goldberg, Robert; Gore, Joel M.; Barton, Bruce; Gurwitz, Jerry

2014-01-01

We provide an overview of the individual and combined clinical endpoints and patient reported outcomes typically used in clinical trials and prospective epidemiological investigations. We discuss the strengths and limitations associated with the utilization of aggregated study endpoints and surrogate measures of important clinical endpoints and patient-centered outcomes. We hope that the points raised in this overview will lead to the collection of clinically rich, relevant, measurable, and cost-efficient study outcomes. PMID:24486289

Meta-analyses evaluating surrogate endpoints for overall survival in cancer randomized trials: A critical review.

PubMed

Savina, Marion; Gourgou, Sophie; Italiano, Antoine; Dinart, Derek; Rondeau, Virginie; Penel, Nicolas; Mathoulin-Pelissier, Simone; Bellera, Carine

2018-03-01

In cancer randomized controlled trials (RCT), alternative endpoints are increasingly being used in place of overall survival (OS) to reduce sample size, duration and cost of trials. It is necessary to ensure that these endpoints are valid surrogates for OS. Our aim was to identify meta-analyses that evaluated surrogate endpoints for OS and assess the strength of evidence for each meta-analysis (MA). We performed a systematic review to identify MA of cancer RCTs assessing surrogate endpoints for OS. We evaluated the strength of the association between the endpoints based on (i) the German Institute of Quality and Efficiency in Health Care guidelines and (ii) the Biomarker-Surrogate Evaluation Schema. Fifty-three publications reported on 164 MA, with heterogeneous statistical methods Disease-free survival (DFS) and progression-free survival (PFS) showed good surrogacy properties for OS in colorectal, lung and head and neck cancers. DFS was highly correlated to OS in gastric cancer. The statistical methodology used to evaluate surrogate endpoints requires consistency in order to facilitate the accurate interpretation of the results. Despite the limited number of clinical settings with validated surrogate endpoints for OS, there is evidence of good surrogacy for DFS and PFS in tumor types that account for a large proportion of cancer cases. Copyright © 2017 Elsevier B.V. All rights reserved.

Evaluation of early efficacy endpoints for proof-of-concept trials.

PubMed

Chen, Cong; Sun, Linda; Li, Chih-Lin

2013-03-11

A Phase II proof-of-concept (POC) trial usually uses an early efficacy endpoint other than a clinical endpoint as the primary endpoint. Because of the advancement in bioscience and technology, which has yielded a number of new surrogate biomarkers, drug developers often have more candidate endpoints to choose from than they can handle. As a result, selection of endpoint and its effect size as well as choice of type I/II error rates are often at the center of heated debates in design of POC trials. While optimization of the trade-off between benefit and cost is the implicit objective in such a decision-making process, it is seldom explicitly accounted for in practice. In this research note, motivated by real examples from the oncology field, we provide practical measures for evaluation of early efficacy endpoints (E4) for POC trials. We further provide optimal design strategies for POC trials that include optimal Go-No Go decision criteria for initiation of Phase III and optimal resource allocation strategies for conducting multiple POC trials in a portfolio under fixed resources. Although oncology is used for illustration purpose, the same idea developed in this research note also applies to similar situations in other therapeutic areas or in early-stage drug development in that a Go-No Go decision has to rely on limited data from an early efficacy endpoint and cost-effectiveness is the main concern.

Adjunctive Therapy to Improve Functional Recovery after Limb Ischemia Reperfusion Injury

DTIC Science & Technology

2017-10-01

end-point for the operative procedure that reads as follows: “If an animal is observed on preparation for surgery to have an elevated exhaled end...protocol, e.g. the agent is effective even when administered after the leg has become ischemic. Given that small animal studies have been performed and...in a large animal model that better simulates the way the human body responds to treatment of this important injury process. 15. SUBJECT TERMS

A prospective randomised trial comparing the novel ridaforolimus-eluting BioNIR stent to the zotarolimus-eluting Resolute stent: six-month angiographic and one-year clinical results of the NIREUS trial.

PubMed

Paradies, Valeria; Ben-Yehuda, Ori; Jonas, Michael; Banai, Shmuel; Iñiguez, Andres; Perlman, Gidon Y; Kandzari, David E; Stone, Gregg W; Smits, Pieter C

2018-05-20

The aim of this study was to evaluate the efficacy and safety of the BioNIR stent compared with the Resolute Integrity stent for the treatment of coronary artery disease. This first-in-human, multicentre, single-blind randomised non-inferiority trial was performed in Europe and Israel. Patients with stable coronary artery disease or acute coronary syndromes were randomly assigned to treatment with BioNIR or Resolute Integrity stents in a 2:1 fashion. The primary endpoint was angiographic in-stent late lumen loss (LLL) at six months. Three hundred and two patients were randomised, of whom 261 (86.0%) underwent six-month angiographic follow-up. The BioNIR stent was non-inferior to the Resolute Integrity stent for the primary endpoint of in-stent LLL at six months (0.04±0.30 mm vs. 0.03±0.31 mm, respectively, pnoninferiority<0.0001). At 12-month follow-up, target lesion failure occurred in 3.4% in the BioNIR group and 5.9% in the Resolute Integrity group (p=0.22). Rates of MACE were similar between the BioNIR and Resolute Integrity groups (4.3% vs. 5.9%, respectively, p=0.45). The BioNIR stent was non-inferior to the Resolute Integrity stent for the primary endpoint of angiographic in-stent LLL at six months. Clinical outcomes at one year were comparable between the two groups.

Subjective and objective perceptions of specular gloss and surface roughness of esthetic resin composites before and after artificial aging.

PubMed

Barucci-Pfister, Nadine; Göhring, Till N

2009-04-01

To correlate measurements of specular gloss and surface roughness of resin composite materials with subjective perception of luster before and after artificial aging. Polished specimens of eight composites were compared with human enamel (HE): microfilled SR Adoro (SR); microhybrid Artemis (AR), Enamel HFO (EHFO), Miris (MI), Tetric Ceram (TC), Venus (VE); and nanohybrid CeramX (CX) and nanofilled Filtek Supreme (FS). Before, during and after artificial aging (6000 thermal changes between 5 degrees C and 50 degrees C in an artificial oral environment, 240 hours storage in a container with ethanol, 300 minutes of toothbrushing), specular gloss and surface roughness were measured. Initial and endpoint gloss results were correlated with subjective luster rankings of 10 individuals. Artificial aging resulted in minor (EHFO, CX, FS), moderate (SR, MI, TC, VE) to high (AR) increases in surface roughness. Specular gloss decreased linearly for SR and FS, but decreased after an initial increase for all other materials. Subjectively, AR and FS were rated more and TC, VE and CX less lustrous than HE at baseline. After aging, luster of EHFO and FS was ranked higher and AR, TC, and VE lower than HE. Surface roughness was consistent with subjective perceptions (correlation coefficient: initial r = 0.913; endpoint r = 0.944, P < or = 0.0006), whereas specular gloss was consistent with subjective perceptions only after artificial aging (initial r = 0.616, P = 0.1084; endpoint r = 0.834, P = 0.0072).

Development and Application of Computational/In Vitro Toxicological Methods for Chemical Hazard Risk Reduction of New Materials for Advanced Weapon Systems

NASA Technical Reports Server (NTRS)

Frazier, John M.; Mattie, D. R.; Hussain, Saber; Pachter, Ruth; Boatz, Jerry; Hawkins, T. W.

2000-01-01

The development of quantitative structure-activity relationship (QSAR) is essential for reducing the chemical hazards of new weapon systems. The current collaboration between HEST (toxicology research and testing), MLPJ (computational chemistry) and PRS (computational chemistry, new propellant synthesis) is focusing R&D efforts on basic research goals that will rapidly transition to useful products for propellant development. Computational methods are being investigated that will assist in forecasting cellular toxicological end-points. Models developed from these chemical structure-toxicity relationships are useful for the prediction of the toxicological endpoints of new related compounds. Research is focusing on the evaluation tools to be used for the discovery of such relationships and the development of models of the mechanisms of action. Combinations of computational chemistry techniques, in vitro toxicity methods, and statistical correlations, will be employed to develop and explore potential predictive relationships; results for series of molecular systems that demonstrate the viability of this approach are reported. A number of hydrazine salts have been synthesized for evaluation. Computational chemistry methods are being used to elucidate the mechanism of action of these salts. Toxicity endpoints such as viability (LDH) and changes in enzyme activity (glutahoione peroxidase and catalase) are being experimentally measured as indicators of cellular damage. Extrapolation from computational/in vitro studies to human toxicity, is the ultimate goal. The product of this program will be a predictive tool to assist in the development of new, less toxic propellants.

Challenges in early clinical development of adjuvanted vaccines.

PubMed

Della Cioppa, Giovanni; Jonsdottir, Ingileif; Lewis, David

2015-06-08

A three-step approach to the early development of adjuvanted vaccine candidates is proposed, the goal of which is to allow ample space for exploratory and hypothesis-generating human experiments and to select dose(s) and dosing schedule(s) to bring into full development. Although the proposed approach is more extensive than the traditional early development program, the authors suggest that by addressing key questions upfront the overall time, size and cost of development will be reduced and the probability of public health advancement enhanced. The immunogenicity end-points chosen for early development should be critically selected: an established immunological parameter with a well characterized assay should be selected as primary end-point for dose and schedule finding; exploratory information-rich end-points should be limited in number and based on pre-defined hypothesis generating plans, including system biology and pathway analyses. Building a pharmacodynamic profile is an important aspect of early development: to this end, multiple early (within 24h) and late (up to one year) sampling is necessary, which can be accomplished by sampling subgroups of subjects at different time points. In most cases the final target population, even if vulnerable, should be considered for inclusion in early development. In order to obtain the multiple formulations necessary for the dose and schedule finding, "bed-side mixing" of various components of the vaccine is often necessary: this is a complex and underestimated area that deserves serious research and logistical support. Copyright © 2015 Elsevier Ltd. All rights reserved.

European Academy of Allergy and Clinical Immunology task force report on 'dose-response relationship in allergen-specific immunotherapy'.

PubMed

Calderón, M A; Larenas, D; Kleine-Tebbe, J; Jacobsen, L; Passalacqua, G; Eng, P A; Varga, E M; Valovirta, E; Moreno, C; Malling, H J; Alvarez-Cuesta, E; Durham, S; Demoly, P

2011-10-01

For a century, allergen-specific immunotherapy (SIT) has proven to be an effective treatment for allergic rhinitis, asthma, and insect sting allergy. However, as allergen doses are frequently adapted to the individual patient, there are few data on dose-response relationship in SIT. Allergen products for SIT are being increasingly required to conform to regulatory requirements for human medicines, which include the need to demonstrate dose-dependent effects. This report, produced by a Task Force of the EAACI Immunotherapy Interest Group, evaluates the currently available data on dose-response relationships in SIT and aims to provide recommendations for the design of future studies. Fifteen dose-ranging studies fulfilled the inclusion criteria and twelve reported a dose-response relationship for clinical efficacy. Several studies also reported a dose-response relationship for immunological and safety endpoints. Due to the use of different reference materials and methodologies for the determination of allergen content, variations in study design, and choice of endpoints, no comparisons could be made between studies and, as a consequence, no general dosing recommendations can be made. Despite recently introduced guidelines on the standardization of allergen preparations and study design, the Task Force identified a need for universally accepted standards for the measurement of allergen content in SIT preparations, dosing protocols, and selection of clinical endpoints to enable dose-response effects to be compared across studies. © 2011 John Wiley & Sons A/S.

ToxCast Profiling in a Human Stem Cell Assay for ...

EPA Pesticide Factsheets

Standard practice for assessing disruptions in embryogenesis involves testing pregnant animals of two species, typically rats and rabbits, exposed during major organogenesis and evaluated just prior to term. Under this design the major manifestations of developmental toxicity are observed as one or more apical endpoints including intrauterine death, fetal growth retardation, structural malformations and variations. Alternative approaches to traditional developmental toxicity testing have been proposed in the form of in vitro data (e.g., embryonic stem cells, zebrafish embryos, HTS assays) and in silico models (e.g., computational toxicology). To increase the diversity of assays used to assess developmental toxicity in EPA’s ToxCast program, we tested the chemicals in Stemina’s metabolomics-based platform that utilizes the commecrially available H9 human embryonic stem cell line. The devTOXqP dataset for ToxCast of high-quality based on replicate samples and model performance (82% balanced accuracy, 0.71 sensitivity and 1.00 specificity). To date, 136 ToxCast chemicals (12.8% of 1065 tested) were positive in this platform; 48 triggered the biomarker signal without any change in hESC viability and 88 triggered activity concurrent with effects on cell viability. Work is in progress to complete the STM dataset entry into the TCPL, compare data with results from zFish and mESC platforms, profile bioactivity (ToxCastDB), endpoints (ToxRefDB), chemotypes (DSSTox)

An engineered human antibody to TNF (CDP571) for active Crohn's disease: a randomized double-blind placebo-controlled trial.

PubMed

Sandborn, W J; Feagan, B G; Hanauer, S B; Present, D H; Sutherland, L R; Kamm, M A; Wolf, D C; Baker, J P; Hawkey, C; Archambault, A; Bernstein, C N; Novak, C; Heath, P K; Targan, S R

2001-05-01

We evaluated CDP571, a humanized antibody to tumor necrosis factor, for the treatment of active Crohn's disease. One hundred sixty-nine patients with moderate-to-severe Crohn's disease were enrolled in a 24-week placebo-controlled trial. Patients were initially randomized to a single dose of 10 or 20 mg/kg CDP571 or placebo to assess dose response. Patients were then retreated with 10 mg/kg CDP571 or placebo every 8 or 12 weeks to assess subsequent dosing intervals. The primary endpoint was clinical response at week 2, defined as a decrease in the Crohn's Disease Activity Index score > or = 70 points. At week 2, clinical response occurred in 45% of CDP571-treated patients compared with 27% of patients in the placebo group (P = 0.023). Patients appeared to benefit from retreatment with CDP571 over 24 weeks, but not all of the results for secondary endpoints were statistically significant. The frequency of severe or serious adverse events was similar among all groups. CDP571 at an initial dose of 10 or 20 mg/kg is safe and effective for treatment of patients with moderate-to-severe Crohn's disease. Preliminary evidence suggests that retreatment with 10 mg/kg CDP571 at dose intervals of 8 or 12 weeks may also be beneficial, but additional studies are needed.

Parietal stimulation destabilizes spatial updating across saccadic eye movements.

PubMed

Morris, Adam P; Chambers, Christopher D; Mattingley, Jason B

2007-05-22

Saccadic eye movements cause sudden and global shifts in the retinal image. Rather than causing confusion, however, eye movements expand our sense of space and detail. In macaques, a stable representation of space is embodied by neural populations in intraparietal cortex that redistribute activity with each saccade to compensate for eye displacement, but little is known about equivalent updating mechanisms in humans. We combined noninvasive cortical stimulation with a double-step saccade task to examine the contribution of two human intraparietal areas to transsaccadic spatial updating. Right hemisphere stimulation over the posterior termination of the intraparietal sulcus (IPSp) broadened and shifted the distribution of second-saccade endpoints, but only when the first-saccade was directed into the contralateral hemifield. By interleaving trials with and without cortical stimulation, we show that the shift in endpoints was caused by an enduring effect of stimulation on neural functioning (e.g., modulation of neuronal gain). By varying the onset time of stimulation, we show that the representation of space in IPSp is updated immediately after the first-saccade. In contrast, stimulation of an adjacent IPS site had no such effects on second-saccades. These experiments suggest that stimulation of IPSp distorts an eye position or displacement signal that updates the representation of space at the completion of a saccade. Such sensory-motor integration in IPSp is crucial for the ongoing control of action, and may contribute to visual stability across saccades.

Control of human pathogenic Yersinia enterocolitica in minced meat: Comparative analysis of different interventions using a risk assessment approach.

PubMed

Van Damme, I; De Zutter, L; Jacxsens, L; Nauta, M J

2017-06-01

This study aimed to evaluate the effect of different processing scenarios along the farm-to-fork chain on the contamination of minced pork with human pathogenic Y. enterocolitica. A modular process risk model (MPRM) was used to perform the assessment of the concentrations of pathogenic Y. enterocolitica in minced meat produced in industrial meat processing plants. The model described the production of minced pork starting from the contamination of pig carcasses with pathogenic Y. enterocolitica just before chilling. The endpoints of the assessment were (i) the proportion of 0.5 kg minced meat packages that contained pathogenic Y. enterocolitica and (ii) the proportion of 0.5 kg minced meat packages that contained more than 10³ pathogenic Y. enterocolitica at the end of storage, just before consumption of raw pork or preparation. Comparing alternative scenarios to the baseline model showed that the initial contamination and different decontamination procedures of carcasses have an important effect on the proportion of highly contaminated minced meat packages at the end of storage. The addition of pork cheeks and minimal quantities of tonsillar tissue into minced meat also had a large effect on the endpoint estimate. Finally, storage time and temperature at consumer level strongly influenced the number of highly contaminated packages. Copyright © 2016 Elsevier Ltd. All rights reserved.

Multiple-endpoints gene alteration-based (MEGA) assay: A toxicogenomics approach for water quality assessment of wastewater effluents.

PubMed

Fukushima, Toshikazu; Hara-Yamamura, Hiroe; Nakashima, Koji; Tan, Lea Chua; Okabe, Satoshi

2017-12-01

Wastewater effluents contain a significant number of toxic contaminants, which, even at low concentrations, display a wide variety of toxic actions. In this study, we developed a multiple-endpoints gene alteration-based (MEGA) assay, a real-time PCR-based transcriptomic analysis, to assess the water quality of wastewater effluents for human health risk assessment and management. Twenty-one genes from the human hepatoblastoma cell line (HepG2), covering the basic health-relevant stress responses such as response to xenobiotics, genotoxicity, and cytotoxicity, were selected and incorporated into the MEGA assay. The genes related to the p53-mediated DNA damage response and cytochrome P450 were selected as markers for genotoxicity and response to xenobiotics, respectively. Additionally, the genes that were dose-dependently regulated by exposure to the wastewater effluents were chosen as markers for cytotoxicity. The alterations in the expression of an individual gene, induced by exposure to the wastewater effluents, were evaluated by real-time PCR and the results were validated by genotoxicity (e.g., comet assay) and cell-based cytotoxicity tests. In summary, the MEGA assay is a real-time PCR-based assay that targets cellular responses to contaminants present in wastewater effluents at the transcriptional level; it is rapid, cost-effective, and high-throughput and can thus complement any chemical analysis for water quality assessment and management. Copyright © 2017 Elsevier Ltd. All rights reserved.

Ecosystem Services as Assessment Endpoints in Ecological Risk Assessment

EPA Science Inventory

The focus of ecological risk assessment (ERA) is on assessment endpoints, explicit expressions of environmental values to be protected. Traditionally, the ecological entities identified in assessment endpoints have been components of ecosystems deemed by risk assessors to be impo...

Ovarian cancer clinical trial endpoints: Society of Gynecologic Oncology white paper.

PubMed

Herzog, Thomas J; Armstrong, Deborah K; Brady, Mark F; Coleman, Robert L; Einstein, Mark H; Monk, Bradley J; Mannel, Robert S; Thigpen, J Tate; Umpierre, Sharee A; Villella, Jeannine A; Alvarez, Ronald D

2014-01-01

To explore the value of multiple clinical endpoints in the unique setting of ovarian cancer. A clinical trial workgroup was established by the Society of Gynecologic Oncology to develop a consensus statement via multiple conference calls, meetings and white paper drafts. Clinical trial endpoints have profound effects on late phase clinical trial design, result interpretation, drug development, and regulatory approval of therapeutics. Selection of the optimal clinical trial endpoint is particularly provocative in ovarian cancer where long overall survival (OS) is observed. The lack of new regulatory approvals and the lack of harmony between regulatory bodies globally for ovarian cancer therapeutics are of concern. The advantages and disadvantages of the numerous endpoints available are herein discussed within the unique context of ovarian cancer where both crossover and post-progression therapies potentially uncouple surrogacy between progression-free survival (PFS) and OS, the two most widely supported and utilized endpoints. The roles of patient reported outcomes (PRO) and health related quality of life (HRQoL) are discussed, but even these widely supported parameters are affected by the unique characteristics of ovarian cancer where a significant percentage of patients may be asymptomatic. Original data regarding the endpoint preferences of ovarian cancer advocates is presented. Endpoint selection in ovarian cancer clinical trials should reflect the impact on disease burden and unique characteristics of the treatment cohort while reflecting true patient benefit. Both OS and PFS have led to regulatory approvals and are clinically important. OS remains the most objective and accepted endpoint because it is least vulnerable to bias; however, the feasibility of OS in ovarian cancer is compromised by the requirement for large trial size, prolonged time-line for final analysis, and potential for unintended loss of treatment effect from active post-progression therapies. A large magnitude of effect in PFS improvement should establish benefit, and further communication with regulatory authorities to clarify acceptable endpoints should be undertaken. Copyright © 2013. Published by Elsevier Inc.

Ovarian cancer clinical trial endpoints: Society of Gynecologic Oncology white paper

PubMed Central

Herzog, Thomas J.; Armstrong, Deborah K.; Brady, Mark F.; Coleman, Robert L.; Einstein, Mark H.; Monk, Bradley J.; Mannel, Robert S.; Thigpen, J. Tate; Umpierre, Sharee A.; Villella, Jeannine A.; Alvarez, Ronald D.

2015-01-01

Objective To explore the value of multiple clinical endpoints in the unique setting of ovarian cancer. Methods A clinical trial workgroup was established by the Society of Gynecologic Oncology to develop a consensus statement via multiple conference calls, meetings and white paper drafts. Results Clinical trial endpoints have profound effects on late phase clinical trial design, result interpretation, drug development, and regulatory approval of therapeutics. Selection of the optimal clinical trial endpoint is particularly provocative in ovarian cancer where long overall survival (OS) is observed. The lack of new regulatory approvals and the lack of harmony between regulatory bodies globally for ovarian cancer therapeutics are of concern. The advantages and disadvantages of the numerous endpoints available are herein discussed within the unique context of ovarian cancer where both crossover and post-progression therapies potentially uncouple surrogacy between progression-free survival (PFS) and OS, the two most widely supported and utilized endpoints. The roles of patient reported outcomes (PRO) and health related quality of life (HRQoL) are discussed, but even these widely supported parameters are affected by the unique characteristics of ovarian cancer where a significant percentage of patients may be asymptomatic. Original data regarding the endpoint preferences of ovarian cancer advocates is presented. Conclusions Endpoint selection in ovarian cancer clinical trials should reflect the impact on disease burden and unique characteristics of the treatment cohort while reflecting true patient benefit. Both OS and PFS have led to regulatory approvals and are clinically important. OS remains the most objective and accepted endpoint because it is least vulnerable to bias; however, the feasibility of OS in ovarian cancer is compromised by the requirement for large trial size, prolonged time-line for final analysis, and potential for unintended loss of treatment effect from active post-progression therapies. A large magnitude of effect in PFS improvement should establish benefit, and further communication with regulatory authorities to clarify acceptable endpoints should be undertaken. PMID:24239753

Sublethal Toxicity Endpoints of Heavy Metals to the Nematode Caenorhabditis elegans

PubMed Central

Wu, Yue; Wang, Qiang; Li, Huixin

2016-01-01

Caenorhabditis elegans, a free-living nematode, is commonly used as a model organism in ecotoxicological studies. The current literatures have provided useful insight into the relative sensitivity of several endpoints, but few direct comparisons of multiple endpoints under a common set of experimental conditions. The objective of this study was to determine appropriate sublethal endpoints to develop an ecotoxicity screening and monitoring system. C. elegans was applied to explore the sublethal toxicity of four heavy metals (copper, zinc, cadmium and chromium). Two physiological endpoints (growth and reproduction), three behavioral endpoints (head thrash frequency, body bend frequency and feeding) and two enzymatic endpoints (acetylcholine esterase [AChE] and superoxide dismutase [SOD]) were selected for the assessment of heavy metal toxicity. The squared correlation coefficients (R2) between the responses observed and fitted by Logit function were higher than 0.90 and the RMSE were lower than 0.10, indicating a good significance statistically. There was no significant difference among the half effect concentration (EC50) endpoints in physiological and behavioral effects of the four heavy metals, indicating similar sensitivity of physiological and behavioral effects. AChE enzyme was more sensitive to copper, zinc, and cadmium than to other physiological and behavioral effects, and SOD enzyme was most sensitive to chromium. The EC50 of copper, zinc, and cadmium, to the AChE enzyme in the nematodes were 0.68 mg/L, 2.76 mg/L, and 0.92 mg/L respectively and the EC50 of chromium to the SOD enzyme in the nematode was 1.58 mg/L. The results of this study showed that there was a good concentration-response relationship between all four heavy metals and the sublethal toxicity effects to C. elegans. Considering these sublethal endpoints in terms of simplicity, accuracy, repeatability and costs of the experiments, feeding is the relatively ideal sublethal toxicity endpoint of heavy metals to C. elegans. PMID:26824831

Prognostic factors of clinical endpoints in elderly patients with atrial fibrillation during a 2-year follow-up in China

PubMed Central

Wang, Hao; Wang, Hai-Jun; Chen, Ya-Dong; Tao, Tao; Guo, Yu-Tao; Zhao, Xiao-Ning; Liu, Hong-Bin; Wang, Yu-Tang

2017-01-01

Abstract This study aimed to reveal the incidence of clinical endpoints in elderly patients with atrial fibrillation (AF) during a 2-year follow-up and evaluate the related prognostic factors of these endpoints. In total, 200 elderly patients with AF and 400 age- and sex-matched patients without AF were enrolled in this prospective observational cohort study. The incidence of clinical endpoints, including thromboembolism, hemorrhage, and all-cause death, during the 2-year follow-up was analyzed. Other follow-up data, including disease history, laboratory examinations, medication status, and other clinical endpoints, were collected. The prognostic factors of these clinical endpoints were then evaluated by Cox-survival analysis. In addition, the predicative role of C-reactive protein (CRP) and platelet-activating factor (PAF) on these clinical endpoints was analyzed. The incidence of clinical endpoints, including thromboembolism, hemorrhage, and all-cause death, was significantly higher in patients with AF than in those without AF (27.8% vs 9.8%, 29.4% vs 12.7%, and 28.7% vs 11.6%, respectively; all P < .001). Antithrombotic therapy significantly reduced the incidences of all-cause deaths (P < .05). Body mass index (BMI) and digoxin were prognostic risk factors of thromboembolism; age, massive hemorrhage history, and digoxin were prognostic risk factors of hemorrhage and age, renal insufficiency history, massive hemorrhage history, and digoxin were prognostic risk factors of all-cause death (P < .05). Further, both CRP and PAF were prognostic risk factors of thromboembolism and massive hemorrhage (P < .05). Age, BMI, massive hemorrhage history, and digoxin appear to be prognostic risk factors of clinical endpoints in elderly patients with AF. Appropriate drug use during follow-up may be beneficial in preventing the occurrence of clinical endpoints in elderly patients with AF. Trial registration number: ChiCTR-OCH-13003479. PMID:28816946

Physiological and lavage fluid cytological and biochemical endpoints of toxicity in the rat

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

Lehnert, B.E.

1992-01-01

Exposure of the respiratory tract to toxic materials can result in a variety of physiologic disturbances that can serve as endpoints of toxicity. In addition to a brief review of commonly assessed physiologic endpoints, attention is given in the first component of this report to the use of both nose breathing and mouth'' breathing rats in toxicity studies that involve measurements of ventilatory functional changes in response to test atmospheres. Additionally, the usefulness of maximum oxygen consumption, or VO[sub 2max], as a physiologic endpoint of toxicity that uses exercising rats after exposure to test atmospheres is described, along with anmore » introduction to post-exposure exercise as an important behavioral activity that can markedly impact on the severity of acute lung injury caused by pneumoedematogenic materials. The second component of this report focuses on bronchoalveolar lavage and cytological and biochemical endpoints that can be assessed in investigations of the toxicities of test materials. As will be shown herein, some of the biochemical endpoints of toxicity, especially, can sensitively detect subtle injury to the lower respiratory tract that may escape detection by changes in some other conventional endpoints of toxicity, including lung gravimetric increases and histopathological alterations.« less

Physiological and lavage fluid cytological and biochemical endpoints of toxicity in the rat

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

Lehnert, B.E.

1992-12-31

Exposure of the respiratory tract to toxic materials can result in a variety of physiologic disturbances that can serve as endpoints of toxicity. In addition to a brief review of commonly assessed physiologic endpoints, attention is given in the first component of this report to the use of both nose breathing and ``mouth`` breathing rats in toxicity studies that involve measurements of ventilatory functional changes in response to test atmospheres. Additionally, the usefulness of maximum oxygen consumption, or VO{sub 2max}, as a physiologic endpoint of toxicity that uses exercising rats after exposure to test atmospheres is described, along with anmore » introduction to post-exposure exercise as an important behavioral activity that can markedly impact on the severity of acute lung injury caused by pneumoedematogenic materials. The second component of this report focuses on bronchoalveolar lavage and cytological and biochemical endpoints that can be assessed in investigations of the toxicities of test materials. As will be shown herein, some of the biochemical endpoints of toxicity, especially, can sensitively detect subtle injury to the lower respiratory tract that may escape detection by changes in some other conventional endpoints of toxicity, including lung gravimetric increases and histopathological alterations.« less

Human papilloma virus in the tonsillar microbiota of an Afghan population group.

PubMed

Ruggiero, F; Carbone, D; Mugavero, R; Cura, F; Baggi, L; Arcuri, C; Nardone, M; Gaudio, R M; Gatto, R; Scapoli, L; Carinci, F

2018-01-01

Cancer of the oral cavity is known to have a diverse aetiology that includes infectious agents. Human papilloma virus has been found to be associated with several types of human cancer, inclusive of cervical, vulvar, vaginal, penile, anal, and cancer of tonsil. The aim of this manuscript is to investigate the presence of human papilloma virus in tonsillar microbiota of an Afghan population group. A sample of the tonsillar microbiota was collected by oral swab paper stick from 80 healthy donors. The sample was investigated for the presence of high-risk human papillomavirus types 16, 18, 31 and 45 by real time PCR. Eight samples produced some positive endpoint signals for human papillomaviruses. The human papillomavirus 31 was the unique papillomavirus detected; its calculated prevalence rate was 0.10 (C.I. 0.05-0.19). However, the viral load was always very low, in the order of 10-3 viral genomes per cell. The high prevalence of high-risk human papillomavirus in healthy population suggest a need for further investigation on virus spreading and supports the development of vaccination strategies.

Surrogate endpoints for overall survival in digestive oncology trials: which candidates? A questionnaires survey among clinicians and methodologists.

PubMed

Methy, Nicolas; Bedenne, Laurent; Bonnetain, Franck

2010-06-10

Overall survival (OS) is the gold standard for the demonstration of a clinical benefit in cancer trials. Replacement of OS by a surrogate endpoint allows to reduce trial duration. To date, few surrogate endpoints have been validated in digestive oncology. The aim of this study was to draw up an ordered list of potential surrogate endpoints for OS in digestive cancer trials, by way of a survey among clinicians and methodologists. Secondary objective was to obtain their opinion on surrogacy and quality of life (QoL). In 2007 and 2008, self administered sequential questionnaires were sent to a panel of French clinicians and methodologists involved in the conduct of cancer clinical trials. In the first questionnaire, panellists were asked to choose the most important characteristics defining a surrogate among six proposals, to give advantages and drawbacks of the surrogates, and to answer questions about their validation and use. Then they had to suggest potential surrogate endpoints for OS in each of the following tumour sites: oesophagus, stomach, liver, pancreas, biliary tract, lymphoma, colon, rectum, and anus. They finally gave their opinion on QoL as surrogate endpoint. In the second questionnaire, they had to classify the previously proposed candidate surrogates from the most (position #1) to the least relevant in their opinion.Frequency at which the endpoints were chosen as first, second or third most relevant surrogates was calculated and served as final ranking. Response rate was 30% (24/80) in the first round and 20% (16/80) in the second one. Participants highlighted key points concerning surrogacy. In particular, they reminded that a surrogate endpoint is expected to predict clinical benefit in a well-defined therapeutic situation. Half of them thought it was not relevant to study QoL as surrogate for OS.DFS, in the neoadjuvant settings or early stages, and PFS, in the non operable or metastatic settings, were ranked first, with a frequency of more than 69% in 20 out of 22 settings. PFS was proposed in association with QoL in metastatic primary liver and stomach cancers (both 81%). This composite endpoint was ranked second in metastatic oesophageal (69%), colorectal (56%) and anal (56%) cancers, whereas QoL alone was also suggested in most metastatic situations.Other endpoints frequently suggested were R0 resection in the neoadjuvant settings (oesophagus (69%), stomach (56%), pancreas (75%) and biliary tract (63%)) and response. An unexpected endpoint was metastatic PFS in non operable oesophageal (31%) and pancreatic (44%) cancers. Quality and results of surgical procedures like sphincter preservation were also cited as eligible surrogate endpoints in rectal (19%) and anal (50% in case of localized disease) cancers. Except for alpha-FP kinetic in hepatocellular carcinoma (13%) and CA19-9 decline (6%) in pancreas, few endpoints based on biological or tumour markers were proposed. The overall results should help prioritise the endpoints to be statistically evaluated as surrogate for OS, so that trialists and clinicians can rely on endpoints that ensure relevant clinical benefit to the patient.

Surrogate endpoints for overall survival in digestive oncology trials: which candidates? A questionnaires survey among clinicians and methodologists

PubMed Central

2010-01-01

Background Overall survival (OS) is the gold standard for the demonstration of a clinical benefit in cancer trials. Replacement of OS by a surrogate endpoint allows to reduce trial duration. To date, few surrogate endpoints have been validated in digestive oncology. The aim of this study was to draw up an ordered list of potential surrogate endpoints for OS in digestive cancer trials, by way of a survey among clinicians and methodologists. Secondary objective was to obtain their opinion on surrogacy and quality of life (QoL). Methods In 2007 and 2008, self administered sequential questionnaires were sent to a panel of French clinicians and methodologists involved in the conduct of cancer clinical trials. In the first questionnaire, panellists were asked to choose the most important characteristics defining a surrogate among six proposals, to give advantages and drawbacks of the surrogates, and to answer questions about their validation and use. Then they had to suggest potential surrogate endpoints for OS in each of the following tumour sites: oesophagus, stomach, liver, pancreas, biliary tract, lymphoma, colon, rectum, and anus. They finally gave their opinion on QoL as surrogate endpoint. In the second questionnaire, they had to classify the previously proposed candidate surrogates from the most (position #1) to the least relevant in their opinion. Frequency at which the endpoints were chosen as first, second or third most relevant surrogates was calculated and served as final ranking. Results Response rate was 30% (24/80) in the first round and 20% (16/80) in the second one. Participants highlighted key points concerning surrogacy. In particular, they reminded that a surrogate endpoint is expected to predict clinical benefit in a well-defined therapeutic situation. Half of them thought it was not relevant to study QoL as surrogate for OS. DFS, in the neoadjuvant settings or early stages, and PFS, in the non operable or metastatic settings, were ranked first, with a frequency of more than 69% in 20 out of 22 settings. PFS was proposed in association with QoL in metastatic primary liver and stomach cancers (both 81%). This composite endpoint was ranked second in metastatic oesophageal (69%), colorectal (56%) and anal (56%) cancers, whereas QoL alone was also suggested in most metastatic situations. Other endpoints frequently suggested were R0 resection in the neoadjuvant settings (oesophagus (69%), stomach (56%), pancreas (75%) and biliary tract (63%)) and response. An unexpected endpoint was metastatic PFS in non operable oesophageal (31%) and pancreatic (44%) cancers. Quality and results of surgical procedures like sphincter preservation were also cited as eligible surrogate endpoints in rectal (19%) and anal (50% in case of localized disease) cancers. Except for alpha-FP kinetic in hepatocellular carcinoma (13%) and CA19-9 decline (6%) in pancreas, few endpoints based on biological or tumour markers were proposed. Conclusion The overall results should help prioritise the endpoints to be statistically evaluated as surrogate for OS, so that trialists and clinicians can rely on endpoints that ensure relevant clinical benefit to the patient. PMID:20537166

The multiple stressor ecological risk assessment for the mercury-contaminated South River and upper Shenandoah River using the Bayesian network-relative risk model.

PubMed

Landis, Wayne G; Ayre, Kimberley K; Johns, Annie F; Summers, Heather M; Stinson, Jonah; Harris, Meagan J; Herring, Carlie E; Markiewicz, April J

2017-01-01

We have conducted a regional scale risk assessment using the Bayesian Network Relative Risk Model (BN-RRM) to calculate the ecological risks to the South River and upper Shenandoah River study area. Four biological endpoints (smallmouth bass, white sucker, Belted Kingfisher, and Carolina Wren) and 4 abiotic endpoints (Fishing River Use, Swimming River Use, Boating River Use, and Water Quality Standards) were included in this risk assessment, based on stakeholder input. Although mercury (Hg) contamination was the original impetus for the site being remediated, other chemical and physical stressors were evaluated. There were 3 primary conclusions from the BN-RRM results. First, risk varies according to location, type and quality of habitat, and exposure to stressors within the landscape. The patterns of risk can be evaluated with reasonable certitude. Second, overall risk to abiotic endpoints was greater than overall risk to biotic endpoints. By including both biotic and abiotic endpoints, we are able to compare risk to endpoints that represent a wide range of stakeholder values. Third, whereas Hg reduction is the regulatory priority for the South River, Hg is not the only stressor driving risk to the endpoints. Ecological and habitat stressors contribute risk to the endpoints and should be considered when managing this site. This research provides the foundation for evaluating the risks of multiple stressors of the South River to a variety of endpoints. From this foundation, tools for the evaluation of management options and an adaptive management tools have been forged. Integr Environ Assess Manag 2017;13:85-99. © 2016 SETAC. © 2016 SETAC.

The Role of Surrogate Endpoints in the Evaluation of Efficacy and Safety of Therapeutic Interventions in Diabetes Mellitus

PubMed Central

Wieczorek, Aleksandra; Rys, Przemyslaw; Skrzekowska-Baran, Iwona; Malecki, Maciej

2008-01-01

In this paper, we examine the concept of surrogate endpoints (i.e. substitute outcome measures) and review their use in clinical trials involving therapies for diabetes mellitus using the example of metformin. Trials such as DCCT and UKPDS, in which patient-important endpoints were evaluated, are relatively rare in diabetology. Clinical decisions, therefore, are often based on evidence obtained using surrogate outcomes, usually fasting or postprandial glycemia or glycated hemoglobin level. In contrast to patient-important endpoints, surrogates do not describe direct clinical benefit to the patient. However, a proven association between a surrogate and patient-important endpoint is essential to draw appropriate therapeutic conclusions. In the process of new drug development, the duration of follow-up, sample size and methodology of the studies initially available are often inadequate to demonstrate the effect of the intervention on patient-important endpoints. Evidence concerning the effect of an intervention on surrogate outcomes usually comes first, followed only later by reports describing its influence on patient-important endpoints. Metformin may serve as an example in several ways. The first publications reported beneficial effects on glycemic control and body weight. Outcomes from the subsequent UKPDS study suggested the patient-important efficacy of metformin measured as a reduction in mortality and a decrease in the incidence of diabetic complications, including myocardial infarction. This reasoning process worked for some but not all strategies. It is particularly questionable whether a change in surrogate endpoint was associated with a potential deterioration in patient-important outcomes. Defining the general relationship between surrogates widely used as measures of metabolic control and patient-important endpoints remains an important challenge in contemporary diabetology. PMID:19099084

The role of surrogate endpoints in the evaluation of efficacy and safety of therapeutic interventions in diabetes mellitus.

PubMed

Wieczorek, Aleksandra; Rys, Przemyslaw; Skrzekowska-Baran, Iwona; Malecki, Maciej

2008-01-01

In this paper, we examine the concept of surrogate endpoints (i.e. substitute outcome measures) and review their use in clinical trials involving therapies for diabetes mellitus using the example of metformin. Trials such as DCCT and UKPDS, in which patient-important endpoints were evaluated, are relatively rare in diabetology. Clinical decisions, therefore, are often based on evidence obtained using surrogate outcomes, usually fasting or postprandial glycemia or glycated hemoglobin level. In contrast to patient-important endpoints, surrogates do not describe direct clinical benefit to the patient. However, a proven association between a surrogate and patient-important endpoint is essential to draw appropriate therapeutic conclusions. In the process of new drug development, the duration of follow-up, sample size and methodology of the studies initially available are often inadequate to demonstrate the effect of the intervention on patient-important endpoints. Evidence concerning the effect of an intervention on surrogate outcomes usually comes first, followed only later by reports describing its influence on patient-important endpoints. Metformin may serve as an example in several ways. The first publications reported beneficial effects on glycemic control and body weight. Outcomes from the subsequent UKPDS study suggested the patient-important efficacy of metformin measured as a reduction in mortality and a decrease in the incidence of diabetic complications, including myocardial infarction. This reasoning process worked for some but not all strategies. It is particularly questionable whether a change in surrogate endpoint was associated with a potential deterioration in patient-important outcomes. Defining the general relationship between surrogates widely used as measures of metabolic control and patient-important endpoints remains an important challenge in contemporary diabetology.

Performance of Crohn's disease Clinical Trial Endpoints based upon Different Cutoffs for Patient Reported Outcomes or Endoscopic Activity: Analysis of EXTEND Data.

PubMed

Feagan, Brian; Sandborn, William J; Rutgeerts, Paul; Levesque, Barrett G; Khanna, Reena; Huang, Bidan; Zhou, Qian; Maa, Jen-Fue; Wallace, Kori; Lacerda, Ana; Thakkar, Roopal B; Robinson, Anne M

2018-04-23

Clinical trial endpoints for Crohn's disease (CD) activity correlate poorly with mucosal inflammation; to assess treatment efficacy, patient-reported outcomes and endoscopic assessments are preferred. This study assessed the impact on treatment efficacy estimations of using different definitions of clinical and endoscopic remission and endoscopic response, and of using site- or central-based endoscopy evaluation. This post hoc analysis of data fromEXTEND (extend the safety and efficacy of adalimumab through endoscopic healing), a placebo (PBO)-controlled, randomized trial of adalimumab (ADA) for mucosal healing, included adults with moderate-to-severe CD. Subsets of patients meeting specified Simplified Endoscopic Score for CD (SES-CD) inclusion criteria, according to site or central reading, and baseline stool frequency (SF) and/or abdominal pain score (AP) thresholds were evaluated. Various endpoint definitions based on the Crohn's Disease Activity Index (CDAI), its SF and AP components, SES-CD, and composite endpoints were compared between treatment groups. Increased stringency of Week 12 clinical endpoints compared to CDAI<150 to SF≤3.0/1.5&AP≤1.0 reduced PBO response rates by ≥12% and increased treatment effects by ≤10%. Amending the SES-CD endpoint from ≤4 to ≤2 reduced the treatment effect from 24% to 8%. Composite endpoints further diminished response rates and effect sizes. Site-based evaluation was associated with lower remission rates versus central reading in the PBO group and, thus, greater ADA-related treatment effects. This analysis is the first to demonstrate that increasing the stringency of clinical and endoscopic endpoint definitions in CD trials, especially lowering SF or SES-CD definitions, reduces the ability to detect treatment-related change in CD activity; focus on endpoints that reflect clinical change is warranted.

Interjoint coupling effects on muscle contributions to endpoint force and acceleration in a musculoskeletal model of the cat hindlimb

PubMed Central

van Antwerp, Keith W.; Burkholder, Thomas J.

2015-01-01

The biomechanical principles underlying the organization of muscle activation patterns during standing balance are poorly understood. The goal of this study was to understand the influence of biomechanical inter-joint coupling on endpoint forces and accelerations induced by the activation of individual muscles during postural tasks. We calculated induced endpoint forces and accelerations of 31 muscles in a 7 degree-of-freedom, 3-dimensional model of the cat hindlimb. To test the effects of inter-joint coupling, we systematically immobilized the joints (excluded kinematic degrees-of-freedom) and evaluated how the endpoint force and acceleration directions changed for each muscle in seven different conditions. We hypothesized that altered inter-joint coupling due to joint immobilization of remote joints would substantially change the induced directions of endpoint force and acceleration of individual muscles. Our results show that for most muscles crossing the knee or the hip, joint immobilization altered the endpoint force or acceleration direction by more than 90° in the dorsal and sagittal planes. Induced endpoint forces were typically consistent with behaviorally-observed forces only when the ankle was immobilized. We then activated a proximal muscle simultaneous with an ankle torque of varying magnitude, which demonstrated that the resulting endpoint force or acceleration direction is modulated by the magnitude of the ankle torque. We argue that this simple manipulation can lend insight into the functional effects of co-activating muscles. We conclude that inter-joint coupling may be an essential biomechanical principle underlying the coordination of proximal and distal muscles to produce functional endpoint actions during motor tasks. PMID:17640652

Evaluation of Mysidopsis bahia fecundity endpoint

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

Griffin, D.; Wahl, E.; Krause, P.R.

1995-12-31

The M. bahia chronic toxicity test is commonly used to test estuarine and marine effluent discharges. The test evaluates three endpoints: survival, growth, and fecundity. The fecundity endpoint is often erratic over time and does not necessarily predict accurately other endpoints of effluent toxicity. Therefore, an analysis of the fecundity endpoint was performed to evaluate its use in compliance testing. The endpoint analysis was conducted in three phases: a literature search, analysis of M. bahia data from 24 separate testing events, and interviews with various policy makers, statisticians, and biologists. The literature search revealed a dozen publications, none of whichmore » evaluated fecundity using the EPA method. The literature suggested that evaluating fecundity was labor-intensive and inadequate for practical compliance testing applications. Analysis of the 24 tests revealed that fecundity was evaluated only half of the time (i.e. when at least 50% of the females in the control were fecund). There was a high coefficient of variation (C.V.) between replicates for fecundity (range = 9.--1209.3,x = 85.2%) as compared to survival (range = 0.0--24.0,x = 13.7 %) and growth (range = 7.5--43.9,x = 19.1%). The fecundity results were erratic and did not always follow a dose-response curve, due in part to the small sample size per replicate. Interviews showed that the fecundity endpoint was being evaluated differently by different laboratories. Some were using fecundity for compliance while others were not. Most people interviewed recognized there were inconsistencies with the endpoint. The conclusions drawn from the evaluation were that (1) fecundity does not lend itself for use as a compliance endpoint, (2) the fecundity evaluation process is time consuming and labor intensive, and (3) interpretation of the results is not consistent from laboratory to laboratory and from region to region.« less

Communicating ecological importance in a risk-based world: linking numeric nutrient criteria to waterbody expectations

NASA Astrophysics Data System (ADS)

Kaufman, G.; Crawford, T. N.

2016-12-01

To protect the integrity of US waters, the Clean Water Act calls for the development of water quality standards. One key component of standards is limits for pollutants, known as water quality criteria. A cornerstone of deriving water quality criteria is determining how nutrients and other chemicals affect the goals for a waterbody set by a state or tribe, known as designated uses. By establishing a quantifiable and predictable relationship between nutrients and nutrient sensitive organisms and processes, known as assessment endpoints, researchers can help policy makers to address the consequences of pollution in a risk-based, understandable way tied to the goals for a waterbody. Furthermore, public buy-in and effectiveness of criteria can be enhanced by using endpoints to show the connection between nutrient pollution and the uses of waters that are important to the public. This talk will communicate the work done by the US Environmental Protection Agency in cooperation with state, federal, and academic partners to explore the connections between biological and ecological responses and nutrient pollution to derive numeric nutrient criteria in estuarine and coastal waters. The presentation will examine the variety of endpoints that have been used in the work of various research efforts and assessment frameworks. Examples will also be given of numeric nutrient criteria development using assessment endpoints and some of the key decisions that were made during endpoint selection and criteria development will be discussed. Aspects of those decisions that will be presented include development of selection factors for endpoints, data considerations when selecting endpoints, and spatial and temporal representation of endpoints for criteria development. Promising endpoints and future research needs will also be highlighted.

Communicating ecological importance in a risk-based world: linking numeric nutrient criteria to waterbody expectations

NASA Astrophysics Data System (ADS)

Kaufman, G.; Crawford, T. N.

2016-02-01

To protect the integrity of US waters, the Clean Water Act calls for the development of water quality standards. One key component of standards is limits for pollutants, known as water quality criteria. A cornerstone of deriving water quality criteria is determining how nutrients and other chemicals affect the goals for a waterbody set by a state or tribe, known as designated uses. By establishing a quantifiable and predictable relationship between nutrients and nutrient sensitive organisms and processes, known as assessment endpoints, researchers can help policy makers to address the consequences of pollution in a risk-based, understandable way tied to the goals for a waterbody. Furthermore, public buy-in and effectiveness of criteria can be enhanced by using endpoints to show the connection between nutrient pollution and the uses of waters that are important to the public. This talk will communicate the work done by the US Environmental Protection Agency in cooperation with state, federal, and academic partners to explore the connections between biological and ecological responses and nutrient pollution to derive numeric nutrient criteria in estuarine and coastal waters. The presentation will examine the variety of endpoints that have been used in the work of various research efforts and assessment frameworks. Examples will also be given of numeric nutrient criteria development using assessment endpoints and some of the key decisions that were made during endpoint selection and criteria development will be discussed. Aspects of those decisions that will be presented include development of selection factors for endpoints, data considerations when selecting endpoints, and spatial and temporal representation of endpoints for criteria development. Promising endpoints and future research needs will also be highlighted.

Automatic streak endpoint localization from the cornerness metric

NASA Astrophysics Data System (ADS)

Sease, Brad; Flewelling, Brien; Black, Jonathan

2017-05-01

Streaked point sources are a common occurrence when imaging unresolved space objects from both ground- and space-based platforms. Effective localization of streak endpoints is a key component of traditional techniques in space situational awareness related to orbit estimation and attitude determination. To further that goal, this paper derives a general detection and localization method for streak endpoints based on the cornerness metric. Corners detection involves searching an image for strong bi-directional gradients. These locations typically correspond to robust structural features in an image. In the case of unresolved imagery, regions with a high cornerness score correspond directly to the endpoints of streaks. This paper explores three approaches for global extraction of streak endpoints and applies them to an attitude and rate estimation routine.

An entropy-based nonparametric test for the validation of surrogate endpoints.

PubMed

Miao, Xiaopeng; Wang, Yong-Cheng; Gangopadhyay, Ashis

2012-06-30

We present a nonparametric test to validate surrogate endpoints based on measure of divergence and random permutation. This test is a proposal to directly verify the Prentice statistical definition of surrogacy. The test does not impose distributional assumptions on the endpoints, and it is robust to model misspecification. Our simulation study shows that the proposed nonparametric test outperforms the practical test of the Prentice criterion in terms of both robustness of size and power. We also evaluate the performance of three leading methods that attempt to quantify the effect of surrogate endpoints. The proposed method is applied to validate magnetic resonance imaging lesions as the surrogate endpoint for clinical relapses in a multiple sclerosis trial. Copyright © 2012 John Wiley & Sons, Ltd.

[Detection of endpoint for segmentation between consonants and vowels in aphasia rehabilitation software based on artificial intelligence scheduling].

PubMed

Deng, Xingjuan; Chen, Ji; Shuai, Jie

2009-08-01

For the purpose of improving the efficiency of aphasia rehabilitation training, artificial intelligence-scheduling function is added in the aphasia rehabilitation software, and the software's performance is improved. With the characteristics of aphasia patient's voice as well as with the need of artificial intelligence-scheduling functions under consideration, the present authors have designed a set of endpoint detection algorithm. It determines the reference endpoints, then extracts every word and ensures the reasonable segmentation points between consonants and vowels, using the reference endpoints. The results of experiments show that the algorithm is able to attain the objects of detection at a higher accuracy rate. Therefore, it is applicable to the detection of endpoint on aphasia-patient's voice.

Effects of defined mixtures of persistent organic pollutants (POPs) on multiple cellular responses in the human hepatocarcinoma cell line, HepG2, using high content analysis screening

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

Wilson, Jodie; Berntsen, Hanne Friis; Zimmer, Karin Elisabeth

Persistent organic pollutants (POPs) are toxic substances, highly resistant to environmental degradation, which can bio-accumulate and have long-range atmospheric transport potential. Most studies focus on single compound effects, however as humans are exposed to several POPs simultaneously, investigating exposure effects of real life POP mixtures on human health is necessary. A defined mixture of POPs was used, where the compound concentration reflected its contribution to the levels seen in Scandinavian human serum (total mix). Several sub mixtures representing different classes of POPs were also constructed. The perfluorinated (PFC) mixture contained six perfluorinated compounds, brominated (Br) mixture contained seven brominated compounds,more » chlorinated (Cl) mixture contained polychlorinated biphenyls and also p,p’-dichlorodiphenyldichloroethylene, hexachlorobenzene, three chlordanes, three hexachlorocyclohexanes and dieldrin. Human hepatocarcinoma (HepG2) cells were used for 2 h and 48 h exposures to the seven mixtures and analysis on a CellInsight™ NXT High Content Screening platform. Multiple cytotoxic endpoints were investigated: cell number, nuclear intensity and area, mitochondrial mass and membrane potential (MMP) and reactive oxygen species (ROS). Both the Br and Cl mixtures induced ROS production but did not lead to apoptosis. The PFC mixture induced ROS production and likely induced cell apoptosis accompanied by the dissipation of MMP. Synergistic effects were evident for ROS induction when cells were exposed to the PFC + Br mixture in comparison to the effects of the individual mixtures. No significant effects were detected in the Br + Cl, PFC + Cl or total mixtures, which contain the same concentrations of chlorinated compounds as the Cl mixture plus additional compounds; highlighting the need for further exploration of POP mixtures in risk assessment. - Highlights: • High content analysis (HCA) is a novel approach for determining toxicity of complex mixtures. • Multiple cytotoxic endpoints were investigated for defined mixtures of persistent organic pollutants (POPs). • POP mixtures are based on levels relevant to human exposure. • POP mixtures can increase ROS induction and impact mitochondrial health, which could result in apoptosis. • HCA can detect pre-lethal and reversible signs of cellular stress.« less

Histological Image Feature Mining Reveals Emergent Diagnostic Properties for Renal Cancer

PubMed Central

Kothari, Sonal; Phan, John H.; Young, Andrew N.; Wang, May D.

2016-01-01

Computer-aided histological image classification systems are important for making objective and timely cancer diagnostic decisions. These systems use combinations of image features that quantify a variety of image properties. Because researchers tend to validate their diagnostic systems on specific cancer endpoints, it is difficult to predict which image features will perform well given a new cancer endpoint. In this paper, we define a comprehensive set of common image features (consisting of 12 distinct feature subsets) that quantify a variety of image properties. We use a data-mining approach to determine which feature subsets and image properties emerge as part of an “optimal” diagnostic model when applied to specific cancer endpoints. Our goal is to assess the performance of such comprehensive image feature sets for application to a wide variety of diagnostic problems. We perform this study on 12 endpoints including 6 renal tumor subtype endpoints and 6 renal cancer grade endpoints. Keywords-histology, image mining, computer-aided diagnosis PMID:28163980

Pollutant threshold concentration determination in marine ecosystems using an ecological interaction endpoint.

PubMed

Wang, Changyou; Liang, Shengkang; Guo, Wenting; Yu, Hua; Xing, Wenhui

2015-09-01

The threshold concentrations of pollutants are determined by extrapolating single-species effect data to community-level effects. This assumes the most sensitive endpoint of the life cycle of individuals and the species sensitivity distribution from single-species toxic effect tests, thus, ignoring the ecological interactions. The uncertainties due to this extrapolation can be partially overcome using the equilibrium point of a customized ecosystem. This method incorporates ecological interactions and integrates the effects on growth, survival, and ingestion into a single effect measure, the equilibrium point excursion in the customized ecosystem, in order to describe the toxic effects on plankton. A case study showed that the threshold concentration of copper calculated with the endpoint of the equilibrium point was 10 μg L(-1), which is significantly different from the threshold calculated with a single-species endpoint. The endpoint calculated using this method provides a more relevant measure of the ecological impact than any single individual-level endpoint. Copyright © 2015 Elsevier Ltd. All rights reserved.

Multi-Toxic Endpoints of the Foodborne Mycotoxins in Nematode Caenorhabditis elegans

PubMed Central

Yang, Zhendong; Xue, Kathy S.; Sun, Xiulan; Tang, Lili; Wang, Jia-Sheng

2015-01-01

Aflatoxins B1 (AFB1), deoxynivalenol (DON), fumonisin B1 (FB1), T-2 toxin (T-2), and zearalenone (ZEA) are the major foodborne mycotoxins of public health concerns. In the present study, the multiple toxic endpoints of these naturally-occurring mycotoxins were evaluated in Caenorhabditis elegans model for their lethality, toxic effects on growth and reproduction, as well as influence on lifespan. We found that the lethality endpoint was more sensitive for T-2 toxicity with the EC50 at 1.38 mg/L, the growth endpoint was relatively sensitive for AFB1 toxic effects, and the reproduction endpoint was more sensitive for toxicities of AFB1, FB1, and ZEA. Moreover, the lifespan endpoint was sensitive to toxic effects of all five tested mycotoxins. Data obtained from this study may serve as an important contribution to knowledge on assessment of mycotoxin toxic effects, especially for assessing developmental and reproductive toxic effects, using the C. elegans model. PMID:26633509

Detection of Bordetella pertussis from Clinical Samples by Culture and End-Point PCR in Malaysian Patients.

PubMed

Ting, Tan Xue; Hashim, Rohaidah; Ahmad, Norazah; Abdullah, Khairul Hafizi

2013-01-01

Pertussis or whooping cough is a highly infectious respiratory disease caused by Bordetella pertussis. In vaccinating countries, infants, adolescents, and adults are relevant patients groups. A total of 707 clinical specimens were received from major hospitals in Malaysia in year 2011. These specimens were cultured on Regan-Lowe charcoal agar and subjected to end-point PCR, which amplified the repetitive insertion sequence IS481 and pertussis toxin promoter gene. Out of these specimens, 275 were positive: 4 by culture only, 6 by both end-point PCR and culture, and 265 by end-point PCR only. The majority of the positive cases were from ≤3 months old patients (77.1%) (P < 0.001). There was no significant association between type of samples collected and end-point PCR results (P > 0.05). Our study showed that the end-point PCR technique was able to pick up more positive cases compared to culture method.

A comparison of chemoembolization endpoints using angiographic versus transcatheter intraarterial perfusion/MR imaging monitoring.

PubMed

Lewandowski, Robert J; Wang, Dingxin; Gehl, James; Atassi, Bassel; Ryu, Robert K; Sato, Kent; Nemcek, Albert A; Miller, Frank H; Mulcahy, Mary F; Kulik, Laura; Larson, Andrew C; Salem, Riad; Omary, Reed A

2007-10-01

Transcatheter arterial chemoembolization (TACE) is an established treatment for unresectable liver cancer. This study was conducted to test the hypothesis that angiographic endpoints during TACE are measurable and reproducible by comparing subjective angiographic versus objective magnetic resonance (MR) endpoints of TACE. The study included 12 consecutive patients who presented for TACE for surgically unresectable HCC or progressive hepatic metastases despite chemotherapy. All procedures were performed with a dedicated imaging system. Angiographic series before and after TACE were reviewed independently by three board-certified interventional radiologists. A subjective angiographic chemoembolization endpoint (SACE) classification scheme, modified from an established angiographic grading system in the cardiology literature, was designed to assist in reproducibly classifying angiographic endpoints. Reproducibility in SACE classification level was compared among operators, and MR imaging perfusion reduction was compared with SACE levels for each observer. Twelve patients successfully underwent 15 separate TACE sessions. SACE levels ranged from I through IV. There was moderate agreement in SACE classification (kappa = 0.46 +/- 0.12). There was no correlation between SACE level and MR perfusion reduction (r = 0.16 for one operator and 0.02 for the other two). Angiographic endpoints during TACE vary widely, have moderate reproducibility among operators, and do not correlate with functional MR imaging perfusion endpoints. Future research should aim to determine ideal angiographic and functional MR imaging endpoints for TACE according to outcome measures such as imaging response, pathologic response, and survival.

Confirmatory versus explorative endpoint analysis: Decision-making on the basis of evidence available from market authorization and early benefit assessment for oncology drugs.

PubMed

Niehaus, Ines; Dintsios, Charalabos-Markos

2018-06-01

The early benefit assessment of pharmaceuticals in Germany and their preceding market authorization pursue different objectives. This is reflected by the inclusion of varying confirmatory endpoints within the evaluation of oncology drugs in early benefit assessment versus market authorization, with both relying on the same evidence. Data from assessments up to July 2015 are used to estimate the impact of explorative in comparison to confirmatory endpoints on market authorization and early benefit assessment by contrasting the benefit-risk ratio of EMA and the benefit-harm balance of the HTA jurisdiction. Agreement between market authorization and early benefit assessment is examined by Cohen's kappa (k). 21 of 41 assessments were considered in the analysis. Market authorization is more confirmatory than early benefit assessment because it includes a higher proportion of primary endpoints. The latter implies a primary endpoint to be relevant for the benefit-harm balance in only 67% of cases (0.078). Explorative mortality endpoints reached the highest agreement regarding the mutual consideration for the risk-benefit ratio and the benefit-harm balance (0.000). For explorative morbidity endpoints (-0.600), quality of life (-0.600) and side effects (-0.949) no agreement is ascertainable. To warrant a broader confirmatory basis for decisions supported by HTA, closer inter-institutional cooperation of approval authorities and HTA jurisdictions by means of reliable joint advice for manufacturers regarding endpoint definition would be favorable. Copyright © 2018 Elsevier B.V. All rights reserved.

Occipital White Matter Tracts in Human and Macaque

PubMed Central

Takemura, Hiromasa; Pestilli, Franco; Weiner, Kevin S.; Landi, Sofia M.; Sliwa, Julia; Ye, Frank Q.; Barnett, Michael A.; Leopold, David A.; Freiwald, Winrich A.; Logothetis, Nikos K.; Wandell, Brian A.

2017-01-01

Abstract We compare several major white-matter tracts in human and macaque occipital lobe using diffusion magnetic resonance imaging. The comparison suggests similarities but also significant differences in the tracts. There are several apparently homologous tracts in the 2 species, including the vertical occipital fasciculus (VOF), optic radiation, forceps major, and inferior longitudinal fasciculus (ILF). There is one large human tract, the inferior fronto-occipital fasciculus, with no corresponding fasciculus in macaque. We could identify the macaque VOF (mVOF), which has been little studied. Its position is consistent with classical invasive anatomical studies by Wernicke. VOF homology is supported by similarity of the endpoints in V3A and ventral V4 across species. The mVOF fibers intertwine with the dorsal segment of the ILF, but the human VOF appears to be lateral to the ILF. These similarities and differences between the occipital lobe tracts will be useful in establishing which circuitry in the macaque can serve as an accurate model for human visual cortex. PMID:28369290

77 FR 49447 - Endpoints for Clinical Trials in Kidney Transplantation; Public Workshop

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-16

...] Endpoints for Clinical Trials in Kidney Transplantation; Public Workshop AGENCY: Food and Drug... public workshop to discuss the endpoints for clinical trials of drugs and therapeutic biologics in kidney... trials of kidney transplantation. The meeting will include a discussion of measure of patient and graft...

Assessing the validity of surrogate endpoints in the context of a controversy about the measurement of effectiveness of hepatitis C virus treatment.

PubMed

Dobler, Claudia C; Morgan, Rebecca L; Falck-Ytter, Yngve; Montori, Victor M; Murad, M Hassan

2018-04-01

Surrogate endpoints are often used in clinical trials, as they allow for indirect measures of outcomes (eg, shorter trials with less participants). Improvements in surrogate endpoints (eg, reduction in low density lipoprotein cholesterol, normalisation of glycated haemoglobin) achieved with an intervention are, however, not always associated with improvements in patient-important outcomes. The common tendency in evidence-based medicine is to view results based on surrogate endpoints as less certain than results based on long term, final patient-important outcomes and rate them as 'lower quality evidence'. However, careful appraisal of the validity of a surrogate endpoint as a measure of the final, patient-important outcome is more useful than an automatic judgement. In this guide, we use a contemporary and currently highly debated example of the surrogate endpoint 'sustained viral response' (ie, viral eradication considered to represent successful treatment) in patients treated for chronic hepatitis C virus. We demonstrate how the validity of a surrogate endpoint can be critically appraised to assess the quality of the evidence (ie, the certainty in estimates) and the implications for decision-making. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

A web-based endpoint adjudication system for interim analyses in clinical trials.

PubMed

Nolen, Tracy L; Dimmick, Bill F; Ostrosky-Zeichner, Luis; Kendrick, Amy S; Sable, Carole; Ngai, Angela; Wallace, Dennis

2009-02-01

A data monitoring committee (DMC) is often employed to assess trial progress and review safety data and efficacy endpoints throughout a trail. Interim analyses performed for the DMC should use data that are as complete and verified as possible. Such analyses are complicated when data verification involves subjective study endpoints or requires clinical expertise to determine each subject's status with respect to the study endpoint. Therefore, procedures are needed to obtain adjudicated data for interim analyses in an efficient manner. In the past, methods for handling such data included using locally reported results as surrogate endpoints, adjusting analysis methods for unadjudicated data, or simply performing the adjudication as rapidly as possible. These methods all have inadequacies that make their sole usage suboptimal. For a study of prophylaxis for invasive candidiasis, adjudication of both study eligibility criteria and clinical endpoints prior to two interim analyses was required. Because the study was expected to enroll at a moderate rate and the sponsor required adjudicated endpoints to be used for interim analyses, an efficient process for adjudication was required. We created a web-based endpoint adjudication system (WebEAS) that allows for expedited review by the endpoint adjudication committee (EAC). This system automatically identifies when a subject's data are complete, creates a subject profile from the study data, and assigns EAC reviewers. The reviewers use the WebEAS to review the subject profile and submit their completed review form. The WebEAS then compares the reviews, assigns an additional review as a tiebreaker if needed, and stores the adjudicated data. The study for which this system was originally built was administratively closed after 10 months with only 38 subjects enrolled. The adjudication process was finalized and the WebEAS system activated prior to study closure. Some website accessibility issues presented initially. However, once these issues were resolved, the reviewers found the system user-friendly and easy to navigate. Web-based data adjudication depends upon expeditious data collection and verification. Further, ability to use web-based technologies, in addition to clinical expertise, must be considered in selecting EAC members. The automated nature of this system makes it a practical mechanism for ensuring timely endpoint adjudication. The authors believe a similar approach could be useful for handling endpoint adjudication for future clinical trials.

Diatoms to human uses: linking nitrogen deposition, aquatic eutrophication, and ecosystem services

DOE PAGES

Rhodes, Charles; Bingham, Andrew; Heard, Andrea M.; ...

2017-07-24

Nitrogen (N) loading to aquatic ecosystems can lead to eutrophication, changing the ecosystem within a waterbody, including primary productivity, water clarity, and food web dynamics. Nutrient loading often first affects the primary productivity of aquatic systems through shifts in phytoplankton communities. However, ecologically important changes in phytoplankton are often not relatable to the general public—whose behavior would need to change to alter patterns of nutrient loading. Therefore, we use the STressor–Ecological Production function–final ecosystem Services Framework to develop 154 chains that link changes in biological indicators of aquatic eutrophication (a shift in phytoplankton community) to final ecosystem services that peoplemore » use or appreciate. We identify 13 ecological production functions (EPF) within three different ecosystems (alpine lakes, lakes, and estuaries) that connect changes in phytoplankton and algae to ecological endpoints that the general public and policy makers can appreciate. Using the Final Ecosystem Goods and Services Classification System, we identify 18 classes of human beneficiaries that potentially will be impacted by a change in one of these endpoints. We further assign strength-of-science scores to each link within the EPFs for the 154 chains according to how well each link is supported by current peer-reviewed literature. By identifying many pathways through which excess N loading in U.S. surface waters can affect ecosystems and ultimately the beneficiaries of ecosystem services, this work intends to draw attention to gaps in empirical ecological literature that constrain understanding of the magnitude of effects that excess N loading can have on human well-being. Here, results highlight the importance of intersections between the natural and social sciences when managers and policy makers evaluate impacts from ecological stressors. A balance between knowledgeable specialists proved key to applying this approach and will continue to remain important.« less

Diatoms to human uses: linking nitrogen deposition, aquatic eutrophication, and ecosystem services

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

Rhodes, Charles; Bingham, Andrew; Heard, Andrea M.

Nitrogen (N) loading to aquatic ecosystems can lead to eutrophication, changing the ecosystem within a waterbody, including primary productivity, water clarity, and food web dynamics. Nutrient loading often first affects the primary productivity of aquatic systems through shifts in phytoplankton communities. However, ecologically important changes in phytoplankton are often not relatable to the general public—whose behavior would need to change to alter patterns of nutrient loading. Therefore, we use the STressor–Ecological Production function–final ecosystem Services Framework to develop 154 chains that link changes in biological indicators of aquatic eutrophication (a shift in phytoplankton community) to final ecosystem services that peoplemore » use or appreciate. We identify 13 ecological production functions (EPF) within three different ecosystems (alpine lakes, lakes, and estuaries) that connect changes in phytoplankton and algae to ecological endpoints that the general public and policy makers can appreciate. Using the Final Ecosystem Goods and Services Classification System, we identify 18 classes of human beneficiaries that potentially will be impacted by a change in one of these endpoints. We further assign strength-of-science scores to each link within the EPFs for the 154 chains according to how well each link is supported by current peer-reviewed literature. By identifying many pathways through which excess N loading in U.S. surface waters can affect ecosystems and ultimately the beneficiaries of ecosystem services, this work intends to draw attention to gaps in empirical ecological literature that constrain understanding of the magnitude of effects that excess N loading can have on human well-being. Here, results highlight the importance of intersections between the natural and social sciences when managers and policy makers evaluate impacts from ecological stressors. A balance between knowledgeable specialists proved key to applying this approach and will continue to remain important.« less

Effects of first formant onset frequency on [-voice] judgments result from auditory processes not specific to humans.

PubMed

Kluender, K R; Lotto, A J

1994-02-01

When F1-onset frequency is lower, longer F1 cut-back (VOT) is required for human listeners to perceive synthesized stop consonants as voiceless. K. R. Kluender [J. Acoust. Soc. Am. 90, 83-96 (1991)] found comparable effects of F1-onset frequency on the "labeling" of stop consonants by Japanese quail (coturnix coturnix japonica) trained to distinguish stop consonants varying in F1 cut-back. In that study, CVs were synthesized with natural-like rising F1 transitions, and endpoint training stimuli differed in the onset frequency of F1 because a longer cut-back resulted in a higher F1 onset. In order to assess whether earlier results were due to auditory predispositions or due to animals having learned the natural covariance between F1 cut-back and F1-onset frequency, the present experiment was conducted with synthetic continua having either a relatively low (375 Hz) or high (750 Hz) constant-frequency F1. Six birds were trained to respond differentially to endpoint stimuli from three series of synthesized /CV/s varying in duration of F1 cut-back. Second and third formant transitions were appropriate for labial, alveolar, or velar stops. Despite the fact that there was no opportunity for animal subjects to use experienced covariation of F1-onset frequency and F1 cut-back, quail typically exhibited shorter labeling boundaries (more voiceless stops) for intermediate stimuli of the continua when F1 frequency was higher. Responses by human subjects listening to the same stimuli were also collected. Results lend support to the earlier conclusion that part or all of the effect of F1 onset frequency on perception of voicing may be adequately explained by general auditory processes.(ABSTRACT TRUNCATED AT 250 WORDS)

Potency of a human monoclonal antibody to diphtheria toxin relative to equine diphtheria anti-toxin in a guinea pig intoxication model

PubMed Central

Smith, Heidi L.; Cheslock, Peter; Leney, Mark; Barton, Bruce; Molrine, Deborah C.

2016-01-01

ABSTRACT Prompt administration of anti-toxin reduces mortality following Corynebacterium diphtheriae infection. Current treatment relies upon equine diphtheria anti-toxin (DAT), with a 10% risk of serum sickness and rarely anaphylaxis. The global DAT supply is extremely limited; most manufacturers have ceased production. S315 is a neutralizing human IgG1 monoclonal antibody to diphtheria toxin that may provide a safe and effective alternative to equine DAT and address critical supply issues. To guide dose selection for IND-enabling pharmacology and toxicology studies, we dose-ranged S315 and DAT in a guinea pig model of diphtheria intoxication based on the NIH Minimum Requirements potency assay. Animals received a single injection of antibody premixed with toxin, were monitored for 30 days, and assigned a numeric score for clinical signs of disease. Animals receiving ≥ 27.5 µg of S315 or ≥ 1.75 IU of DAT survived whereas animals receiving ≤ 22.5 µg of S315 or ≤ 1.25 IU of DAT died, yielding a potency estimate of 17 µg S315/IU DAT (95% CI 16–21) for an endpoint of survival. Because some surviving animals exhibited transient limb weakness, likely a systemic sign of toxicity, DAT and S315 doses required to prevent hind limb paralysis were also determined, yielding a relative potency of 48 µg/IU (95% CI 38–59) for this alternate endpoint. To support advancement of S315 into clinical trials, potency estimates will be used to evaluate the efficacy of S315 versus DAT in an animal model with antibody administration after toxin exposure, more closely modeling anti-toxin therapy in humans. PMID:27070129

Epidemiology of Rickettsia sp. strain Atlantic rainforest in a spotted fever-endemic area of southern Brazil.

PubMed

Barbieri, Amalia R M; Filho, Jonas M; Nieri-Bastos, Fernanda A; Souza, Julio C; Szabó, Matias P J; Labruna, Marcelo B

2014-10-01

The present study was performed in Vila Itoupava, an area of the state of Santa Catarina, southern Brazil, in which a tick-borne spotted fever illness has been endemic since 2003. Notably, both the etiological agent and the vector of these spotted fever cases remain unknown. During January 2011, humans, domestic dogs, and their ticks were sampled in households that are typically surrounded by highly preserved Atlantic rainforest fragments. Ticks collected from dogs were Amblyomma ovale (34% prevalence), Amblyomma aureolatum (18.9%), and Rhipicephalus sanguineus (3.8%). A total of 7.8% (6/77) A. ovale and 9.3% (4/43) A. aureolatum were infected by Rickettsia sp. strain Atlantic rainforest, a Rickettsia parkeri-like agent recently shown to cause spotted fever illness in southeastern Brazil. Overall, 67.3% (35/52) of the dogs were seroreactive to spotted fever group rickettsiae, mostly with highest endpoint titers to R. parkeri. Among humans, 46.7% (7/15) reacted serologically to rickettsiae at low to moderate endpoint titers. Because canine seroreactivity to R. parkeri was strongly associated with frequent contact with forests (the preferred habitat for A. ovale and A. aureolatum), it is concluded that sampled dogs have been infected by strain Atlantic rainforest through the parasitism of these tick species. The present study provides epidemiological evidence that the spotted fever in the study area has been caused by Rickettsia sp. strain Atlantic rainforest, transmitted to humans by either A. ovale or A. aureolatum. Further studies encompassing direct diagnostic methods on clinical specimens from patients are needed to confirm the above epidemiological evidence. Copyright © 2014 Elsevier GmbH. All rights reserved.

The Human Skin Microbiome Associates with the Outcome of and Is Influenced by Bacterial Infection

PubMed Central

van Rensburg, Julia J.; Lin, Huaiying; Gao, Xiang; Toh, Evelyn; Fortney, Kate R.; Ellinger, Sheila; Zwickl, Beth; Janowicz, Diane M.; Katz, Barry P.; Nelson, David E.; Dong, Qunfeng

2015-01-01

ABSTRACT The influence of the skin microbiota on host susceptibility to infectious agents is largely unexplored. The skin harbors diverse bacterial species that may promote or antagonize the growth of an invading pathogen. We developed a human infection model for Haemophilus ducreyi in which human volunteers are inoculated on the upper arm. After inoculation, papules form and either spontaneously resolve or progress to pustules. To examine the role of the skin microbiota in the outcome of H. ducreyi infection, we analyzed the microbiomes of four dose-matched pairs of “resolvers” and “pustule formers” whose inoculation sites were swabbed at multiple time points. Bacteria present on the skin were identified by amplification and pyrosequencing of 16S rRNA genes. Nonmetric multidimensional scaling (NMDS) using Bray-Curtis dissimilarity between the preinfection microbiomes of infected sites showed that sites from the same volunteer clustered together and that pustule formers segregated from resolvers (P = 0.001, permutational multivariate analysis of variance [PERMANOVA]), suggesting that the preinfection microbiomes were associated with outcome. NMDS using Bray-Curtis dissimilarity of the endpoint samples showed that the pustule sites clustered together and were significantly different than the resolved sites (P = 0.001, PERMANOVA), suggesting that the microbiomes at the endpoint differed between the two groups. In addition to H. ducreyi, pustule-forming sites had a greater abundance of Proteobacteria, Bacteroidetes, Micrococcus, Corynebacterium, Paracoccus, and Staphylococcus species, whereas resolved sites had higher levels of Actinobacteria and Propionibacterium species. These results suggest that at baseline, resolvers and pustule formers have distinct skin bacterial communities which change in response to infection and the resultant immune response. PMID:26374122

Using physiologically based pharmacokinetic modeling and benchmark dose methods to derive an occupational exposure limit for N-methylpyrrolidone.

PubMed

Poet, T S; Schlosser, P M; Rodriguez, C E; Parod, R J; Rodwell, D E; Kirman, C R

2016-04-01

The developmental effects of NMP are well studied in Sprague-Dawley rats following oral, inhalation, and dermal routes of exposure. Short-term and chronic occupational exposure limit (OEL) values were derived using an updated physiologically based pharmacokinetic (PBPK) model for NMP, along with benchmark dose modeling. Two suitable developmental endpoints were evaluated for human health risk assessment: (1) for acute exposures, the increased incidence of skeletal malformations, an effect noted only at oral doses that were toxic to the dam and fetus; and (2) for repeated exposures to NMP, changes in fetal/pup body weight. Where possible, data from multiple studies were pooled to increase the predictive power of the dose-response data sets. For the purposes of internal dose estimation, the window of susceptibility was estimated for each endpoint, and was used in the dose-response modeling. A point of departure value of 390 mg/L (in terms of peak NMP in blood) was calculated for skeletal malformations based on pooled data from oral and inhalation studies. Acceptable dose-response model fits were not obtained using the pooled data for fetal/pup body weight changes. These data sets were also assessed individually, from which the geometric mean value obtained from the inhalation studies (470 mg*hr/L), was used to derive the chronic OEL. A PBPK model for NMP in humans was used to calculate human equivalent concentrations corresponding to the internal dose point of departure values. Application of a net uncertainty factor of 20-21, which incorporates data-derived extrapolation factors, to the point of departure values yields short-term and chronic occupational exposure limit values of 86 and 24 ppm, respectively. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Poxvirus Antigen Staining of Immune Cells as a Biomarker to Predict Disease Outcome in Monkeypox and Cowpox Virus Infection in Non-Human Primates

PubMed Central

Song, Haifeng; Janosko, Krisztina; Johnson, Reed F.; Qin, Jing; Josleyn, Nicole; Jett, Catherine; Byrum, Russell; Claire, Marisa St.; Dyall, Julie; Blaney, Joseph E.; Jennings, Gerald; Jahrling, Peter B.

2013-01-01

Infection of non-human primates (NHPs) such as rhesus and cynomolgus macaques with monkeypox virus (MPXV) or cowpox virus (CPXV) serve as models to study poxvirus pathogenesis and to evaluate vaccines and anti-orthopox therapeutics. Intravenous inoculation of macaques with high dose of MPXV (>1–2×107 PFU) or CPXV (>102 PFU) results in 80% to 100% mortality and 66 to 100% mortality respectively. Here we report that NHPs with positive detection of poxvirus antigens in immune cells by flow cytometric staining, especially in monocytes and granulocytes succumbed to virus infection and that early positive pox staining is a strong predictor for lethality. Samples from four independent studies were analyzed. Eighteen NHPs from three different experiments were inoculated with two different MPXV strains at lethal doses. Ten NHPs displayed positive pox-staining and all 10 NHPs reached moribund endpoint. In contrast, none of the three NHPs that survived anticipated lethal virus dose showed apparent virus staining in the monocytes and granulocytes. In addition, three NHPs that were challenged with a lethal dose of MPXV and received cidofovir treatment were pox-antigen negative and all three NHPs survived. Furthermore, data from a CPXV study also demonstrated that 6/9 NHPs were pox-antigen staining positive and all 6 NHPs reached euthanasia endpoint, while the three survivors were pox-antigen staining negative. Thus, we conclude that monitoring pox-antigen staining in immune cells can be used as a biomarker to predict the prognosis of virus infection. Future studies should focus on the mechanisms and implications of the pox-infection of immune cells and the correlation between pox-antigen detection in immune cells and disease progression in human poxviral infection. PMID:23577120

Perfluoroalkylated substances (PFAS) affect neither estrogen and androgen receptor activity nor steroidogenesis in human cells in vitro.

PubMed

Behr, Anne-Cathrin; Lichtenstein, Dajana; Braeuning, Albert; Lampen, Alfonso; Buhrke, Thorsten

2018-07-01

The perfluoroalkylated substances (PFAS) perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) are used for the fabrication of water- and dirt-repellent surfaces. The use of PFOS and PFOA was restricted due to their reprotoxic properties and their environmental persistence. Therefore, industry switches to alternative PFAS, however, in contrast to PFOA and PFOS only few toxicological data are available for their substitutes. The molecular mechanism(s) underlying reproductive toxicity of PFOA and PFOS are largely unknown. Here, the endocrine properties of PFOA, PFOS, and of six substitutes including perfluorohexanesulfonic acid (PFHxS), perfluorobutanesulfonic acid (PFBS), perfluorohexanoic acid (PFHxA), perfluorobutanoic acid (PFBA), ammonium perfluoro(2-methyl-3-oxahexanoate) (PMOH), and 3H-perfluoro-3-[(3-methoxypropoxy) propanoic acid] (PMPP) were examined in vitro by using human cell lines such as MCF-7, H295R, LNCaP and MDA-kb2. PFOA, PFOS and PMOH enhanced 17β-estradiol-stimulated estrogen receptor β activity, and PFOS, PMOH, PFHxA and PFBA enhanced dihydrotestosterone-stimulated androgen receptor activity. In the H295R steroidogenesis assay, PFOA and PFOS slightly enhanced estrone secretion, and progesterone secretion was marginally increased by PFOA. All these effects were only observed at concentrations above 10 μM, and none of the PFAS displayed any effect on any of the molecular endocrine endpoints at concentrations of 10 μM or below. Thus, as the blood serum concentrations of the different PFAS in the general Western population are in the range of 10 nM or below, the results suggest that PFAS might not exert endocrine effects in humans at exposure-relevant concentrations according to the molecular endpoints examined in this study. Copyright © 2018 Elsevier B.V. All rights reserved.

Potency of a human monoclonal antibody to diphtheria toxin relative to equine diphtheria anti-toxin in a guinea pig intoxication model.

PubMed

Smith, Heidi L; Cheslock, Peter; Leney, Mark; Barton, Bruce; Molrine, Deborah C

2016-08-17

Prompt administration of anti-toxin reduces mortality following Corynebacterium diphtheriae infection. Current treatment relies upon equine diphtheria anti-toxin (DAT), with a 10% risk of serum sickness and rarely anaphylaxis. The global DAT supply is extremely limited; most manufacturers have ceased production. S315 is a neutralizing human IgG1 monoclonal antibody to diphtheria toxin that may provide a safe and effective alternative to equine DAT and address critical supply issues. To guide dose selection for IND-enabling pharmacology and toxicology studies, we dose-ranged S315 and DAT in a guinea pig model of diphtheria intoxication based on the NIH Minimum Requirements potency assay. Animals received a single injection of antibody premixed with toxin, were monitored for 30 days, and assigned a numeric score for clinical signs of disease. Animals receiving ≥ 27.5 µg of S315 or ≥ 1.75 IU of DAT survived whereas animals receiving ≤ 22.5 µg of S315 or ≤ 1.25 IU of DAT died, yielding a potency estimate of 17 µg S315/IU DAT (95% CI 16-21) for an endpoint of survival. Because some surviving animals exhibited transient limb weakness, likely a systemic sign of toxicity, DAT and S315 doses required to prevent hind limb paralysis were also determined, yielding a relative potency of 48 µg/IU (95% CI 38-59) for this alternate endpoint. To support advancement of S315 into clinical trials, potency estimates will be used to evaluate the efficacy of S315 versus DAT in an animal model with antibody administration after toxin exposure, more closely modeling anti-toxin therapy in humans.

Painting analysis of chromosome aberrations induced by energetic heavy ions in human cells

NASA Astrophysics Data System (ADS)

Wu, H.; Hada, M.; Cucinotta, F. A.

Energetic heavy ions pose a great health risk to astronauts in extended ISS and future exploration missions High-LET heavy ions are particularly effective in causing various biological effects including cell inactivation genetic mutations and cancer induction Most of these biological endpoints are closely related to chromosomal damage which can be utilized as a biomarker for radiation insults Over the years we have studied chromosomal damage in human fibroblast epithelia and lymphocyte cells exposed in vitro to energetic charged particles generated at several accelerator facilities in the world Various fluorescence in situ hybridization painting techniques have been used to identify from only the telomere region of the chromosome to every chromosome in a human cell We will summarize the results of the investigations and discuss the unique radiation signatures and biomarkers for space radiation exposure

Surrogate endpoints for overall survival in advanced colorectal cancer: a clinician's perspective.

PubMed

Piedbois, Pascal; Miller Croswell, Jennifer

2008-10-01

Surrogate endpoints in oncology research and practice have garnered increasing attention over the past two decades. This activity has largely been driven by the promise surrogate endpoints appear to hold: the potential to get new therapies to seriously ill patients more rapidly. However, uncertainties abound. Even agreeing upon a definition of a "valid" surrogate endpoint has not been a straightforward exercise; this article begins by highlighting differences in how this term has been previously captured and applied, as well as laying out the basic criteria essential for its application in advanced colorectal cancer. Ideally, these elements include (but are not limited to) ease of measurement, rapid indication of treatment effect, and, most importantly, reliable and consistent prediction of the true impact of a treatment on the ultimate outcome of interest: overall survival. The strengths and weaknesses of current potential surrogate endpoints in advanced colorectal cancer, including performance status, carcinoembryonic antigen plasma level, overall response rate, time to progression, and disease-free survival, are each considered in turn. Finally, limitations of surrogate endpoints in the clinical setting, including challenges in extrapolation to new therapies, and the incomplete provision of information about potential adverse effects, are discussed. Work remains to be done between physicians and statisticians to bridge the gap between that which is statistically demonstrable and that which will be clinically useful.The term ;surrogate endpoint' was virtually unknown by most oncologists 15 years ago. A search in PubMed [http://www.ncbi.nlm.nih.gov] based on the words ;surrogate and cancer' shows that more than 2000 papers were published in medical journals in the last 20 years, with a dramatic increase of interest in the last five years. Interestingly, the same trend is observed when the words ;surrogate and heart' are entered into PubMed, suggesting that the issue of surrogate endpoints goes beyond the field of oncology, although the frequency of discussion varies (Figure 1; note different y-axis scales for oncology and cardiology).The goal of the present paper is to discuss the main issues surrounding surrogate endpoints from a clinician's point of view, using as an example surrogate endpoints of overall survival (OS) in advanced colorectal cancer (ACC).

207-nm UV Light-A Promising Tool for Safe Low-Cost Reduction of Surgical Site Infections. II: In-Vivo Safety Studies.

PubMed

Buonanno, Manuela; Stanislauskas, Milda; Ponnaiya, Brian; Bigelow, Alan W; Randers-Pehrson, Gerhard; Xu, Yanping; Shuryak, Igor; Smilenov, Lubomir; Owens, David M; Brenner, David J

2016-01-01

UVC light generated by conventional germicidal lamps is a well-established anti-microbial modality, effective against both bacteria and viruses. However, it is a human health hazard, being both carcinogenic and cataractogenic. Earlier studies showed that single-wavelength far-UVC light (207 nm) generated by excimer lamps kills bacteria without apparent harm to human skin tissue in vitro. The biophysical explanation is that, due to its extremely short range in biological material, 207 nm UV light cannot penetrate the human stratum corneum (the outer dead-cell skin layer, thickness 5-20 μm) nor even the cytoplasm of individual human cells. By contrast, 207 nm UV light can penetrate bacteria and viruses because these cells are physically much smaller. To test the biophysically-based hypothesis that 207 nm UV light is not cytotoxic to exposed mammalian skin in vivo. Hairless mice were exposed to a bactericidal UV fluence of 157 mJ/cm2 delivered by a filtered Kr-Br excimer lamp producing monoenergetic 207-nm UV light, or delivered by a conventional 254-nm UV germicidal lamp. Sham irradiations constituted the negative control. Eight relevant cellular and molecular damage endpoints including epidermal hyperplasia, pre-mutagenic UV-associated DNA lesions, skin inflammation, and normal cell proliferation and differentiation were evaluated in mice dorsal skin harvested 48 h after UV exposure. While conventional germicidal UV (254 nm) exposure produced significant effects for all the studied skin damage endpoints, the same fluence of 207 nm UV light produced results that were not statistically distinguishable from the zero exposure controls. As predicted by biophysical considerations and in agreement with earlier in vitro studies, 207-nm light does not appear to be significantly cytotoxic to mouse skin. These results suggest that excimer-based far-UVC light could potentially be used for its anti-microbial properties, but without the associated hazards to skin of conventional germicidal UV lamps.

207-nm UV Light—A Promising Tool for Safe Low-Cost Reduction of Surgical Site Infections. II: In-Vivo Safety Studies

PubMed Central

Buonanno, Manuela; Stanislauskas, Milda; Ponnaiya, Brian; Bigelow, Alan W.; Randers-Pehrson, Gerhard; Xu, Yanping; Shuryak, Igor; Smilenov, Lubomir; Owens, David M.; Brenner, David J.

2016-01-01

Background UVC light generated by conventional germicidal lamps is a well-established anti-microbial modality, effective against both bacteria and viruses. However, it is a human health hazard, being both carcinogenic and cataractogenic. Earlier studies showed that single-wavelength far-UVC light (207 nm) generated by excimer lamps kills bacteria without apparent harm to human skin tissue in vitro. The biophysical explanation is that, due to its extremely short range in biological material, 207 nm UV light cannot penetrate the human stratum corneum (the outer dead-cell skin layer, thickness 5–20 μm) nor even the cytoplasm of individual human cells. By contrast, 207 nm UV light can penetrate bacteria and viruses because these cells are physically much smaller. Aims To test the biophysically-based hypothesis that 207 nm UV light is not cytotoxic to exposed mammalian skin in vivo. Methods Hairless mice were exposed to a bactericidal UV fluence of 157 mJ/cm2 delivered by a filtered Kr-Br excimer lamp producing monoenergetic 207-nm UV light, or delivered by a conventional 254-nm UV germicidal lamp. Sham irradiations constituted the negative control. Eight relevant cellular and molecular damage endpoints including epidermal hyperplasia, pre-mutagenic UV-associated DNA lesions, skin inflammation, and normal cell proliferation and differentiation were evaluated in mice dorsal skin harvested 48 h after UV exposure. Results While conventional germicidal UV (254 nm) exposure produced significant effects for all the studied skin damage endpoints, the same fluence of 207 nm UV light produced results that were not statistically distinguishable from the zero exposure controls. Conclusions As predicted by biophysical considerations and in agreement with earlier in vitro studies, 207-nm light does not appear to be significantly cytotoxic to mouse skin. These results suggest that excimer-based far-UVC light could potentially be used for its anti-microbial properties, but without the associated hazards to skin of conventional germicidal UV lamps. PMID:27275949

Treatment Paradigms for Advanced Non‐Small Cell Lung Cancer at Academic Medical Centers: Involvement in Clinical Trial Endpoint Design

PubMed Central

Borghaei, Hossein

2017-01-01

Abstract Based on the positive results of various clinical trials, treatment options for non‐small cell lung cancer (NSCLC) have expanded greatly over the last 25 years. While regulatory approvals of chemotherapeutic agents for NSCLC have largely been based on improvements in overall survival, recent approvals of many targeted agents for NSCLC (afatinib, crizotinib, ceritinib, osimertinib) have been based on surrogate endpoints such as progression‐free survival and objective response. As such, selection of appropriate clinical endpoints for examining the efficacy of investigational agents for NSCLC is of vital importance in clinical trial design. This review provides an overview of clinical trial endpoints previously utilized for approved agents for NSCLC and highlights the key efficacy results for these trials. Trends for more recent approvals in NSCLC, including those for the immunotherapeutic agents nivolumab and pembrolizumab, are also discussed. The results of a correlative analysis of endpoints from 18 clinical trials that supported approvals of investigational agents in clinical trials for NSCLC are also presented. Implications for Practice. While improving survival remains the ultimate goal of oncology clinical trials, overall survival may not always be the most feasible or appropriate endpoint to assess patient response. Recently, several investigational agents, both targeted agents and immunotherapies, have gained U.S. Food and Drug Administration approval in non‐small cell lung cancer based on alternate endpoints such as progression‐free survival or response rate. An understanding of the assessment of response and trial endpoint choice is important for future oncology clinical trial design. PMID:28408617

Computational fluid dynamics endpoints to characterize obstructive sleep apnea syndrome in children

PubMed Central

Luo, Haiyan; Persak, Steven C.; Sin, Sanghun; McDonough, Joseph M.; Isasi, Carmen R.; Arens, Raanan

2013-01-01

Computational fluid dynamics (CFD) analysis may quantify the severity of anatomical airway restriction in obstructive sleep apnea syndrome (OSAS) better than anatomical measurements alone. However, optimal CFD model endpoints to characterize or assess OSAS have not been determined. To model upper airway fluid dynamics using CFD and investigate the strength of correlation between various CFD endpoints, anatomical endpoints, and OSAS severity, in obese children with OSAS and controls. CFD models derived from magnetic resonance images were solved at subject-specific peak tidal inspiratory flow; pressure at the choanae was set by nasal resistance. Model endpoints included airway wall minimum pressure (Pmin), flow resistance in the pharynx (Rpharynx), and pressure drop from choanae to a minimum cross section where tonsils and adenoids constrict the pharynx (dPTAmax). Significance of endpoints was analyzed using paired comparisons (t-test or Wilcoxon signed rank test) and Spearman correlation. Fifteen subject pairs were analyzed. Rpharynx and dPTAmax were higher in OSAS than control and most significantly correlated to obstructive apnea-hypopnea index (oAHI), r = 0.48 and r = 0.49, respectively (P < 0.01). Airway minimum cross-sectional correlation to oAHI was weaker (r = −0.39); Pmin was not significantly correlated. CFD model endpoints based on pressure drops in the pharynx were more closely associated with the presence and severity of OSAS than pressures including nasal resistance, or anatomical endpoints. This study supports the usefulness of CFD to characterize anatomical restriction of the pharynx and as an additional tool to evaluate subjects with OSAS. PMID:24265282

Comparing three novel endpoints for developmental osteotoxicity in the embryonic stem cell test

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

Nieden, Nicole I. zur, E-mail: nicole.zurnieden@ucr.ed; Department of Cell Biology and Neuroscience and Stem Cell Center, University of California Riverside, Riverside, CA 92521; Fraunhofer Institute for Cell Therapy and Immunology, Perlickstrasse 1, 04103 Leipzig

Birth defects belong to the most serious side effects of pharmaceutical compounds or environmental chemicals. In vivo, teratogens most often affect the normal development of bones, causing growth retardation, limb defects or craniofacial malformations. The embryonic stem cell test (EST) is one of the most promising models that allow the in vitro prediction of embryotoxicity, with one of its endpoints being bone tissue development. The present study was designed to describe three novel inexpensive endpoints to assess developmental osteotoxicity using the model compounds penicillin G (non-teratogenic), 5-fluorouracil (strong teratogen) and all-trans retinoic acid (bone teratogen). These three endpoints were: quantificationmore » of matrix incorporated calcium by (1) morphometric analysis and (2) measurement of calcium levels as well as (3) activity of alkaline phosphatase, an enzyme involved in matrix calcification. To evaluate our data, we have compared the concentration curves and resulting ID{sub 50}s of the new endpoints with mRNA expression for osteocalcin. Osteocalcin is an exclusive marker found only in mineralized tissues, is regulated upon compound treatment and reliably predicts the potential of a chemical entity acting as a bone teratogen. By comparing the new endpoints to quantitative expression of osteocalcin, which we previously identified as suitable to detect developmental osteotoxicity, we were ultimately able to illustrate IMAGE analysis and Ca{sup 2+} deposition assays as two reliable novel endpoints for the EST. This is of particular importance for routine industrial assessment of novel compounds as these two new endpoints may substitute previously used molecular read-out methods, which are often costly and time-consuming.« less

PROMISE: a tool to identify genomic features with a specific biologically interesting pattern of associations with multiple endpoint variables.

PubMed

Pounds, Stan; Cheng, Cheng; Cao, Xueyuan; Crews, Kristine R; Plunkett, William; Gandhi, Varsha; Rubnitz, Jeffrey; Ribeiro, Raul C; Downing, James R; Lamba, Jatinder

2009-08-15

In some applications, prior biological knowledge can be used to define a specific pattern of association of multiple endpoint variables with a genomic variable that is biologically most interesting. However, to our knowledge, there is no statistical procedure designed to detect specific patterns of association with multiple endpoint variables. Projection onto the most interesting statistical evidence (PROMISE) is proposed as a general procedure to identify genomic variables that exhibit a specific biologically interesting pattern of association with multiple endpoint variables. Biological knowledge of the endpoint variables is used to define a vector that represents the biologically most interesting values for statistics that characterize the associations of the endpoint variables with a genomic variable. A test statistic is defined as the dot-product of the vector of the observed association statistics and the vector of the most interesting values of the association statistics. By definition, this test statistic is proportional to the length of the projection of the observed vector of correlations onto the vector of most interesting associations. Statistical significance is determined via permutation. In simulation studies and an example application, PROMISE shows greater statistical power to identify genes with the interesting pattern of associations than classical multivariate procedures, individual endpoint analyses or listing genes that have the pattern of interest and are significant in more than one individual endpoint analysis. Documented R routines are freely available from www.stjuderesearch.org/depts/biostats and will soon be available as a Bioconductor package from www.bioconductor.org.

Fixed and equilibrium endpoint problems in uneven-aged stand management

Treesearch

Robert G. Haight; Wayne M. Getz

1987-01-01

Studies in uneven-aged management have concentrated on the determination of optimal steady-state diameter distribution harvest policies for single and mixed species stands. To find optimal transition harvests for irregular stands, either fixed endpoint or equilibrium endpoint constraints can be imposed after finite transition periods. Penalty function and gradient...

76 FR 1620 - Trials to Verify and Describe Clinical Benefit of Midodrine Hydrochloride; Establishment of...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-11

... a surrogate endpoint that is reasonably likely to predict clinical benefit or based on a clinical endpoint other than survival or irreversible morbidity. Approval of PROAMATINE was based on trials... surrogate endpoints are ``subject to the requirement that the applicant study the drug further to verify and...

An information-theoretic approach to surrogate-marker evaluation with failure time endpoints.

PubMed

Pryseley, Assam; Tilahun, Abel; Alonso, Ariel; Molenberghs, Geert

2011-04-01

Over the last decades, the evaluation of potential surrogate endpoints in clinical trials has steadily been growing in importance, not only thanks to the availability of ever more potential markers and surrogate endpoints, also because more methodological development has become available. While early work has been devoted, to a large extent, to Gaussian, binary, and longitudinal endpoints, the case of time-to-event endpoints is in need of careful scrutiny as well, owing to the strong presence of such endpoints in oncology and beyond. While work had been done in the past, it was often cumbersome to use such tools in practice, because of the need for fitting copula or frailty models that were further embedded in a hierarchical or two-stage modeling approach. In this paper, we present a methodologically elegant and easy-to-use approach based on information theory. We resolve essential issues, including the quantification of "surrogacy" based on such an approach. Our results are put to the test in a simulation study and are applied to data from clinical trials in oncology. The methodology has been implemented in R.

A unified framework for the evaluation of surrogate endpoints in mental-health clinical trials.

PubMed

Molenberghs, Geert; Burzykowski, Tomasz; Alonso, Ariel; Assam, Pryseley; Tilahun, Abel; Buyse, Marc

2010-06-01

For a number of reasons, surrogate endpoints are considered instead of the so-called true endpoint in clinical studies, especially when such endpoints can be measured earlier, and/or with less burden for patient and experimenter. Surrogate endpoints may occur more frequently than their standard counterparts. For these reasons, it is not surprising that the use of surrogate endpoints in clinical practice is increasing. Building on the seminal work of Prentice(1) and Freedman et al.,(2) Buyse et al. (3) framed the evaluation exercise within a meta-analytic setting, in an effort to overcome difficulties that necessarily surround evaluation efforts based on a single trial. In this article, we review the meta-analytic approach for continuous outcomes, discuss extensions to non-normal and longitudinal settings, as well as proposals to unify the somewhat disparate collection of validation measures currently on the market. Implications for design and for predicting the effect of treatment in a new trial, based on the surrogate, are discussed. A case study in schizophrenia is analysed.

THE 6-MINUTE WALK TEST AND OTHER CLINICAL ENDPOINTS IN DUCHENNE MUSCULAR DYSTROPHY: RELIABILITY, CONCURRENT VALIDITY, AND MINIMAL CLINICALLY IMPORTANT DIFFERENCES FROM A MULTICENTER STUDY

PubMed Central

McDonald, Craig M; Henricson, Erik K; Abresch, R Ted; Florence, Julaine; Eagle, Michelle; Gappmaier, Eduard; Glanzman, Allan M; Spiegel, Robert; Barth, Jay; Elfring, Gary; Reha, Allen; Peltz, Stuart W

2013-01-01

Introduction: An international clinical trial enrolled 174 ambulatory males ≥5 years old with nonsense mutation Duchenne muscular dystrophy (nmDMD). Pretreatment data provide insight into reliability, concurrent validity, and minimal clinically important differences (MCIDs) of the 6-minute walk test (6MWT) and other endpoints. Methods: Screening and baseline evaluations included the 6-minute walk distance (6MWD), timed function tests (TFTs), quantitative strength by myometry, the PedsQL, heart rate–determined energy expenditure index, and other exploratory endpoints. Results: The 6MWT proved feasible and reliable in a multicenter context. Concurrent validity with other endpoints was excellent. The MCID for 6MWD was 28.5 and 31.7 meters based on 2 statistical distribution methods. Conclusions: The ratio of MCID to baseline mean is lower for 6MWD than for other endpoints. The 6MWD is an optimal primary endpoint for Duchenne muscular dystrophy (DMD) clinical trials that are focused therapeutically on preservation of ambulation and slowing of disease progression. Muscle Nerve 48: 357–368, 2013 PMID:23674289

Cytotoxicity screening of 23 engineered nanomaterials using a test matrix of ten cell lines and three different assays

PubMed Central

2011-01-01

Background Engineered nanomaterials display unique properties that may have impact on human health, and thus require a reliable evaluation of their potential toxicity. Here, we performed a standardized in vitro screening of 23 engineered nanomaterials. We thoroughly characterized the physicochemical properties of the nanomaterials and adapted three classical in vitro toxicity assays to eliminate nanomaterial interference. Nanomaterial toxicity was assessed in ten representative cell lines. Results Six nanomaterials induced oxidative cell stress while only a single nanomaterial reduced cellular metabolic activity and none of the particles affected cell viability. Results from heterogeneous and chemically identical particles suggested that surface chemistry, surface coating and chemical composition are likely determinants of nanomaterial toxicity. Individual cell lines differed significantly in their response, dependent on the particle type and the toxicity endpoint measured. Conclusion In vitro toxicity of the analyzed engineered nanomaterials cannot be attributed to a defined physicochemical property. Therefore, the accurate identification of nanomaterial cytotoxicity requires a matrix based on a set of sensitive cell lines and in vitro assays measuring different cytotoxicity endpoints. PMID:21345205

Structural and functional screening in human induced-pluripotent stem cell-derived cardiomyocytes accurately identifies cardiotoxicity of multiple drug types

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

Doherty, Kimberly R., E-mail: kimberly.doherty@quintiles.com; Talbert, Dominique R.; Trusk, Patricia B.

Safety pharmacology studies that evaluate new drug entities for potential cardiac liability remain a critical component of drug development. Current studies have shown that in vitro tests utilizing human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CM) may be beneficial for preclinical risk evaluation. We recently demonstrated that an in vitro multi-parameter test panel assessing overall cardiac health and function could accurately reflect the associated clinical cardiotoxicity of 4 FDA-approved targeted oncology agents using hiPS-CM. The present studies expand upon this initial observation to assess whether this in vitro screen could detect cardiotoxicity across multiple drug classes with known clinical cardiac risks.more » Thus, 24 drugs were examined for their effect on both structural (viability, reactive oxygen species generation, lipid formation, troponin secretion) and functional (beating activity) endpoints in hiPS-CM. Using this screen, the cardiac-safe drugs showed no effects on any of the tests in our panel. However, 16 of 18 compounds with known clinical cardiac risk showed drug-induced changes in hiPS-CM by at least one method. Moreover, when taking into account the Cmax values, these 16 compounds could be further classified depending on whether the effects were structural, functional, or both. Overall, the most sensitive test assessed cardiac beating using the xCELLigence platform (88.9%) while the structural endpoints provided additional insight into the mechanism of cardiotoxicity for several drugs. These studies show that a multi-parameter approach examining both cardiac cell health and function in hiPS-CM provides a comprehensive and robust assessment that can aid in the determination of potential cardiac liability. - Highlights: • 24 drugs were tested for cardiac liability using an in vitro multi-parameter screen. • Changes in beating activity were the most sensitive in predicting cardiac risk. • Structural effects add in-depth insight towards mechanism of cardiac toxicity. • Testing functional and structural endpoints enhances early cardiac risk assessment.« less

Identifying the production process of new physics at colliders; symmetric or asymmetric?

NASA Astrophysics Data System (ADS)

Lim, Sung Hak

2016-06-01

We propose a class of kinematic variables, which is a smooth generalization of min-max type mass variables such as the Cambridge- M T 2 and M 2, for measuring a mass spectrum of intermediate resonances in a semi-invisibly decaying pair production. While kinematic endpoints of min-max type mass variables are only sensitive to a heavier resonance mass, kinematic endpoints of new variables are sensitive to all masses. These new mass variables can be used to resolve a mass spectrum, so that if the true mass spectrum is asymmetric, then the kinematic endpoints are separate while the endpoints are the same for the symmetric true mass spectrum. We demonstrate the behavior of kinematic endpoint of these new variables in pair production of two-body and three-body decays with one invisible particle.

A Mode-of-Action Approach for the Identification of Genotoxic Carcinogens

PubMed Central

Hernández, Lya G.; van Benthem, Jan; Johnson, George E.

2013-01-01

Distinguishing between clastogens and aneugens is vital in cancer risk assessment because the default assumption is that clastogens and aneugens have linear and non-linear dose-response curves, respectively. Any observed non-linearity must be supported by mode of action (MOA) analyses where biological mechanisms are linked with dose-response evaluations. For aneugens, the MOA has been well characterised as disruptors of mitotic machinery where chromosome loss via micronuclei (MN) formation is an accepted endpoint used in risk assessment. In this study we performed the cytokinesis-block micronucleus assay and immunofluorescence mitotic machinery visualisation in human lymphoblastoid (AHH-1) and Chinese Hamster fibroblast (V79) cell lines after treatment with the aneugen 17-β-oestradiol (E2). Results were compared to previously published data on bisphenol-A (BPA) and Rotenone data. Two concentration-response approaches (the threshold-[Td] and benchmark-dose [BMD] approaches) were applied to derive a point of departure (POD) for in vitro MN induction. BMDs were also derived from the most sensitive carcinogenic endpoint. Ranking comparisons of the PODs from the in vitro MN and the carcinogenicity studies demonstrated a link between these two endpoints for BPA, E2 and Rotenone. This analysis was extended to include 5 additional aneugens, 5 clastogens and 3 mutagens and further concentration and dose-response correlations were observed between PODs from the in vitro MN and carcinogenicity. This approach is promising and may be further extended to other genotoxic carcinogens, where MOA and quantitative information from the in vitro MN studies could be used in a quantitative manner to further inform cancer risk assessment. PMID:23675539

Ecotoxicity of boric acid in standard laboratory tests with plants and soil organisms.

PubMed

Princz, Juliska; Becker, Leonie; Scheffczyk, Adam; Stephenson, Gladys; Scroggins, Rick; Moser, Thomas; Römbke, Jörg

2017-05-01

To verify the continuous sensitivity of ecotoxicological tests (mainly the test organisms), reference substances with known toxicity are regularly tested. Ideally, this substance(s) would lack specificity in its mode action, be bioavailable and readily attainable with cost-effective means of chemical characterization. Boric acid has satisfied these criteria, but has most recently been characterized as a substance of very high concern, due to reproductive effects in humans, thus limiting its recommendation as an ideal reference toxicant. However, there is probably no other chemical for which ecotoxicity in soil has been so intensively studied; an extensive literature review yielded lethal (including avoidance) and sublethal data for 38 taxa. The ecotoxicity data were evaluated using species sensitivity distributions, collectively across all taxa, and separately according to species type, endpoints, soil type and duration. The lack of specificity in the mode of action yielded broad toxicity among soil taxa and soil types, and provided a collective approach to assessing species sensitivity, while taking into consideration differences in test methodologies and exposure durations. Toxicity was species-specific with Folsomia candida and enchytraied species demonstrating the most sensitivity; among plants, the following trend occurred: dicotyledonous (more sensitive) ≫ monocotyledonous ≫ gymnosperm species. Sensitivity was also time and endpoint specific, with endpoints such as lethality and avoidance being less sensitive than reproduction effects. Furthermore, given the breadth of data and toxicity demonstrated by boric acid, lessons learned from its evaluation are discussed to recommend the properties required by an ideal reference substance for the soil compartment.

Core body temperature as adjunct to endpoint determination in murine median lethal dose testing of rattlesnake venom.

PubMed

Cates, Charles C; McCabe, James G; Lawson, Gregory W; Couto, Marcelo A

2014-12-01

Median lethal dose (LD50) testing in mice is the 'gold standard' for evaluating the lethality of snake venoms and the effectiveness of interventions. As part of a study to determine the murine LD50 of the venom of 3 species of rattlesnake, temperature data were collected in an attempt to more precisely define humane endpoints. We used an 'up-and-down' methodology of estimating the LD50 that involved serial intraperitoneal injection of predetermined concentrations of venom. By using a rectal thermistor probe, body temperature was taken once before administration and at various times after venom exposure. All but one mouse showed a marked, immediate, dose-dependent drop in temperature of approximately 2 to 6°C at 15 to 45 min after administration. The lowest temperature sustained by any surviving mouse was 33.2°C. Surviving mice generally returned to near-baseline temperatures within 2 h after venom administration, whereas mice that did not survive continued to show a gradual decline in temperature until death or euthanasia. Logistic regression modeling controlling for the effects of baseline core body temperature and venom type showed that core body temperature was a significant predictor of survival. Linear regression of the interaction of time and survival was used to estimate temperatures predictive of death at the earliest time point and demonstrated that venom type had a significant influence on temperature values. Overall, our data suggest that core body temperature is a useful adjunct to monitoring for endpoints in LD50 studies and may be a valuable predictor of survival in venom studies.

Equipment management risk rating system based on engineering endpoints.

PubMed

James, P J

1999-01-01

The equipment management risk ratings system outlined here offers two significant departures from current practice: risk classifications are based on intrinsic device risks, and the risk rating system is based on engineering endpoints. Intrinsic device risks are categorized as physical, clinical and technical, and these flow from the incoming equipment assessment process. Engineering risk management is based on verification of engineering endpoints such as clinical measurements or energy delivery. This practice eliminates the ambiguity associated with ranking risk in terms of physiologic and higher-level outcome endpoints such as no significant hazards, low significance, injury, or mortality.

Evaluating surrogate endpoints, prognostic markers, and predictive markers: Some simple themes.

PubMed

Baker, Stuart G; Kramer, Barnett S

2015-08-01

A surrogate endpoint is an endpoint observed earlier than the true endpoint (a health outcome) that is used to draw conclusions about the effect of treatment on the unobserved true endpoint. A prognostic marker is a marker for predicting the risk of an event given a control treatment; it informs treatment decisions when there is information on anticipated benefits and harms of a new treatment applied to persons at high risk. A predictive marker is a marker for predicting the effect of treatment on outcome in a subgroup of patients or study participants; it provides more rigorous information for treatment selection than a prognostic marker when it is based on estimated treatment effects in a randomized trial. We organized our discussion around a different theme for each topic. "Fundamentally an extrapolation" refers to the non-statistical considerations and assumptions needed when using surrogate endpoints to evaluate a new treatment. "Decision analysis to the rescue" refers to use the use of decision analysis to evaluate an additional prognostic marker because it is not possible to choose between purely statistical measures of marker performance. "The appeal of simplicity" refers to a straightforward and efficient use of a single randomized trial to evaluate overall treatment effect and treatment effect within subgroups using predictive markers. The simple themes provide a general guideline for evaluation of surrogate endpoints, prognostic markers, and predictive markers. © The Author(s) 2014.

Surrogate endpoints for cancer screening trials: general principles and an illustration using the UK Flexible Sigmoidoscopy Screening Trial.

PubMed

Cuzick, Jack; Cafferty, Fay H; Edwards, Robert; Møller, Henrik; Duffy, Stephen W

2007-01-01

Cancer screening is aimed primarily at reducing deaths. Thus, site-specific cancer mortality is the appropriate endpoint for evaluating screening interventions. However, it is also the most demanding endpoint, requiring follow-up and a large numbers of patients order to have adequate power. Therefore, it is highly desirable to have surrogate endpoints that can reliably predict mortality reductions many years earlier. We here review a range of surrogate markers in terms of their potential advantages and pitfalls, and argue that a measure which weights incident cancers according to their predicted mortality has many advantages over other measures and should be used more routinely. Application to the UK Flexible Sigmoidoscopy Screening Trial data suggests that predicted colorectal cancer mortality, based on stage-specific incidence, is a more powerful endpoint than actual mortality and could advance the analysis time by about three years. Total colorectal cancer incidence as a surrogate endpoint provides little advance in the analysis time over actual mortality. The approach requires reliable prognostic data, (e.g. stage), for both the study cohort and a representative sample of the whole population. The routine collection of such data should be a priority for cancer registries. Surrogate endpoints should not replace a long-term analysis based directly on mortality, but can provide reliable early indicators which can be useful both for monitoring ongoing screening programmes and for making policy decisions.

Clinical endpoints in allogeneic hematopoietic stem cell transplantation studies: the cost of freedom.

PubMed

Kim, Haesook T; Armand, Philippe

2013-06-01

When designing a study for allogeneic hematopoietic stem cell transplantation (HSCT), many choices must be made, including conditioning regimen, stem cell source, and graft-versus-host disease (GVHD) prevention method. For each of these, there are a growing number of options, which can be combined into a bewildering number of possible HSCT protocols. To properly interpret the results of a given strategy and compare them with others, it is essential that there be agreement on the definitions and estimation methods of HSCT endpoints. We report a survey of the recent HSCT literature that confirms the heterogeneity of endpoint definitions and estimation methods used. Unfortunately, this heterogeneity may lead to significant biases in the estimates of key endpoints, including nonrelapse mortality, relapse, GVHD, or engraftment. This can preclude adequate comparisons among studies, even though such comparisons are the major tool with which to improve HSCT outcome. In the context of our survey, we discuss some of the statistical issues that arise when dealing with HSCT endpoints and the ramifications of the choice of endpoint definition, when the endpoint occurs in the context of competing risks. Our hope is to generate discussion and motivate a search for consensus among those who perform transplantations and statisticians. Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Potential human exposures to neonicotinoid insecticides: A review.

PubMed

Zhang, Q; Li, Z; Chang, C H; Lou, J L; Zhao, M R; Lu, C

2018-05-01

Due to their systemic character and high efficacy to insect controls, neonicotinoid insecticides (neonics) have been widely used in global agriculture since its introduction in early 1990. Recent studies have indicated that neonics may be ubiquitous, have longer biological half-lives in the environment once applied, and therefore implicitly suggested the increasing probability for human exposure to neonics. Despite of neonics' persistent characters and widespread uses, scientific literature in regard of pathways in which human exposure could occur is relatively meager. In this review, we summarized results from peer-reviewed articles published prior to 2017 that address potential human exposures through ingestion and inhalation, as well as results from human biomonitoring studies. In addition, we proposed the use of relative potency factor approach in order to facilitate the assessment of concurrent exposure to a mixture of neonics with similar chemical structures and toxicological endpoints. We believe that the scientific information that we presented in this review will aid to future assessment of total neonic exposure and subsequently human health risk characterization. Copyright © 2018 Elsevier Ltd. All rights reserved.

Biomedical consequences of ozone depletion

NASA Astrophysics Data System (ADS)

Coohill, Thomas P.

1994-07-01

It is widely agreed that a portion of the earth's protective stratospheric ozone layer is being depleted. The major effect of this ozone loss will be an increase in the amount of ultraviolet radiation (UV reaching the biosphere. This increase will be completely contained within the UVB (290nm - 320nm). It is imperative that assessments be made of the effects of this additional UVB on living organisms. This requires a detailed knowledge of the UVB photobiology of these life forms. One analytical technique to aid in the approximations is the construction of UV action spectra for such important biological end-points as human skin cancer, cataracts, immune suppression; plant photosynthesis and crop yields; and aquatic organism responses to UVB, especially the phytoplankton. Combining these action spectra with the known solar spectrum (and estimates for various ozone depletion scenarios) can give rise to a series of effectiveness spectra for these parameters. This manuscript gives a first approximation, rough estimate, for the effectiveness spectra for some of these bioresponses, and a series of crude temporary values for how a 10% ozone loss would affect the above end-points. These are not intended to masquerade as final answers, but rather, to serve as beginning attempts for a process which should be continually refined. It is hoped that these estimates will be of some limited use to agencies, such as government and industry, that have to plan now for changes in human activities that might alter future atmospheric chemistry in a beneficial manner.

Towards free 3D end-point control for robotic-assisted human reaching using binocular eye tracking.

PubMed

Maimon-Dror, Roni O; Fernandez-Quesada, Jorge; Zito, Giuseppe A; Konnaris, Charalambos; Dziemian, Sabine; Faisal, A Aldo

2017-07-01

Eye-movements are the only directly observable behavioural signals that are highly correlated with actions at the task level, and proactive of body movements and thus reflect action intentions. Moreover, eye movements are preserved in many movement disorders leading to paralysis (or amputees) from stroke, spinal cord injury, Parkinson's disease, multiple sclerosis, and muscular dystrophy among others. Despite this benefit, eye tracking is not widely used as control interface for robotic interfaces in movement impaired patients due to poor human-robot interfaces. We demonstrate here how combining 3D gaze tracking using our GT3D binocular eye tracker with custom designed 3D head tracking system and calibration method enables continuous 3D end-point control of a robotic arm support system. The users can move their own hand to any location of the workspace by simple looking at the target and winking once. This purely eye tracking based system enables the end-user to retain free head movement and yet achieves high spatial end point accuracy in the order of 6 cm RMSE error in each dimension and standard deviation of 4 cm. 3D calibration is achieved by moving the robot along a 3 dimensional space filling Peano curve while the user is tracking it with their eyes. This results in a fully automated calibration procedure that yields several thousand calibration points versus standard approaches using a dozen points, resulting in beyond state-of-the-art 3D accuracy and precision.

Induction of human breast cell carcinogenesis by triclocarban and intervention by curcumin

PubMed Central

Sood, Shilpa; Choudhary, Shambhunath; Wang, Hwa-Chain Robert

2013-01-01

More than 85% of breast cancers are sporadic and attributable to long-term exposure to environmental carcinogens and co-carcinogens. To identify co-carcinogens with abilities to induce cellular pre-malignancy, we studied the activity of triclocarban (TCC), an antimicrobial agent commonly used in household and personal care products. Here, we demonstrated, for the first time, that chronic exposure to TCC at physiologically-achievable nanomolar concentrations resulted in progressive carcinogenesis of human breast cells from non-cancerous to pre-malignant. Pre-malignant carcinogenesis was measured by increasingly-acquired cancer-associated properties of reduced dependence on growth factors, anchorage- independent growth and increased cell proliferation, without acquisition of cellular tumorigenicity. Long-term TCC exposure also induced constitutive activation of the Erk–Nox pathway and increases of reactive oxygen species (ROS) in cells. A single TCC exposure induced transient induction of the Erk–Nox pathway, ROS elevation, increased cell proliferation, and DNA damage in not only non-cancerous breast cells but also breast cancer cells. Using these constitutively- and transiently-induced changes as endpoints, we revealed that non-cytotoxic curcumin was effective in intervention of TCC-induced cellular pre-malignancy. Our results lead us to suggest that the co-carcinogenic potential of TCC should be seriously considered in epidemiological studies to reveal the significance of TCC in the development of sporadic breast cancer. Using TCC-induced transient and constitutive endpoints as targets will likely help identify non-cytotoxic preventive agents, such as curcumin, effective in suppressing TCC-induced cellular pre-malignancy. PMID:23942114

Relative biological effectiveness (RBE) of alpha radiation in cultured porcine aortic endothelial cells.

PubMed

Thomas, Patricia; Tracy, Bliss; Ping, Tilly; Baweja, Anar; Wickstrom, Mark; Sidhu, Narinder; Hiebert, Linda

2007-03-01

Northern peoples can receive elevated radiation doses (1- 10 mSv/y) from transfer of polonium-210 (210Po) through the lichen-caribou-human food chain. Ingested 210Po is primarily blood-borne and thus many of its short range alpha particles irradiate the endothelial cells lining the blood vessels. The relative biological effectiveness (RBE) of alpha particles vs. x-rays was examined in porcine aortic endothelial cells as a surrogate for understanding what might happen to human endothelial cells in northern populations consuming traditional foods. Cultured porcine aortic endothelial cells were exposed to x-ray and 210Po alpha particle radiation. Alpha irradiation was applied to the cell cultures internally via the culture medium and externally, using thin-bottomed culture dishes. The results given here are based on the external irradiation method, which was found to be more reliable. Dose-response curves were compared for four lethal endpoints (cell viability, live cell fraction, release of lactate dehydrogenase [LDH] and clonogenic survival) to determine the relative biological effectiveness (RBE) of alpha radiation. The alpha RBE for porcine cells varied from 1.6-21, depending on the endpoint: 21.2+/-4.5 for cell viability, 12.9+/-2.7 for decrease in live cell number, 5.3+/-0.4 for LDH release to the medium but only 1.6 +/-0.1 for clonogenic survival. The low RBE of 1.6 was due to x-ray hypersensitivity of endothelial cells at low doses.

Restoration for the future: endpoints, targets, and indicators of progress and success

Treesearch

Daniel C. Dey; Callie Jo. Schweitzer

2014-01-01

Setting endpoints and targets in forest restoration is a complicated task that is best accomplished in cooperative partnerships that account for the ecology of the system, production of desired ecosystem goods and services, economics and well-being of society, and future environments. Clearly described and quantitative endpoints and intermediary targets are needed to...

SITE-SPECIFIC VALIDATION OF A CHRONIC TOXICITY TEST WITH THE AMPHIPOD HYALELLA AZTECA : AN INTEGRATED STUDY OF HEAVY METAL CONTAMINATED SEDIMENTS IN PEAK CREEK, VIRGINIA

EPA Science Inventory

We will measure the correspondence of endpoints from chronic toxicity tests with the amphipod, Hyalella azteca, to a series of in situ macrobenthic community endpoints, starting with those endpoints most similar to those monitored in the laboratory test, then expanding to include...

Relevance of Changes in Serum Creatinine During a Heart Failure Trial of Decongestive Strategies: Insights From the DOSE Trial

PubMed Central

BRISCO, MEREDITH A.; ZILE, MICHAEL R.; HANBERG, JENNIFER S.; WILSON, F. PERRY; PARIKH, CHIRAG R.; COCA, STEVEN G.; TANG, W.H. WILSON; TESTANI, JEFFREY M.

2017-01-01

Background Worsening renal function (WRF) is a common endpoint in decompensated heart failure clinical trials because of associations between WRF and adverse outcomes. However, WRF has not universally been identified as a poor prognostic sign, challenging the validity of WRF as a surrogate endpoint. Our aim was to describe the associations between changes in creatinine and adverse outcomes in a clinical trial of decongestive therapies. Methods and Results We investigated the association between changes in creatinine and the composite endpoint of death, rehospitalization or emergency room visit within 60 days in 301 patients in the Diuretic Optimization Strategies Evaluation (DOSE) trial. WRF was defined as an increase in creatinine >0.3 mg/dL and improvement in renal function (IRF) as a decrease >0.3 mg/dL. When examining linear changes in creatinine from baseline to 72 hours (the coprimary endpoint of DOSE), increasing creatinine was associated with lower risk for the composite outcome (HR = 0.81 per 0.3 mg/dL increase, 95% CI 0.67–0.98, P = .026). Compared with patients with stable renal function (n = 219), WRF (n = 54) was not associated with the composite endpoint (HR = 1.17, 95% CI = 0.77–1.78, P = .47). However, compared with stable renal function, there was a strong relationship between IRF (n = 28) and the composite endpoint (HR = 2.52, 95% CI = 1.57–4.03, P <.001). Conclusion The coprimary endpoint of the DOSE trial, a linear increase in creatinine, was paradoxically associated with improved outcomes. This was driven by absence of risk attributable to WRF and a strong risk associated with IRF. These results argue against using changes in serum creatinine as a surrogate endpoint in trials of decongestive strategies. PMID:27374839

Two Decades of Cardiovascular Trials With Primary Surrogate Endpoints: 1990-2011.

PubMed

Bikdeli, Behnood; Punnanithinont, Natdanai; Akram, Yasir; Lee, Ike; Desai, Nihar R; Ross, Joseph S; Krumholz, Harlan M

2017-03-21

Surrogate endpoint trials test strategies more efficiently but are accompanied by uncertainty about the relationship between changes in surrogate markers and clinical outcomes. We identified cardiovascular trials with primary surrogate endpoints published in the New England Journal of Medicine , Lancet , and JAMA: Journal of the American Medical Association from 1990 to 2011 and determined the trends in publication of surrogate endpoint trials and the success of the trials in meeting their primary endpoints. We tracked for publication of clinical outcome trials on the interventions tested in surrogate trials. We screened 3016 articles and identified 220 surrogate endpoint trials. From the total of 220 surrogate trials, 157 (71.4%) were positive for their primary endpoint. Only 59 (26.8%) surrogate trials had a subsequent clinical outcomes trial. Among these 59 trials, 24 outcomes trial results validated the positive surrogates, whereas 20 subsequent outcome trials were negative following positive results on a surrogate. We identified only 3 examples in which the surrogate trial was negative but a subsequent outcomes trial was conducted and showed benefit. Findings were consistent in a sample cohort of 383 screened articles inclusive of 37 surrogate endpoint trials from 6 other high-impact journals. Although cardiovascular surrogate outcomes trials frequently show superiority of the tested intervention, they are infrequently followed by a prominent outcomes trial. When there was a high-profile clinical outcomes study, nearly half of the positive surrogate trials were not validated. Cardiovascular surrogate outcome trials may be more appropriate for excluding benefit from the patient perspective than for identifying it. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

A step towards standardization: A method for end-point titer determination by fluorescence index of an automated microscope. End-point titer determination by fluorescence index.

PubMed

Carbone, Teresa; Gilio, Michele; Padula, Maria Carmela; Tramontano, Giuseppina; D'Angelo, Salvatore; Pafundi, Vito

2018-05-01

Indirect Immunofluorescence (IIF) is widely considered the Gold Standard for Antinuclear Antibody (ANA) screening. However, the high inter-reader variability remains the major disadvantage associated with ANA testing and the main reason for the increasing demand of the computer-aided immunofluorescence microscope. Previous studies proposed the quantification of the fluorescence intensity as an alternative for the classical end-point titer evaluation. However, the different distribution of bright/dark light linked to the nature of the self-antigen and its location in the cells result in different mean fluorescence intensities. The aim of the present study was to correlate Fluorescence Index (F.I.) with end-point titers for each well-defined ANA pattern. Routine serum samples were screened for ANA testing on HEp-2000 cells using Immuno Concepts Image Navigator System, and positive samples were serially diluted to assign the end-point titer. A comparison between F.I. and end-point titers related to 10 different staining patterns was made. According to our analysis, good technical performance of F.I. (97% sensitivity and 94% specificity) was found. A significant correlation between quantitative reading of F.I. and end-point titer groups was observed using Spearman's test and regression analysis. A conversion scale of F.I. in end-point titers for each recognized ANA-pattern was obtained. The Image Navigator offers the opportunity to improve worldwide harmonization of ANA test results. In particular, digital F.I. allows quantifying ANA titers by using just one sample dilution. It could represent a valuable support for the routine laboratory and an effective tool to reduce inter- and intra-laboratory variability. Copyright © 2018. Published by Elsevier B.V.

Root length of aquatic plant, Lemna minor L., as an optimal toxicity endpoint for biomonitoring of mining effluents.

PubMed

Gopalapillai, Yamini; Vigneault, Bernard; Hale, Beverley A

2014-10-01

Lemna minor, a free-floating macrophyte, is used for biomonitoring of mine effluent quality under the Metal Mining Effluent Regulations (MMER) of the Environmental Effects Monitoring (EEM) program in Canada and is known to be sensitive to trace metals commonly discharged in mine effluents such as Ni. Environment Canada's standard toxicity testing protocol recommends frond count (FC) and dry weight (DW) as the 2 required toxicity endpoints-this is similar to other major protocols such as those by the US Environmental Protection Agency (USEPA) and the Organisation for Economic Co-operation and Development (OECD)-that both require frond growth or biomass endpoints. However, we suggest that similar to terrestrial plants, average root length (RL) of aquatic plants will be an optimal and relevant endpoint. As expected, results demonstrate that RL is the ideal endpoint based on the 3 criteria: accuracy (i.e., toxicological sensitivity to contaminant), precision (i.e., lowest variance), and ecological relevance (metal mining effluents). Roots are known to play a major role in nutrient uptake in conditions of low nutrient conditions-thus having ecological relevance to freshwater from mining regions. Root length was the most sensitive and precise endpoint in this study where water chemistry varied greatly (pH and varying concentrations of Ca, Mg, Na, K, dissolved organic carbon, and an anthropogenic organic contaminant, sodium isopropyl xanthates) to match mining effluent ranges. Although frond count was a close second, dry weight proved to be an unreliable endpoint. We conclude that toxicity testing for the floating macrophyte should require average RL measurement as a primary endpoint. © 2014 SETAC.

Daily remote monitoring of implantable cardioverter-defibrillators: insights from the pooled patient-level data from three randomized controlled trials (IN-TIME, ECOST, TRUST).

PubMed

Hindricks, Gerhard; Varma, Niraj; Kacet, Salem; Lewalter, Thorsten; Søgaard, Peter; Guédon-Moreau, Laurence; Proff, Jochen; Gerds, Thomas A; Anker, Stefan D; Torp-Pedersen, Christian

2017-06-07

Remote monitoring of implantable cardioverter-defibrillators may improve clinical outcome. A recent meta-analysis of three randomized controlled trials (TRUST, ECOST, IN-TIME) using a specific remote monitoring system with daily transmissions [Biotronik Home Monitoring (HM)] demonstrated improved survival. We performed a patient-level analysis to verify this result with appropriate time-to-event statistics and to investigate further clinical endpoints. Individual data of the TRUST, ECOST, and IN-TIME patients were pooled to calculate absolute risks of endpoints at 1-year follow-up for HM vs. conventional follow-up. All-cause mortality analysis involved all three trials (2405 patients). Other endpoints involved two trials, ECOST and IN-TIME (1078 patients), in which an independent blinded endpoint committee adjudicated the underlying causes of hospitalizations and deaths. The absolute risk of death at 1 year was reduced by 1.9% in the HM group (95% CI: 0.1-3.8%; P = 0.037), equivalent to a risk ratio of 0.62. Also the combined endpoint of all-cause mortality or hospitalization for worsening heart failure (WHF) was significantly reduced (by 5.6%; P = 0.007; risk ratio 0.64). The composite endpoint of all-cause mortality or cardiovascular (CV) hospitalization tended to be reduced by a similar degree (4.1%; P = 0.13; risk ratio 0.85) but without statistical significance. In a pooled analysis of the three trials, HM reduced all-cause mortality and the composite endpoint of all-cause mortality or WHF hospitalization. The similar magnitudes of absolute risk reductions for WHF and CV endpoints suggest that the benefit of HM is driven by the prevention of heart failure exacerbation.

PROMISE: a tool to identify genomic features with a specific biologically interesting pattern of associations with multiple endpoint variables

PubMed Central

Pounds, Stan; Cheng, Cheng; Cao, Xueyuan; Crews, Kristine R.; Plunkett, William; Gandhi, Varsha; Rubnitz, Jeffrey; Ribeiro, Raul C.; Downing, James R.; Lamba, Jatinder

2009-01-01

Motivation: In some applications, prior biological knowledge can be used to define a specific pattern of association of multiple endpoint variables with a genomic variable that is biologically most interesting. However, to our knowledge, there is no statistical procedure designed to detect specific patterns of association with multiple endpoint variables. Results: Projection onto the most interesting statistical evidence (PROMISE) is proposed as a general procedure to identify genomic variables that exhibit a specific biologically interesting pattern of association with multiple endpoint variables. Biological knowledge of the endpoint variables is used to define a vector that represents the biologically most interesting values for statistics that characterize the associations of the endpoint variables with a genomic variable. A test statistic is defined as the dot-product of the vector of the observed association statistics and the vector of the most interesting values of the association statistics. By definition, this test statistic is proportional to the length of the projection of the observed vector of correlations onto the vector of most interesting associations. Statistical significance is determined via permutation. In simulation studies and an example application, PROMISE shows greater statistical power to identify genes with the interesting pattern of associations than classical multivariate procedures, individual endpoint analyses or listing genes that have the pattern of interest and are significant in more than one individual endpoint analysis. Availability: Documented R routines are freely available from www.stjuderesearch.org/depts/biostats and will soon be available as a Bioconductor package from www.bioconductor.org. Contact: stanley.pounds@stjude.org Supplementary information: Supplementary data are available at Bioinformatics online. PMID:19528086

Photodynamic therapy in prostate cancer: optical dosimetry and response of normal tissue

NASA Astrophysics Data System (ADS)

Chen, Qun; Shetty, Sugandh D.; Heads, Larry; Bolin, Frank; Wilson, Brian C.; Patterson, Michael S.; Sirls, Larry T., II; Schultz, Daniel; Cerny, Joseph C.; Hetzel, Fred W.

1993-06-01

The present study explores the possibility of utilizing photodynamic therapy (PDT) in treating localized prostate carcinoma. Optical properties of ex vivo human prostatectomy specimens, and in vivo and ex vivo dog prostate glands were studied. The size of the PDT induced lesion in dog prostate was pathologically evaluated as a biological endpoint. The data indicate that the human normal and carcinoma prostate tissues have similar optical properties. The average effective attenuation depth is less in vivo than that of ex vivo. The PDT treatment generated a lesion size of up to 16 mm in diameter. The data suggest that PDT is a promising modality in prostate cancer treatment. Multiple fiber system may be required for clinical treatment.

Selecting surrogate endpoints for estimating pesticide effects on avian reproductive success.

PubMed

Bennett, Richard S; Etterson, Matthew A

2013-10-01

A Markov chain nest productivity model (MCnest) has been developed for projecting the effects of a specific pesticide-use scenario on the annual reproductive success of avian species of concern. A critical element in MCnest is the use of surrogate endpoints, defined as measured endpoints from avian toxicity tests that represent specific types of effects possible in field populations at specific phases of a nesting attempt. In this article, we discuss the attributes of surrogate endpoints and provide guidance for selecting surrogates from existing avian laboratory tests as well as other possible sources. We also discuss some of the assumptions and uncertainties related to using surrogate endpoints to represent field effects. The process of explicitly considering how toxicity test results can be used to assess effects in the field helps identify uncertainties and data gaps that could be targeted in higher-tier risk assessments. © 2013 SETAC.

Fencing direct memory access data transfers in a parallel active messaging interface of a parallel computer

DOEpatents

Blocksome, Michael A.; Mamidala, Amith R.

2013-09-03

Fencing direct memory access (`DMA`) data transfers in a parallel active messaging interface (`PAMI`) of a parallel computer, the PAMI including data communications endpoints, each endpoint including specifications of a client, a context, and a task, the endpoints coupled for data communications through the PAMI and through DMA controllers operatively coupled to segments of shared random access memory through which the DMA controllers deliver data communications deterministically, including initiating execution through the PAMI of an ordered sequence of active DMA instructions for DMA data transfers between two endpoints, effecting deterministic DMA data transfers through a DMA controller and a segment of shared memory; and executing through the PAMI, with no FENCE accounting for DMA data transfers, an active FENCE instruction, the FENCE instruction completing execution only after completion of all DMA instructions initiated prior to execution of the FENCE instruction for DMA data transfers between the two endpoints.

Fencing direct memory access data transfers in a parallel active messaging interface of a parallel computer

DOEpatents

Blocksome, Michael A; Mamidala, Amith R

2014-02-11

Fencing direct memory access (`DMA`) data transfers in a parallel active messaging interface (`PAMI`) of a parallel computer, the PAMI including data communications endpoints, each endpoint including specifications of a client, a context, and a task, the endpoints coupled for data communications through the PAMI and through DMA controllers operatively coupled to segments of shared random access memory through which the DMA controllers deliver data communications deterministically, including initiating execution through the PAMI of an ordered sequence of active DMA instructions for DMA data transfers between two endpoints, effecting deterministic DMA data transfers through a DMA controller and a segment of shared memory; and executing through the PAMI, with no FENCE accounting for DMA data transfers, an active FENCE instruction, the FENCE instruction completing execution only after completion of all DMA instructions initiated prior to execution of the FENCE instruction for DMA data transfers between the two endpoints.

Fencing network direct memory access data transfers in a parallel active messaging interface of a parallel computer

DOEpatents

Blocksome, Michael A.; Mamidala, Amith R.

2015-07-07

Fencing direct memory access (`DMA`) data transfers in a parallel active messaging interface (`PAMI`) of a parallel computer, the PAMI including data communications endpoints, each endpoint including specifications of a client, a context, and a task, the endpoints coupled for data communications through the PAMI and through DMA controllers operatively coupled to a deterministic data communications network through which the DMA controllers deliver data communications deterministically, including initiating execution through the PAMI of an ordered sequence of active DMA instructions for DMA data transfers between two endpoints, effecting deterministic DMA data transfers through a DMA controller and the deterministic data communications network; and executing through the PAMI, with no FENCE accounting for DMA data transfers, an active FENCE instruction, the FENCE instruction completing execution only after completion of all DMA instructions initiated prior to execution of the FENCE instruction for DMA data transfers between the two endpoints.

Fencing network direct memory access data transfers in a parallel active messaging interface of a parallel computer

DOEpatents

Blocksome, Michael A.; Mamidala, Amith R.

2015-07-14

Fencing direct memory access (`DMA`) data transfers in a parallel active messaging interface (`PAMI`) of a parallel computer, the PAMI including data communications endpoints, each endpoint including specifications of a client, a context, and a task, the endpoints coupled for data communications through the PAMI and through DMA controllers operatively coupled to a deterministic data communications network through which the DMA controllers deliver data communications deterministically, including initiating execution through the PAMI of an ordered sequence of active DMA instructions for DMA data transfers between two endpoints, effecting deterministic DMA data transfers through a DMA controller and the deterministic data communications network; and executing through the PAMI, with no FENCE accounting for DMA data transfers, an active FENCE instruction, the FENCE instruction completing execution only after completion of all DMA instructions initiated prior to execution of the FENCE instruction for DMA data transfers between the two endpoints.

When Progressive Disease Does Not Mean Treatment Failure: Reconsidering the Criteria for Progression

PubMed Central

2012-01-01

Although progression-based endpoints, such as progression-free survival, are often key clinical trial endpoints for anticancer agents, the clinical meaning of “objective progression” is much less certain. As scrutiny of progression-based endpoints in clinical trials increases, it should be remembered that the Response Evaluation Criteria In Solid Tumors (RECIST) progression criteria were not developed as a surrogate for survival. Now that progression-free survival has come to be an increasingly important trial endpoint, the criteria that define progression deserve critical evaluation to determine whether alternate definitions of progression might facilitate the development of stronger surrogate endpoints and more meaningful trial results. In this commentary, we review the genesis of the criteria for progression, highlight recent data that question their value as a marker of treatment failure, and advocate for several research strategies that could lay the groundwork for a clinically validated definition of disease progression in solid tumor oncology. PMID:22927506

Effects of Chronic Social Defeat Stress on Sleep and Circadian Rhythms Are Mitigated by Kappa-Opioid Receptor Antagonism.

PubMed

Wells, Audrey M; Ridener, Elysia; Bourbonais, Clinton A; Kim, Woori; Pantazopoulos, Harry; Carroll, F Ivy; Kim, Kwang-Soo; Cohen, Bruce M; Carlezon, William A

2017-08-09

Stress plays a critical role in the neurobiology of mood and anxiety disorders. Sleep and circadian rhythms are affected in many of these conditions. Here we examined the effects of chronic social defeat stress (CSDS), an ethological form of stress, on sleep and circadian rhythms. We exposed male mice implanted with wireless telemetry transmitters to a 10 day CSDS regimen known to produce anhedonia (a depressive-like effect) and social avoidance (an anxiety-like effect). EEG, EMG, body temperature, and locomotor activity data were collected continuously during the CSDS regimen and a 5 day recovery period. CSDS affected numerous endpoints, including paradoxical sleep (PS) and slow-wave sleep (SWS), as well as the circadian rhythmicity of body temperature and locomotor activity. The magnitude of the effects increased with repeated stress, and some changes (PS bouts, SWS time, body temperature, locomotor activity) persisted after the CSDS regimen had ended. CSDS also altered mRNA levels of the circadian rhythm-related gene mPer2 within brain areas that regulate motivation and emotion. Administration of the κ-opioid receptor (KOR) antagonist JDTic (30 mg/kg, i.p.) before CSDS reduced stress effects on both sleep and circadian rhythms, or hastened their recovery, and attenuated changes in mPer2 Our findings show that CSDS produces persistent disruptions in sleep and circadian rhythmicity, mimicking attributes of stress-related conditions as they appear in humans. The ability of KOR antagonists to mitigate these disruptions is consistent with previously reported antistress effects. Studying homologous endpoints across species may facilitate the development of improved treatments for psychiatric illness. SIGNIFICANCE STATEMENT Stress plays a critical role in the neurobiology of mood and anxiety disorders. We show that chronic social defeat stress in mice produces progressive alterations in sleep and circadian rhythms that resemble features of depression as it appears in humans. Whereas some of these alterations recover quickly upon cessation of stress, others persist. Administration of a kappa-opioid receptor (KOR) antagonist reduced stress effects or hastened recovery, consistent with the previously reported antistress effects of this class of agents. Use of endpoints, such as sleep and circadian rhythm, that are homologous across species will facilitate the implementation of translational studies that better predict clinical outcomes in humans, improve the success of clinical trials, and facilitate the development of more effective therapeutics. Copyright © 2017 the authors 0270-6474/17/377656-13$15.00/0.

Restoration for the future: Setting endpoints and targets and selecting indicators of progress and success

Treesearch

Daniel C. Dey; Callie Jo Schweitzer; John M. Kabrick

2014-01-01

Setting endpoints and targets in forest restoration is a complicated task that is best accomplished in cooperative partnerships that account for the ecology of the system, production of desired ecosystem goods and services, economics and well-being of society, and future environments. Clearly written and quantitative endpoints and intermediary targets need to be...

Template for Conceptual Model Construction: Model Components and Application of the Template

DTIC Science & Technology

2007-09-01

stressors, focused through EECs, result in endpoints (Lubinski and Barko 2003). Endpoints are quantifiable, ecologically significant, and important to...Monitoring Plan (Thomas et al. 2001) Lake Okeechobee (Havens 1999) EPA Ecological Risk Assessment on Terrestrial Ecosystem (Suter 1996) Grassland...endpoints (Havens 1999) are examples of Hydrologic Resources: Water Quality, and Terrestrial Resources: Biota. The EPA Ecological Risk Assessment (Suter

Considerations for development of surrogate endpoints for antifracture efficacy of new treatments in osteoporosis: a perspective.

PubMed

Bouxsein, Mary L; Delmas, Pierre D

2008-08-01

Because of the broad availability of efficacious osteoporosis therapies, conduct of placebo-controlled trials in subjects at high risk for fracture is becoming increasing difficult. Alternative trial designs include placebo-controlled trials in patients at low risk for fracture or active comparator studies, both of which would require enormous sample sizes and associated financial resources. Another more attractive alternative is to develop and validate surrogate endpoints for fracture. In this perspective, we review the concept of surrogate endpoints as it has been developed in other fields of medicine and discuss how it could be applied in clinical trials of osteoporosis. We outline a stepwise approach and possible study designs to qualify a biomarker as a surrogate endpoint in osteoporosis and review the existing data for several potential surrogate endpoints to assess their success in meeting the proposed criteria. Finally, we suggest a research agenda needed to advance the development of biomarkers as surrogate endpoints for fracture in osteoporosis trials. To ensure optimal development and best use of biomarkers to accelerate drug development, continuous dialog among the health professionals, industry, and regulators is of paramount importance.

[Selection of "surrogate" and "endpoints" evaluation of the efficacy of medical interventions].

PubMed

Lazebnik, L B; Gusein-Zade, M G; Efremov, L I

2011-01-01

With the advent of new medical technologies and medicines, as well as due to changes in disease patterns and demographic problems rises the need for continued increases in health spending. Increased costs can be totally inadequate, if it has been done without studying the effectiveness of medical interventions, based on the results of evidence-based medicine and economic of their feasibility. To evaluate the clinical effectiveness of medical interventions have been recently used specific criteria, so called points of clinical efficacy (surrogate and endpoints), that allow to conclude feasibility or harmfulness of the introduction or application of the intervention in clinical practice. The endpoint is reliable indicator the effectiveness of medical intervention. Surrogate point--is a biomarker that is intended to replace the endpoint and is a predictor of the effectiveness of medical intervention. The use of surrogate points has several advantages such as simple in identification and measurement, as well as more higher in compare with endpoints the vents frequency, that can significantly reduce the size of the selection and duration and cost of clinical trials, respectively. Finally, the surrogate points allow to evaluate treatment effect in situations where the use of endpoints is difficult or is unethical.

Traditional and new composite endpoints in heart failure clinical trials: facilitating comprehensive efficacy assessments and improving trial efficiency.

PubMed

Anker, Stefan D; Schroeder, Stefan; Atar, Dan; Bax, Jeroen J; Ceconi, Claudio; Cowie, Martin R; Crisp, Adam; Dominjon, Fabienne; Ford, Ian; Ghofrani, Hossein-Ardeschir; Gropper, Savion; Hindricks, Gerhard; Hlatky, Mark A; Holcomb, Richard; Honarpour, Narimon; Jukema, J Wouter; Kim, Albert M; Kunz, Michael; Lefkowitz, Martin; Le Floch, Chantal; Landmesser, Ulf; McDonagh, Theresa A; McMurray, John J; Merkely, Bela; Packer, Milton; Prasad, Krishna; Revkin, James; Rosano, Giuseppe M C; Somaratne, Ransi; Stough, Wendy Gattis; Voors, Adriaan A; Ruschitzka, Frank

2016-05-01

Composite endpoints are commonly used as the primary measure of efficacy in heart failure clinical trials to assess the overall treatment effect and to increase the efficiency of trials. Clinical trials still must enrol large numbers of patients to accrue a sufficient number of outcome events and have adequate power to draw conclusions about the efficacy and safety of new treatments for heart failure. Additionally, the societal and health system perspectives on heart failure have raised interest in ascertaining the effects of therapy on outcomes such as repeat hospitalization and the patient's burden of disease. Thus, novel methods for using composite endpoints in clinical trials (e.g. clinical status composite endpoints, recurrent event analyses) are being applied in current and planned trials. Endpoints that measure functional status or reflect the patient experience are important but used cautiously because heart failure treatments may improve function yet have adverse effects on mortality. This paper discusses the use of traditional and new composite endpoints, identifies qualities of robust composites, and outlines opportunities for future research. © 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.

Measuring titratable alkalinity by single versus double endpoint titration: An evaluation in two cyprinodont species and implications for characterizing net H+ flux in aquatic organisms.

PubMed

Brix, Kevin V; Wood, Chris M; Grosell, Martin

2013-01-01

In this study, Na(+) uptake and acid-base balance in the euryhaline pupfish Cyprinodon variegatus variegatus were characterized when fish were exposed to pH 4.5 freshwater (7mM Na(+)). Similar to the related cyprinodont, Fundulus heteroclitus, Na(+) uptake was significantly inhibited when exposed to low pH water. However, it initially appeared that C. v. variegatus increased apparent net acid excretion at low pH relative to circumneutral pH. This result is opposite to previous observations for F. heteroclitus under similar conditions where fish were observed to switch from apparent net H(+) excretion at circumneutral pH to apparent net H(+) uptake at low pH. Further investigation revealed disparate observations between these studies were the result of using double endpoint titrations to measure titratable alkalinity fluxes in the current study, while the earlier study utilized single endpoint titrations to measure these fluxes (i.e.,. Cyprinodon acid-base transport is qualitatively similar to Fundulus when characterized using single endpoint titrations). This led to a comparative investigation of these two methods. We hypothesized that either the single endpoint methodology was being influenced by a change in the buffer capacity of the water (e.g., mucus being released by the fish) at low pH, or the double endpoint methodology was not properly accounting for ammonia flux by the fish. A series of follow-up experiments indicated that buffer capacity of the water did not change significantly, that excretion of protein (a surrogate for mucus) was actually reduced at low pH, and that the double endpoint methodology does not properly account for NH(3) excretion by fish under low pH conditions. As a result, it overestimates net H(+) excretion during low pH exposure. After applying the maximum possible correction for this error (i.e., assuming that all ammonia is excreted as NH(3)), the double endpoint methodology indicates that net H(+) transport was reduced to effectively zero in both species at pH 4.5. However, significant differences between the double endpoint (no net H(+) transport at low pH) and single endpoint titrations (net H(+) uptake at low pH) remain to be explained. Copyright © 2012 Elsevier Inc. All rights reserved.

Application of the Navigation Guide systematic review methodology to the evidence for developmental and reproductive toxicity of triclosan.

PubMed

Johnson, Paula I; Koustas, Erica; Vesterinen, Hanna M; Sutton, Patrice; Atchley, Dylan S; Kim, Allegra N; Campbell, Marlissa; Donald, James M; Sen, Saunak; Bero, Lisa; Zeise, Lauren; Woodruff, Tracey J

2016-01-01

There are reports of developmental and reproductive health effects associated with the widely used biocide triclosan. Apply the Navigation Guide systematic review methodology to answer the question: Does exposure to triclosan have adverse effects on human development or reproduction? We applied the first 3 steps of the Navigation Guide methodology: 1) Specify a study question, 2) Select the evidence, and 3) Rate quality and strength of the evidence. We developed a protocol, conducted a comprehensive search of the literature, and identified relevant studies using pre-specified criteria. We assessed the number and type of all relevant studies. We evaluated each included study for risk of bias and rated the quality and strength of the evidence for the selected outcomes. We conducted a meta-analysis on a subset of suitable data. We found 4282 potentially relevant records, and 81 records met our inclusion criteria. Of the more than 100 endpoints identified by our search, we focused our evaluation on hormone concentration outcomes, which had the largest human and non-human mammalian data set. Three human studies and 8 studies conducted in rats reported thyroxine levels as outcomes. The rat data were amenable to meta-analysis. Because only one of the human thyroxine studies quantified exposure, we did not conduct a meta-analysis of the human data. Through meta-analysis of the data for rats, we estimated for prenatal exposure a 0.09% (95% CI: -0.20, 0.02) reduction in thyroxine concentration per mg triclosan/kg-bw in fetal and young rats compared to control. For postnatal exposure we estimated a 0.31% (95% CI: -0.38, -0.23) reduction in thyroxine per mg triclosan/kg-bw, also compared to control. Overall, we found low to moderate risk of bias across the human studies and moderate to high risk of bias across the non-human studies, and assigned a "moderate/low" quality rating to the body of evidence for human thyroid hormone alterations and a "moderate" quality rating to the body of evidence for non-human thyroid hormone alterations. Based on this application of the Navigation Guide systematic review methodology, we concluded that there was "sufficient" non-human evidence and "inadequate" human evidence of an association between triclosan exposure and thyroxine concentrations, and consequently, triclosan is "possibly toxic" to reproductive and developmental health. Thyroid hormone disruption is an upstream indicator of developmental toxicity. Additional endpoints may be identified as being of equal or greater concern as other data are developed or evaluated. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Application of the Navigation Guide Systematic Review Methodology to the Evidence for Developmental and Reproductive Toxicity of Triclosan

PubMed Central

Johnson, Paula I.; Koustas, Erica; Vesterinen, Hanna M.; Sutton, Patrice; Atchley, Dylan S.; Kim, Allegra N.; Campbell, Marlissa; Donald, James M.; Sen, Saunak; Bero, Lisa; Zeise, Lauren; Woodruff, Tracey J.

2016-01-01

Background There are reports of developmental and reproductive health effects associated with the widely used biocide triclosan. Objective Apply the Navigation Guide systematic review methodology to answer the question: Does exposure to triclosan have adverse effects on human development or reproduction? Methods We applied the first 3 steps of the Navigation Guide methodology: 1) Specify a study question, 2) Select the evidence, and 3) Rate quality and strength of the evidence. We developed a protocol, conducted a comprehensive search of the literature, and identified relevant studies using pre-specified criteria. We assessed the number and type of all relevant studies. We evaluated each included study for risk of bias and rated the quality and strength of the evidence for the selected outcomes. We conducted a meta-analysis on a subset of suitable data. Results We found 4,282 potentially relevant records, and 81 records met our inclusion criteria. Of the more than 100 endpoints identified by our search, we focused our evaluation on hormone concentration outcomes, which had the largest human and non-human mammalian data set. Three human studies and 8 studies conducted in rats reported thyroxine levels as outcomes. The rat data were amenable to meta-analysis. Because only one of the human thyroxine studies quantified exposure, we did not conduct a meta-analysis of the human data. Through meta-analysis of the data for rats, we estimated for prenatal exposure a 0.09% (95% CI: −0.20, 0.02) reduction in thyroxine concentration per mg triclosan/kg-bw in fetal and young rats compared to control. For postnatal exposure we estimated a 0.31% (95% CI: −0.38, −0.23) reduction in thyroxine per mg triclosan/kg-bw, also compared to control. Overall we found low to moderate risk of bias across the human studies and moderate to high risk of bias across the non-human studies, and assigned a “moderate/low” quality rating to the body of evidence for human thyroid hormone alterations and a “moderate” quality rating to the body of evidence for non-human thyroid hormone alterations. Conclusion Based on this application of the Navigation Guide systematic review methodology, we concluded that there was “sufficient” non-human evidence and “inadequate” human evidence of an association between triclosan exposure and thyroxine concentrations, and consequently, triclosan is “possibly toxic” to reproductive and developmental health. Thyroid hormone disruption is an upstream indicator of developmental toxicity. Additional endpoints may be identified as being of equal or greater concern as other data are developed or evaluated. PMID:27156197

The PREDIMED trial, Mediterranean diet and health outcomes: How strong is the evidence?

PubMed

Guasch-Ferré, M; Salas-Salvadó, J; Ros, E; Estruch, R; Corella, D; Fitó, M; Martínez-González, M A

2017-07-01

To address potential controversies on the health benefits of the Mediterranean diet (MedDiet) after PREDIMED, a randomized trial of MedDiet for primary cardiovascular prevention. We have focused on: a) the PREDIMED study design, b) analysis of PREDIMED data and c) interpretation of its results. Regarding the design of the trial, its early termination and between-group differences in the intensity of the intervention are potential causes of concern. The planned duration was 6 years but the trial was prematurely stopped when an interim analysis at 4.8-year provided sufficient evidence of benefit for the two MedDiets. In the MedDiet groups supplemented with extra-virgin olive oil or mixed-nuts, the primary composite endpoint (myocardial infarction, stroke, or cardiovascular death) was reduced by 30% and 28% respectively, as compared with the control group. Final results did not change after taking into account the different intensity of educational efforts during the trial. Other potential doubts related to data analysis (e.g., intention to treat versus a per-protocol approach, and consequences of dropouts) should not be causes of concern. Finally, we addressed alternative interpretations of the effect on all-cause mortality. The protocol-defined primary endpoint was a composite cardiovascular endpoint, not all-cause mortality. To analyze total mortality, we would have needed a much larger sample size and longer follow-up. Therefore, the PREDIMED results cannot be used to draw firm conclusions on MedDiets and all-cause mortality. The PREDIMED study was designed to overcome three major problems of previous nutritional research: a) residual confounding, addressed by using a randomized design; b) single-nutrient approaches, by randomizing an overall dietary pattern; and c) the limitations of assessing only intermediate risk markers, by using hard clinical end-points. Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Effects of the lipid regulator drug gemfibrozil: A toxicological and behavioral perspective.

PubMed

Henriques, Jorge F; Almeida, Ana Rita; Andrade, Thayres; Koba, Olga; Golovko, Oksana; Soares, Amadeu M V M; Oliveira, Miguel; Domingues, Inês

2016-01-01

Pharmaceuticals are emerging contaminants as their worldwide consumption increases. Fibrates such as gemfibrozil (GEM) are used in human medicine to reduce blood concentrations of cholesterol and triacylglycerol and also are some of the most frequently reported pharmaceuticals in waste waters and surface waters. Despite some studies have already demonstrated the negative impact in physiological and/or reproductive endpoints in adult fish, data on survival and behavioral effects in fish larvae are lacking. This study aimed to assess the effects of GEM on zebrafish eleutheroembryo development and locomotor behavior. A fish embryo toxicity (FET) test was undertaken to evaluate GEM acute toxicity by exposing embryos to 0, 6.58, 9.87, 14.81, 22.22, 33.33 and 50mg/L. Developmental endpoints such as hatching success, edemas and malformations were recorded. A second test was undertaken by exposing embryos to 0, 1.5, 3 and 6mg/L in order to evaluate the effects of GEM on 120 and 144h post fertilization (hpf) larvae locomotor activity by video tracking, using a Zebrabox(®) (Viewpoint, France) device. From the data recorded, several parameters such as total swimming distance (TSD) and total swimming time (TST) in each 120s integration time were calculated. Data showed that this compound has a moderate toxic effect on fish embryo development, affecting both survival and hatching success with a calculated 96h LC50 of 11.01mg/L and no effects at the developmental level at 6mg/L. GEM seems to impair locomotor activity, even at concentrations where developmental abnormalities were unperceived, at concentrations as low as 1.5mg/L. Both TSD and TST were sensitive to GEM exposure. These effects do not seem to be independent of the developmental stage as 120hpf larvae seem to present a development bias with repercussions in locomotor behavior. This study highlights the need to include behavioral endpoints in ecotoxicological assays as this seems to be a more sensitive endpoint often disregarded. Copyright © 2015 Elsevier B.V. All rights reserved.

A model of the hierarchy of behaviour, cognition, and consciousness.

PubMed

Toates, Frederick

2006-03-01

Processes comparable in important respects to those underlying human conscious and non-conscious processing can be identified in a range of species and it is argued that these reflect evolutionary precursors of the human processes. A distinction is drawn between two types of processing: (1) stimulus-based and (2) higher-order. For 'higher-order,' in humans the operations of processing are themselves associated with conscious awareness. Conscious awareness sets the context for stimulus-based processing and its end-point is accessible to conscious awareness. However, the mechanics of the translation between stimulus and response proceeds without conscious control. The paper argues that higher-order processing is an evolutionary addition to stimulus-based processing. The model's value is shown for gaining insight into a range of phenomena and their link with consciousness. These include brain damage, learning, memory, development, vision, emotion, motor control, reasoning, the voluntary versus involuntary debate, and mental disorder.

Progress and Challenges Associated with the Development of Ricin Toxin Subunit Vaccines

PubMed Central

Vance, David J.; Mantis, Nicholas J.

2016-01-01

Summary The past several years have seen major advances in the development of a safe and efficacious ricin toxin vaccine, including the completion of two Phase I clinical trials with two different recombinant A subunit (RTA)-based vaccines: RiVax™ and RVEc™ adsorbed to aluminum salt adjuvant, as well as a non-human primate study demonstrating that parenteral immunization with RiVax elicits a serum antibody response that was sufficient to protect against a lethal dose aerosolized ricin exposure. One of the major obstacles moving forward is assessing vaccine efficacy in humans, when neither ricin-specific serum IgG endpoint titers nor toxin-neutralizing antibody levels are accepted as definitive predictors of protective immunity. In this review we summarize ongoing efforts to leverage recent advances in our understanding of RTA-antibody interactions at the structural level to develop novel assays to predict vaccine efficacy in humans. PMID:26998662

Progress and challenges associated with the development of ricin toxin subunit vaccines.

PubMed

Vance, David J; Mantis, Nicholas J

2016-09-01

The past several years have seen major advances in the development of a safe and efficacious ricin toxin vaccine, including the completion of two Phase I clinical trials with two different recombinant A subunit (RTA)-based vaccines: RiVax™ and RVEc™ adsorbed to aluminum salt adjuvant, as well as a non-human primate study demonstrating that parenteral immunization with RiVax elicits a serum antibody response that was sufficient to protect against a lethal dose aerosolized ricin exposure. One of the major obstacles moving forward is assessing vaccine efficacy in humans, when neither ricin-specific serum IgG endpoint titers nor toxin-neutralizing antibody levels are accepted as definitive predictors of protective immunity. In this review we summarize ongoing efforts to leverage recent advances in our understanding of RTA-antibody interactions at the structural level to develop novel assays to predict vaccine efficacy in humans.

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

Shalat, S.L.; Walker, D.B.; Finnell, R.H.

Arsenic has been recognized as a human toxicant for over 2000 years. More recently it has been readily accepted as a human carcinogen. Animal research has demonstrated arsenic`s ability to have profound detrimental effects on the developing embryo in avian and mamalian species. This article comprehensively reviews the human and animal literature on the subject of the reproductive toxicity of arsenic. A variety of endpoints are considered, including spontaneous abortion, cardiovascular defects, and arsenic`s role in the causation of neural tube defects (NTDs). A summary of the literature that has examined the various postulated mechanisms by which arsenic may producemore » NTDs is also considered. In addition, a discussion of literature relative to the presence of arsenic in the general environment and in the workplace presented. This article reaches the conclusion that while further research is clearly needed, particularly on the potential toxicity of organic arsenical compounds, the current literature suggests it may be prudent and appropriate to treat inorganic arsenic as a probable human reproductive toxin. 132 refs.« less

Surrogate outcomes are associated with low methodological quality of studies of rheumatoid arthritis treated with antitumour necrosis factor agents: a systematic review.

PubMed

Nobre, Moacyr Roberto Cuce; da Costa, Frnanda Marques

2012-02-01

Surrogate endpoints may be used as substitutes for, but often do not predict clinically relevant events. Objective To assess the methodological quality of articles that present their conclusions based on clinically relevant or surrogate outcomes in a systematic review of randomised trials and cohort studies of patients with rheumatoid arthritis treated with antitumour necrosis factor (TNF) agents. PubMed, Embase and Cochrane databases were searched. The Jadad score, the percentage of Consolidated Standards Of Reporting Trials (CONSORT) statement items adequately reported and levels-of-evidence (Center for Evidence-based Medicine, Oxford) were used in a descriptive synthesis. Among 88 articles appraised, 27 had surrogate endpoints, mainly radiographic, and 44 were duplicate publications; 74% of articles with surrogate and 39% of articles with clinical endpoints (p=0.006). Fewer articles with surrogate endpoints represented a high level of evidence (Level 1b, 33% vs 62%, p=0.037) and the mean percentage of CONSORT statement items met was also lower for articles with surrogate endpoints (62.5 vs 70.7, p=0.026). Although fewer articles with surrogate endpoints were randomised trials (63% vs 74%, p=0.307) and articles with surrogate endpoints had lower Jadad scores (3.0 vs 3.2, p=0.538), these differences were not statistically significant. Studies of anti-TNF agents that report surrogate outcomes are of lesser methodological quality. As such, inclusion of such studies in evidence syntheses may bias results.

The Use of Surrogate Endpoints in Regulating Medicines for Cardio-Renal Disease: Opinions of Stakeholders

PubMed Central

Schievink, Bauke; Lambers Heerspink, Hiddo; Leufkens, Hubert; De Zeeuw, Dick; Hoekman, Jarno

2014-01-01

Aim There is discussion whether medicines can be authorized on the market based on evidence from surrogate endpoints. We assessed opinions of different stakeholders on this topic. Methods We conducted an online questionnaire that targeted various stakeholder groups (regulatory agencies, pharmaceutical industry, academia, relevant public sector organisations) and medical specialties (cardiology or nephrology vs. other). Participants were enrolled through purposeful sampling. We inquired for conditions under which surrogate endpoints can be used, the validity of various cardio-renal biomarkers and new approaches for biomarker use. Results Participants agreed that surrogate endpoints can be used when the surrogate is scientifically valid (5-point Likert response format, mean score: 4.3, SD: 0.9) or when there is an unmet clinical need (mean score: 3.8, SD: 1.2). Industry participants agreed to a greater extent than regulators and academics. However, out of four proposed surrogates (blood pressure (BP), HbA1c, albuminuria, CRP) for cardiovascular outcomes or end-stage renal disease, only use of BP for cardiovascular outcomes was deemed moderately accurate (mean: 3.6, SD: 1.1). Specialists in cardiology or nephrology tended to be more positive about the use of surrogate endpoints. Conclusion Stakeholders in drug development do not oppose to the use of surrogate endpoints in drug marketing authorization, but most surrogates are not considered valid. To solve this impasse, increased efforts are required to validate surrogate endpoints and to explore alternative ways to use them. PMID:25268242

Evaluating surrogate endpoints, prognostic markers, and predictive markers — some simple themes

PubMed Central

Baker, Stuart G.; Kramer, Barnett S.

2014-01-01

Background A surrogate endpoint is an endpoint observed earlier than the true endpoint (a health outcome) that is used to draw conclusions about the effect of treatment on the unobserved true endpoint. A prognostic marker is a marker for predicting the risk of an event given a control treatment; it informs treatment decisions when there is information on anticipated benefits and harms of a new treatment applied to persons at high risk. A predictive marker is a marker for predicting the effect of treatment on outcome in a subgroup of patients or study participants; it provides more rigorous information for treatment selection than a prognostic marker when it is based on estimated treatment effects in a randomized trial. Methods We organized our discussion around a different theme for each topic. Results “Fundamentally an extrapolation” refers to the non-statistical considerations and assumptions needed when using surrogate endpoints to evaluate a new treatment. “Decision analysis to the rescue” refers to use the use of decision analysis to evaluate an additional prognostic marker because it is not possible to choose between purely statistical measures of marker performance. “The appeal of simplicity” refers to a straightforward and efficient use of a single randomized trial to evaluate overall treatment effect and treatment effect within subgroups using predictive markers. Conclusion The simple themes provide a general guideline for evaluation of surrogate endpoints, prognostic markers, and predictive markers. PMID:25385934

The use of surrogate endpoints in regulating medicines for cardio-renal disease: opinions of stakeholders.

PubMed

Schievink, Bauke; Lambers Heerspink, Hiddo; Leufkens, Hubert; De Zeeuw, Dick; Hoekman, Jarno

2014-01-01

There is discussion whether medicines can be authorized on the market based on evidence from surrogate endpoints. We assessed opinions of different stakeholders on this topic. We conducted an online questionnaire that targeted various stakeholder groups (regulatory agencies, pharmaceutical industry, academia, relevant public sector organisations) and medical specialties (cardiology or nephrology vs. other). Participants were enrolled through purposeful sampling. We inquired for conditions under which surrogate endpoints can be used, the validity of various cardio-renal biomarkers and new approaches for biomarker use. Participants agreed that surrogate endpoints can be used when the surrogate is scientifically valid (5-point Likert response format, mean score: 4.3, SD: 0.9) or when there is an unmet clinical need (mean score: 3.8, SD: 1.2). Industry participants agreed to a greater extent than regulators and academics. However, out of four proposed surrogates (blood pressure (BP), HbA1c, albuminuria, CRP) for cardiovascular outcomes or end-stage renal disease, only use of BP for cardiovascular outcomes was deemed moderately accurate (mean: 3.6, SD: 1.1). Specialists in cardiology or nephrology tended to be more positive about the use of surrogate endpoints. Stakeholders in drug development do not oppose to the use of surrogate endpoints in drug marketing authorization, but most surrogates are not considered valid. To solve this impasse, increased efforts are required to validate surrogate endpoints and to explore alternative ways to use them.

The use of intermediate endpoints in the design of type 1 diabetes prevention trials.

PubMed

Krischer, Jeffrey P

2013-09-01

This paper presents a rationale for the selection of intermediate endpoints to be used in the design of type 1 diabetes prevention clinical trials. Relatives of individuals diagnosed with type 1 diabetes were enrolled on the TrialNet Natural History Study and screened for diabetes-related autoantibodies. Those with two or more such autoantibodies were analysed with respect to increased HbA1c, decreased C-peptide following an OGTT, or abnormal OGTT values as intermediate markers of disease progression. Over 2 years, a 10% increase in HbA1c, and a 20% or 30% decrease in C-peptide from baseline, or progression to abnormal OGTT, occurred with a frequency between 20% and 41%. The 3- to 5-year risk of type 1 diabetes following each intermediate endpoint was high, namely 47% to 84%. The lower the incidence of the endpoint being reached, the higher the risk of diabetes. A diabetes prevention trial using these intermediate endpoints would require a 30% to 50% smaller sample size than one using type 1 diabetes as the endpoint. The use of an intermediate endpoint in diabetes prevention is based on the generally held view of disease progression from initial occurrence of autoantibodies through successive immunological and metabolic changes to manifest type 1 diabetes. Thus, these markers are suitable for randomised phase 2 trials, which can more rapidly screen promising new therapies, allowing them to be subsequently confirmed in definitive phase 3 trials.

The use of intermediate endpoints in the design of type 1 diabetes prevention trials

PubMed Central

Krischer, Jeffrey P.

2013-01-01

Aims/hypothesis This paper presents a rationale for the selection of intermediate endpoints to be used in the design of type 1 diabetes prevention clinical trials. Methods Relatives of individuals diagnosed with type 1 diabetes were enrolled on the TrialNet Natural History Study and screened for diabetes-related autoantibodies. Those with two or more such autoantibodies were analysed with respect to increased HbA1c, decreased C-peptide following an OGTT, or abnormal OGTT values as intermediate markers of disease progression. Results Over 2 years, a 10% increase in HbA1c, and a 20% or 30% decrease in C-peptide from baseline, or progression to abnormal OGTT, occurred with a frequency between 20% and 41%. The 3- to 5-year risk of type 1 diabetes following each intermediate endpoint was high, namely 47% to 84%. The lower the incidence of the endpoint being reached, the higher the risk of diabetes. A diabetes prevention trial using these intermediate endpoints would require a 30% to 50% smaller sample size than one using type 1 diabetes as the endpoint. Conclusions/interpretation The use of an intermediate endpoint in diabetes prevention is based on the generally held view of disease progression from initial occurrence of autoantibodies through successive immunological and metabolic changes to manifest type 1 diabetes. Thus, these markers are suitable for randomised phase 2 trials, which can more rapidly screen promising new therapies, allowing them to be subsequently confirmed in definitive phase 3 trials. PMID:23744306

Mutagenicity, anticancer activity and blood brain barrier: similarity and dissimilarity of molecular alerts.

PubMed

Toropov, Andrey A; Toropova, Alla P; Benfenati, Emilio; Salmona, Mario

2018-06-01

The aim of the present work is an attempt to define computable measure of similarity between different endpoints. The similarity of structural alerts of different biochemical endpoints can be used to solve tasks of medicinal chemistry. Optimal descriptors are a tool to build up models for different endpoints. The optimal descriptor is calculated with simplified molecular input-line entry system (SMILES). A group of elements (single symbol or pair of symbols) can represent any SMILES. Each element of SMILES can be represented by so-called correlation weight i.e. coefficient that should be used to calculate descriptor. Numerical data on the correlation weights are calculated by the Monte Carlo method, i.e. by optimization procedure, which gives maximal correlation coefficient between the optimal descriptor and endpoint for the training set. Statistically stable correlation weights observed in several runs of the optimization can be examined as structural alerts, which are promoters of the increase or the decrease of a biochemical activity of a substance. Having data on several runs of the optimization correlation weights, one can extract list of promoters of increase and list of promoters of decrease for an endpoint. The study of similarity and dissimilarity of the above lists has been carried out for the following pairs of endpoints: (i) mutagenicity and anticancer activity; (ii) mutagenicity and blood brain barrier; and (iii) blood brain barrier and anticancer activity. The computational experiment confirms that similarity and dissimilarity for pairs of endpoints can be measured.

Surrogate endpoints and competing risk of death in cardiac arrest research.

PubMed

McCredie, Victoria A; Scales, Damon C

2016-06-29

We urgently need new therapies to improve outcomes after cardiac arrest. Initial studies typically target surrogate endpoints, and these studies help to inform subsequent larger trials that are powered to measure more patient-orientated clinical outcomes such as survival. The competing risk of death and premature assessment of neurological prognosis pose significant challenges to measuring these surrogate endpoints after cardiac arrest.

Surrogate and Intermediate Endpoints in Randomized Trials: What's the Goal?

PubMed

Korn, Edward L; Freidlin, Boris

2018-05-15

Establishing trial-level surrogacy of an intermediate endpoint for predicting survival benefit in future trials is extremely challenging because of the extrapolations required, but there are other useful drug development and patient management applications of intermediate endpoints. Clin Cancer Res; 24(10); 2239-40. ©2018 AACR See related article by Mushti et al., p. 2268 . ©2018 American Association for Cancer Research.

Automatic knowledge extraction from chemical structures: the case of mutagenicity prediction.

PubMed

Ferrari, T; Cattaneo, D; Gini, G; Golbamaki Bakhtyari, N; Manganaro, A; Benfenati, E

2013-01-01

This work proposes a new structure-activity relationship (SAR) approach to mine molecular fragments that act as structural alerts for biological activity. The entire process is designed to fit with human reasoning, not only to make the predictions more reliable but also to permit clear control by the user in order to meet customized requirements. This approach has been tested on the mutagenicity endpoint, showing marked prediction skills and, more interestingly, bringing to the surface much of the knowledge already collected in the literature as well as new evidence.

Does the decision in a validation process of a surrogate endpoint change with level of significance of treatment effect? A proposal on validation of surrogate endpoints.

PubMed

Sertdemir, Y; Burgut, R

2009-01-01

In recent years the use of surrogate end points (S) has become an interesting issue. In clinical trials, it is important to get treatment outcomes as early as possible. For this reason there is a need for surrogate endpoints (S) which are measured earlier than the true endpoint (T). However, before a surrogate endpoint can be used it must be validated. For a candidate surrogate endpoint, for example time to recurrence, the validation result may change dramatically between clinical trials. The aim of this study is to show how the validation criterion (R(2)(trial)) proposed by Buyse et al. are influenced by the magnitude of treatment effect with an application using real data. The criterion R(2)(trial) proposed by Buyse et al. (2000) is applied to the four data sets from colon cancer clinical trials (C-01, C-02, C-03 and C-04). Each clinical trial is analyzed separately for treatment effect on survival (true endpoint) and recurrence free survival (surrogate endpoint) and this analysis is done also for each center in each trial. Results are used for standard validation analysis. The centers were grouped by the Wald statistic in 3 equal groups. Validation criteria R(2)(trial) were 0.641 95% CI (0.432-0.782), 0.223 95% CI (0.008-0.503), 0.761 95% CI (0.550-0.872) and 0.560 95% CI (0.404-0.687) for C-01, C-02, C-03 and C-04 respectively. The R(2)(trial) criteria changed by the Wald statistics observed for the centers used in the validation process. Higher the Wald statistic groups are higher the R(2)(trial) values observed. The recurrence free survival is not a good surrogate for overall survival in clinical trials with non significant treatment effects and moderate for significant treatment effects. This shows that the level of significance of treatment effect should be taken into account in validation process of surrogate endpoints.

Surrogate Endpoint Evaluation: Principal Stratification Criteria and the Prentice Definition.

PubMed

Gilbert, Peter B; Gabriel, Erin E; Huang, Ying; Chan, Ivan S F

2015-09-01

A common problem of interest within a randomized clinical trial is the evaluation of an inexpensive response endpoint as a valid surrogate endpoint for a clinical endpoint, where a chief purpose of a valid surrogate is to provide a way to make correct inferences on clinical treatment effects in future studies without needing to collect the clinical endpoint data. Within the principal stratification framework for addressing this problem based on data from a single randomized clinical efficacy trial, a variety of definitions and criteria for a good surrogate endpoint have been proposed, all based on or closely related to the "principal effects" or "causal effect predictiveness (CEP)" surface. We discuss CEP-based criteria for a useful surrogate endpoint, including (1) the meaning and relative importance of proposed criteria including average causal necessity (ACN), average causal sufficiency (ACS), and large clinical effect modification; (2) the relationship between these criteria and the Prentice definition of a valid surrogate endpoint; and (3) the relationship between these criteria and the consistency criterion (i.e., assurance against the "surrogate paradox"). This includes the result that ACN plus a strong version of ACS generally do not imply the Prentice definition nor the consistency criterion, but they do have these implications in special cases. Moreover, the converse does not hold except in a special case with a binary candidate surrogate. The results highlight that assumptions about the treatment effect on the clinical endpoint before the candidate surrogate is measured are influential for the ability to draw conclusions about the Prentice definition or consistency. In addition, we emphasize that in some scenarios that occur commonly in practice, the principal strata sub-populations for inference are identifiable from the observable data, in which cases the principal stratification framework has relatively high utility for the purpose of effect modification analysis, and is closely connected to the treatment marker selection problem. The results are illustrated with application to a vaccine efficacy trial, where ACN and ACS for an antibody marker are found to be consistent with the data and hence support the Prentice definition and consistency.

Surrogate Endpoint Evaluation: Principal Stratification Criteria and the Prentice Definition

PubMed Central

Gilbert, Peter B.; Gabriel, Erin E.; Huang, Ying; Chan, Ivan S.F.

2015-01-01

A common problem of interest within a randomized clinical trial is the evaluation of an inexpensive response endpoint as a valid surrogate endpoint for a clinical endpoint, where a chief purpose of a valid surrogate is to provide a way to make correct inferences on clinical treatment effects in future studies without needing to collect the clinical endpoint data. Within the principal stratification framework for addressing this problem based on data from a single randomized clinical efficacy trial, a variety of definitions and criteria for a good surrogate endpoint have been proposed, all based on or closely related to the “principal effects” or “causal effect predictiveness (CEP)” surface. We discuss CEP-based criteria for a useful surrogate endpoint, including (1) the meaning and relative importance of proposed criteria including average causal necessity (ACN), average causal sufficiency (ACS), and large clinical effect modification; (2) the relationship between these criteria and the Prentice definition of a valid surrogate endpoint; and (3) the relationship between these criteria and the consistency criterion (i.e., assurance against the “surrogate paradox”). This includes the result that ACN plus a strong version of ACS generally do not imply the Prentice definition nor the consistency criterion, but they do have these implications in special cases. Moreover, the converse does not hold except in a special case with a binary candidate surrogate. The results highlight that assumptions about the treatment effect on the clinical endpoint before the candidate surrogate is measured are influential for the ability to draw conclusions about the Prentice definition or consistency. In addition, we emphasize that in some scenarios that occur commonly in practice, the principal strata sub-populations for inference are identifiable from the observable data, in which cases the principal stratification framework has relatively high utility for the purpose of effect modification analysis, and is closely connected to the treatment marker selection problem. The results are illustrated with application to a vaccine efficacy trial, where ACN and ACS for an antibody marker are found to be consistent with the data and hence support the Prentice definition and consistency. PMID:26722639

The persistence of human DNA in soil following surface decomposition.

PubMed

Emmons, Alexandra L; DeBruyn, Jennifer M; Mundorff, Amy Z; Cobaugh, Kelly L; Cabana, Graciela S

2017-09-01

Though recent decades have seen a marked increase in research concerning the impact of human decomposition on the grave soil environment, the fate of human DNA in grave soil has been relatively understudied. With the purpose of supplementing the growing body of literature in forensic soil taphonomy, this study assessed the relative persistence of human DNA in soil over the course of decomposition. Endpoint PCR was used to assess the presence or absence of human nuclear and mitochondrial DNA, while qPCR was used to evaluate the quantity of human DNA recovered from the soil beneath four cadavers at the University of Tennessee's Anthropology Research Facility (ARF). Human nuclear DNA from the soil was largely unrecoverable, while human mitochondrial DNA was detectable in the soil throughout all decomposition stages. Mitochondrial DNA copy abundances were not significantly different between decomposition stages and were not significantly correlated to soil edaphic parameters tested. There was, however, a significant positive correlation between mitochondrial DNA copy abundances and the human associated bacteria, Bacteroides, as estimated by 16S rRNA gene abundances. These results show that human mitochondrial DNA can persist in grave soil and be consistently detected throughout decomposition. Copyright © 2017 The Chartered Society of Forensic Sciences. Published by Elsevier B.V. All rights reserved.

Ochratoxin A and human health risk: a review of the evidence.

PubMed

Bui-Klimke, Travis R; Wu, Felicia

2015-01-01

Ochratoxin A (OTA) is a mycotoxin produced by several fungal species including Aspergillus ochraceus, A. carbonarius, A. niger, and Penicillium verrucosum. OTA causes nephrotoxicity and renal tumors in a variety of animal species; however, human health effects are less well-characterized. Various studies have linked OTA exposure with the human diseases Balkan endemic nephropathy (BEN) and chronic interstitial nephropathy (CIN), as well as other renal diseases. This study reviews the epidemiological literature on OTA exposure and adverse health effects in different populations worldwide, and assesses the potential human health risks of OTA exposure. Epidemiological studies identified in a systematic review were used to calculate unadjusted odds ratios for OTA associated with various health endpoints. With one exception, there appears to be no statistically significant evidence for human health risks associated with OTA exposure. One Egyptian study showed a significantly higher risk of nephritic syndrome in those with very high urinary OTA levels compared with relatively unexposed individuals; however, other potential risk factors were not controlled for in the study. Larger cohort or case-control studies are needed in the future to better establish potential OTA-related human health effects, and further duplicate-diet studies are needed to validate biomarkers of OTA exposure in humans.

End-point sharpness in thermometric titrimetry.

PubMed

Tyrrell, H J

1967-07-01

It is shown that the sharpness of an end-point in a thermometric titration where the simple reaction A + B right harpoon over left harpoon AB takes place, depends on Kc(A') where K is the equilibrium constant for the reaction, and c(A') is the total concentration of the titrand (A) in the reaction mixture. The end-point is sharp if, (i) the enthalpy change in the reaction is not negligible, and (ii) Kc(A') > 10(3). This shows that it should, for example, be possible to titrate 0.1 M acid, pK(A) = 10, using a thennometric end-point. Some aspects of thermometric titrimetry when Kc(A') < 10(3) are also considered.

An efficient method to compute spurious end point contributions in PO solutions. [Physical Optics

NASA Technical Reports Server (NTRS)

Gupta, Inder J.; Burnside, Walter D.; Pistorius, Carl W. I.

1987-01-01

A method is given to compute the spurious endpoint contributions in the physical optics solution for electromagnetic scattering from conducting bodies. The method is applicable to general three-dimensional structures. The only information required to use the method is the radius of curvature of the body at the shadow boundary. Thus, the method is very efficient for numerical computations. As an illustration, the method is applied to several bodies of revolution to compute the endpoint contributions for backscattering in the case of axial incidence. It is shown that in high-frequency situations, the endpoint contributions obtained using the method are equal to the true endpoint contributions.

Predicting treatment effect from surrogate endpoints and historical trials: an extrapolation involving probabilities of a binary outcome or survival to a specific time

PubMed Central

Sargent, Daniel J.; Buyse, Marc; Burzykowski, Tomasz

2011-01-01

SUMMARY Using multiple historical trials with surrogate and true endpoints, we consider various models to predict the effect of treatment on a true endpoint in a target trial in which only a surrogate endpoint is observed. This predicted result is computed using (1) a prediction model (mixture, linear, or principal stratification) estimated from historical trials and the surrogate endpoint of the target trial and (2) a random extrapolation error estimated from successively leaving out each trial among the historical trials. The method applies to either binary outcomes or survival to a particular time that is computed from censored survival data. We compute a 95% confidence interval for the predicted result and validate its coverage using simulation. To summarize the additional uncertainty from using a predicted instead of true result for the estimated treatment effect, we compute its multiplier of standard error. Software is available for download. PMID:21838732

Does bisphenol A induce superfeminization in Marisa cornuarietis? Part I: intra- and inter-laboratory variability in test endpoints.

PubMed

Forbes, Valery E; Selck, Henriette; Palmqvist, Annemette; Aufderheide, John; Warbritton, Ryan; Pounds, Nadine; Thompson, Roy; van der Hoeven, Nelly; Caspers, Norbert

2007-03-01

It has been claimed that bisphenol A (BPA) induces superfeminization in the freshwater gastropod, Marisa cornuarietis. To explore the reproducibility of prior work, here we present results from a three-laboratory study, the objectives of which were to determine the mean and variability in test endpoints (i.e., adult fecundity, egg hatchability, and juvenile growth) under baseline conditions and to identify the sources of variability. A major source of variability for all of the measured endpoints was due to differences within and among individuals. With few exceptions, variability among laboratories and among replicate tanks within laboratories contributed little to the observed variability in endpoints. The results highlight the importance of obtaining basic knowledge of husbandry requirements and baseline information on life-history traits of potential test species prior to designing toxicity test protocols. Understanding of the levels and sources of endpoint variability is essential so that statistically robust and ecologically relevant tests of chemicals can be conducted.

Fencing direct memory access data transfers in a parallel active messaging interface of a parallel computer

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

Blocksome, Michael A.; Mamidala, Amith R.

2013-09-03

Fencing direct memory access (`DMA`) data transfers in a parallel active messaging interface (`PAMI`) of a parallel computer, the PAMI including data communications endpoints, each endpoint including specifications of a client, a context, and a task, the endpoints coupled for data communications through the PAMI and through DMA controllers operatively coupled to segments of shared random access memory through which the DMA controllers deliver data communications deterministically, including initiating execution through the PAMI of an ordered sequence of active DMA instructions for DMA data transfers between two endpoints, effecting deterministic DMA data transfers through a DMA controller and a segmentmore » of shared memory; and executing through the PAMI, with no FENCE accounting for DMA data transfers, an active FENCE instruction, the FENCE instruction completing execution only after completion of all DMA instructions initiated prior to execution of the FENCE instruction for DMA data transfers between the two endpoints.« less

Correlates of protection for rotavirus vaccines: Possible alternative trial endpoints, opportunities, and challenges.

PubMed

Angel, Juana; Steele, A Duncan; Franco, Manuel A

2014-01-01

Rotavirus (RV) is a major vaccine-preventable killer of young children worldwide. Two RV vaccines are globally commercially available and other vaccines are in different stages of development. Due to the absence of a suitable correlate of protection (CoP), all RV vaccine efficacy trials have had clinical endpoints. These trials represent an important challenge since RV vaccines have to be introduced in many different settings, placebo-controlled studies are unethical due to the availability of licensed vaccines, and comparator assessments for new vaccines with clinical endpoints are very large, complex, and expensive to conduct. A CoP as a surrogate endpoint would allow predictions of vaccine efficacy for new RV vaccines and enable a regulatory pathway, contributing to the more rapid development of new RV vaccines. The goal of this review is to summarize experiences from RV natural infection and vaccine studies to evaluate potential CoP for use as surrogate endpoints for assessment of new RV vaccines, and to explore challenges and opportunities in the field.

RIFM fragrance ingredient safety assessment, linalyl cinnamate, CAS Registry Number 78-37-5.

PubMed

Api, A M; Belsito, D; Bhatia, S; Bruze, M; Calow, P; Dagli, M L; Dekant, W; Fryer, A D; Kromidas, L; La Cava, S; Lalko, J F; Lapczynski, A; Liebler, D C; Penning, T M; Politano, V T; Ritacco, G; Salvito, D; Schultz, T W; Shen, J; Sipes, I G; Wall, B; Wilcox, D K

2016-11-01

The use of this material under current conditions is supported by existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, as well as environmental safety. Data show that this material is not genotoxic nor does it have skin sensitization potential. The reproductive and local respiratory toxicity endpoints were completed using the TTC (Threshold of Toxicological Concern) for a Cramer Class I material (0.03 and 1.4 mg/day, respectively). The developmental toxicity endpoint was completed using linalool (CAS # 78-70-6), dehydrolinalool (CAS # 29171-20-8) and cinnamic acid (CAS # 621-82-9) as suitable read across analogs, which provided a MOE > 100. The repeated dose toxicity endpoint was completed using data on the target material which provided a MOE > 100. The phototoxicity/photoallergenicity endpoint was completed based on suitable UV spectra. The environmental endpoint was completed as described in the RIFM Framework. Copyright © 2016 Elsevier Ltd. All rights reserved.

On assessing surrogacy in a single trial setting using a semi-competing risks paradigm

PubMed Central

Ghosh, Debashis

2009-01-01

Summary There has been a recent emphasis on the identification of biomarkers and other biologic measures that may be potentially used as surrogate endpoints in clinical trials. We focus on the setting of data from a single clinical trial. In this paper, we consider a framework in which the surrogate must occur before the true endpoint. This suggests viewing the surrogate and true endpoints as semi-competing risks data; this approach is new to the literature on surrogate endpoints and leads to an asymmetrical treatment of the surrogate and true endpoints. However, such a data structure also conceptually complicates many of the previously considered measures of surrogacy in the literature. We propose novel estimation and inferential procedures for the relative effect and adjusted association quantities proposed by Buyse and Molenberghs (1998, Biometrics, 1014 – 1029). The proposed methodology is illustrated with application to simulated data, as well as to data from a leukemia study. PMID:18759839

Review of meta-analyses evaluating surrogate endpoints for overall survival in oncology.

PubMed

Sherrill, Beth; Kaye, James A; Sandin, Rickard; Cappelleri, Joseph C; Chen, Connie

2012-01-01

Overall survival (OS) is the gold standard in measuring the treatment effect of new drug therapies for cancer. However, practical factors may preclude the collection of unconfounded OS data, and surrogate endpoints are often used instead. Meta-analyses have been widely used for the validation of surrogate endpoints, specifically in oncology. This research reviewed published meta-analyses on the types of surrogate measures used in oncology studies and examined the extent of correlation between surrogate endpoints and OS for different cancer types. A search was conducted in October 2010 to compile available published evidence in the English language for the validation of disease progression-related endpoints as surrogates of OS, based on meta-analyses. We summarize published meta-analyses that quantified the correlation between progression-based endpoints and OS for multiple advanced solid-tumor types. We also discuss issues that affect the interpretation of these findings. Progression-free survival is the most commonly used surrogate measure in studies of advanced solid tumors, and correlation with OS is reported for a limited number of cancer types. Given the increased use of crossover in trials and the availability of second-/third-line treatment options available to patients after progression, it will become increasingly more difficult to establish correlation between effects on progression-free survival and OS in additional tumor types.

Surrogate endpoints for overall survival in lung cancer trials: a review.

PubMed

Fiteni, Frédéric; Westeel, Virginie; Bonnetain, Franck

2017-05-01

Intermediate endpoints are often used as primary endpoints instead of overall survival (OS) in lung cancer trials but they are not systematically validated as surrogate endpoints for OS. Areas covered: The aim of the study was to review the studies which assessed potential surrogate endpoints for OS in lung cancer trials. Expert commentary: Twenty studies were identified. In operable non-small cell lung cancer (NSCLC) (adjuvant trials) and locally advanced NSCLC (radiotherapy trials), one individual-patient data meta-analysis found a high correlation of disease-free survival (DFS) and progression-free survival (PFS) with OS at patient and trial level. In trials of adjuvant chemotherapy, correlation between disease-free survival DFS and OS were 0.83 at the individual level (95% CI 0.83-0.83) and 0.92 at trial level (95% CI 0.88-0.95). In locally advanced disease, correlation between PFS and OS was 0.77 to 0.85 at the individual level, and 0.89 to 0.97 at trial level. This study provides a 'proof' of the surrogacy of PFS and DFS on OS according to the IQWiG framework and the surrogacy of PFS and DFS on OS was classified level 2 according to Fleming hierarchy. In all the other setting, no endpoint was judged to be valid surrogate for OS.

Use of endpoint adjudication to improve the quality and validity of endpoint assessment for medical device development and post marketing evaluation: Rationale and best practices. A report from the cardiac safety research consortium.

PubMed

Seltzer, Jonathan H; Heise, Ted; Carson, Peter; Canos, Daniel; Hiatt, Jo Carol; Vranckx, Pascal; Christen, Thomas; Cutlip, Donald E

2017-08-01

This white paper provides a summary of presentations, discussions and conclusions of a Thinktank entitled "The Role of Endpoint Adjudication in Medical Device Clinical Trials". The think tank was cosponsored by the Cardiac Safety Research Committee, MDEpiNet and the US Food and Drug Administration (FDA) and was convened at the FDA's White Oak headquarters on March 11, 2016. Attention was focused on tailoring best practices for evaluation of endpoints in medical device clinical trials, practical issues in endpoint adjudication of therapeutic, diagnostic, biomarker and drug-device combinations, and the role of adjudication in regulatory and reimbursement issues throughout the device lifecycle. Attendees included representatives from medical device companies, the FDA, Centers for Medicare and Medicaid Services (CMS), end point adjudication specialist groups, clinical research organizations, and active, academically based adjudicators. The manuscript presents recommendations from the think tank regarding (1) rationale for when adjudication is appropriate, (2) best practices establishment and operation of a medical device adjudication committee and (3) the role of endpoint adjudication for post market evaluation in the emerging era of real world evidence. Copyright © 2017. Published by Elsevier Inc.

Feeding Behavior of an Aquatic Snail as a Simple Endpoint to Assess the Exposure to Cadmium.

PubMed

Alonso, Álvaro; Valle-Torres, Guillermo

2018-01-01

One of the aims of ecotoxicology is the assessment of the effects of chemicals on the ecosystems. Bioassays assessing lethality are frequently used in ecotoxicology, however they usually employ supra-environmental toxic concentrations. Toxicity tests employing behavioral endpoints may present a balance between simplicity (i.e., laboratory bioassays) and complexity (i.e., relevant ecological effects). The aim of this study was to develop a feeding behavioral bioassay with the aquatic snail, Potamopyrgus antipodarum, which included a 2 days exposure to cadmium, followed by a 9 days post-exposure observational period. Several behavioral feeding endpoints were monitored, including percentage of actively feeding animals, percentage of animals in food quadrants and a mobility index. The percentage of actively feeding animals was reduced by the four cadmium treatments (0.009, 0.026, 0.091 and 0.230 mg Cd/L) with the stronger effect in the highest concentration. The two highest cadmium concentrations significantly reduced the percentage of animals in food quadrants and the mobility index. Therefore, the percentage of actively feeding animals was the most sensitive endpoint to cadmium toxicity as the four cadmium concentrations caused a significant decrease in this endpoint. It is concluded that feeding behavior is a useful endpoint to detect the exposure of aquatic snails to cadmium.

Randomized study of adjunctive belimumab in participants with generalized myasthenia gravis

PubMed Central

Hewett, Karen; Sanders, Donald B.; Grove, Richard A.; Broderick, Christine L.; Rudo, Todd J.; Bassiri, Ashlyn; Zvartau-Hind, Marina

2018-01-01

Objective To investigate the efficacy and safety of belimumab, a fully human immunoglobulin G1λ monoclonal antibody against B-lymphocyte stimulator, in participants with generalized myasthenia gravis (MG) who remained symptomatic despite standard of care (SoC) therapy. Methods Eligible participants with MG were randomized 1:1 to receive IV belimumab 10 mg/kg or placebo in this phase II, placebo-controlled, multicenter, double-blind study (NCT01480596; BEL115123). Participants received SoC therapies throughout the 24-week treatment phase and 12-week follow-up period. The primary efficacy endpoint was mean change from baseline in the Quantitative Myasthenia Gravis (QMG) scale at week 24; safety assessments included the frequency and severity of adverse events (AEs) and serious AEs. Results Forty participants were randomized (placebo n = 22; belimumab n = 18). The mean change in QMG score from baseline at week 24 was not significantly different for belimumab vs placebo (p = 0.256). There were no statistically significant differences between treatment groups for secondary endpoints, including the MG Composite and MG–Activity of Daily Living scores. Acetylcholine receptor antibody levels decreased over time in both treatment groups. No unexpected AEs were identified and occurrence was similar in the belimumab (78%) and placebo (91%) groups. One participant receiving placebo died (severe sepsis) during the treatment phase. Conclusions The primary endpoint was not met for belimumab in participants with generalized MG receiving SoC. There was no significant difference in mean change in the QMG score at week 24 for belimumab vs placebo. The safety profile of belimumab was consistent with previous systemic lupus erythematosus studies. Classification of evidence This study provides Class I evidence that for participants with generalized MG, belimumab did not significantly improve QMG score compared with placebo. PMID:29661905

Efficacy and safety of sirukumab in Japanese patients with active rheumatoid arthritis who were refractory or intolerant to anti-tumor necrosis factor therapy: Subgroup analysis of a randomized, double-blind, multicenter, phase 3 study (SIRROUND-T).

PubMed

Tanaka, Yoshiya; Takeuchi, Tsutomu; Harigai, Masayoshi; Yamanaka, Hisashi; Nakano, Toshikazu; Akagi, Koshiro; Ukyo, Yoshifumi; Hsu, Benjamin

2018-04-13

To evaluate the efficacy and safety of sirukumab, a human anti-interleukin six monoclonal antibody, in Japanese patients with rheumatoid arthritis who were refractory to anti-tumor necrosis factor therapy. This subgroup analysis, based on a double-blind, placebo-controlled, 52-week phase 3, global study (SIRROUND-T) assessed the American College of Rheumatology (ACR) 20 response at week 16 (primary endpoint). Secondary endpoints: ACR 50, Disease Activity Score in 28 joints-C reactive protein, Health Assessment Questionnaire-Disability Index and safety were assessed. Results 116/878 patients received sirukumab 50 mg/4 weeks (q4w, n = 35), 100 mg/2 weeks (q2w, n = 44) or placebo (n = 37) subcutaneously. Significantly more patients achieved ACR 20 response at week 16 with sirukumab (50 mg q4w:20 [57.1%]; p < .001, 100 mg q2w:24 [54.5%]; p = .001) versus placebo (7 [18.9%]); consistent significant improvement in secondary endpoints at week 24 and 52 was observed. At week 24, incidence of treatment-emergent adverse events (TEAEs) was numerically higher with sirukumab groups (50 mg q4w:29 [82.9%]; 100 mg q2w:38 [86.4%] versus placebo (28 [75.7%]); however, at week 52, sirukumab combined groups had comparable incidence of TEAEs. Efficacy findings through 52 weeks were comparable between sirukumab doses in Japanese patients and consistent with primary SIRROUND-T study results. No new safety signals were observed.

Comparison of dinner with bedtime administration of insulin glargine in type 1 diabetic patients treated with basal-bolus regimen.

PubMed

Grimaldi, A; Vialettes, B; Blayo, A; Brun, J M; Halimi, S

2007-04-01

To establish the equivalence in efficacy (HbA(1c)) of insulin glargine injected at dinner versus bedtime in a large number of patients with type 1 diabetes using a fast-acting analogue (FAA) or regular human insulin (RHI) as prandial insulin in an insulin glargine-bolus regimen. In a 26-week trial, 1178 patients with type 1 diabetes and treated with different basal-bolus regimens were randomized to receive insulin glargine once daily at dinner (n=589) or at bedtime (n=589) while continuing their previous prandial insulin (FAA: 75%; RHI: 25% of patients). The primary objective was to demonstrate equivalence in terms of HbA(1c) levels at endpoint. Baseline characteristics were similar in the two groups. At endpoint, HbA(1c) (mean+/-standard deviation [S.D.]) had decreased by 0.25+/-0.66% to 7.77+/-0.96% in the dinnertime group (P<0.0001), and by 0.24+/-0.76% to 7.83+/-1.07% in the bedtime group (P<0.0001). The HbA(1c) difference between dinner and bedtime was -0.022% (two-sided 90% confidence interval [CI] -0.09; 0.05), demonstrating statistical equivalence of HbA(1c) at endpoint between the two groups. Equivalence was also demonstrated within prandial groups: HbA(1c) difference between dinner and bedtime was -0.03% (two-sided 90% CI: -0.11; 0.06) for FAAs and -0.04% (two-sided 90% CI: -0.19; 0.11) for RHIs. The incidence of severe hypoglycaemia did not differ between the treatment groups. These data confirm that insulin glargine in combination with either FAA or RHI is equally effective and safe, whether it is administered at dinner or bedtime.

Improved Efficiency and Robustness in qPCR and Multiplex End-Point PCR by Twisted Intercalating Nucleic Acid Modified Primers

PubMed Central

Schneider, Uffe Vest; Mikkelsen, Nikolaj Dam; Lindqvist, Anja; Okkels, Limei Meng; Jøhnk, Nina; Lisby, Gorm

2012-01-01

We introduce quantitative polymerase chain reaction (qPCR) primers and multiplex end-point PCR primers modified by the addition of a single ortho-Twisted Intercalating Nucleic Acid (o-TINA) molecule at the 5′-end. In qPCR, the 5′-o-TINA modified primers allow for a qPCR efficiency of 100% at significantly stressed reaction conditions, increasing the robustness of qPCR assays compared to unmodified primers. In samples spiked with genomic DNA, 5′-o-TINA modified primers improve the robustness by increased sensitivity and specificity compared to unmodified DNA primers. In unspiked samples, replacement of unmodified DNA primers with 5′-o-TINA modified primers permits an increased qPCR stringency. Compared to unmodified DNA primers, this allows for a qPCR efficiency of 100% at lowered primer concentrations and at increased annealing temperatures with unaltered cross-reactivity for primers with single nucleobase mismatches. In a previously published octaplex end-point PCR targeting diarrheagenic Escherichia coli, application of 5′-o-TINA modified primers allows for a further reduction (>45% or approximately one hour) in overall PCR program length, while sustaining the amplification and analytical sensitivity for all targets in crude bacterial lysates. For all crude bacterial lysates, 5′-o-TINA modified primers permit a substantial increase in PCR stringency in terms of lower primer concentrations and higher annealing temperatures for all eight targets. Additionally, crude bacterial lysates spiked with human genomic DNA show lesser formation of non-target amplicons implying increased robustness. Thus, 5′-o-TINA modified primers are advantageous in PCR assays, where one or more primer pairs are required to perform at stressed reaction conditions. PMID:22701644

Copper Oxide Nanoparticles Impact Several Toxicological Endpoints and Cause Neurodegeneration in Caenorhabditis elegans

PubMed Central

Zanon, Tyler; Kappell, Anthony D.; Petrella, Lisa N.; Andersen, Erik C.; Hristova, Krassimira R.

2016-01-01

Engineered nanoparticles are becoming increasingly incorporated into technology and consumer products. In 2014, over 300 tons of copper oxide nanoparticles were manufactured in the United States. The increased production of nanoparticles raises concerns regarding the potential introduction into the environment or human exposure. Copper oxide nanoparticles commonly release copper ions into solutions, which contribute to their toxicity. We quantified the inhibitory effects of both copper oxide nanoparticles and copper sulfate on C. elegans toxicological endpoints to elucidate their biological effects. Several toxicological endpoints were analyzed in C. elegans, including nematode reproduction, feeding behavior, and average body length. We examined three wild C. elegans isolates together with the Bristol N2 laboratory strain to explore the influence of different genotypic backgrounds on the physiological response to copper challenge. All strains exhibited greater sensitivity to copper oxide nanoparticles compared to copper sulfate, as indicated by reduction of average body length and feeding behavior. Reproduction was significantly reduced only at the highest copper dose, though still more pronounced with copper oxide nanoparticles compared to copper sulfate treatment. Furthermore, we investigated the effects of copper oxide nanoparticles and copper sulfate on neurons, cells with known vulnerability to heavy metal toxicity. Degeneration of dopaminergic neurons was observed in up to 10% of the population after copper oxide nanoparticle exposure. Additionally, mutants in the divalent-metal transporters, smf-1 or smf-2, showed increased tolerance to copper exposure, implicating both transporters in copper-induced neurodegeneration. These results highlight the complex nature of CuO nanoparticle toxicity, in which a nanoparticle-specific effect was observed in some traits (average body length, feeding behavior) and a copper ion specific effect was observed for other traits (neurodegeneration, response to stress). PMID:27911941

Randomized Controlled Trial of Daily Text Messages to Support Adherence to Preexposure Prophylaxis in Individuals at Risk for Human Immunodeficiency Virus: The TAPIR Study.

PubMed

Moore, David J; Jain, Sonia; Dubé, Michael P; Daar, Eric S; Sun, Xiaoying; Young, Jason; Corado, Katya; Ellorin, Eric; Milam, Joel; Collins, Deborah; Blumenthal, Jill; Best, Brookie M; Anderson, Peter; Haubrich, Richard; Morris, Sheldon R

2018-05-02

Adherence is critical for efficacy of tenofovir disoproxil fumarate/emtricitabine (FTC) as preexposure prophylaxis (PrEP). Between February 2013 and February 2016, 398 men who have sex with men and transgender women were randomized 1:1 to receive individualized texting for adherence building (iTAB) or standard care (SoC) for 48 weeks. The primary endpoint was dried blood spot (DBS) tenofovir diphosphate (TFV-DP) concentrations at both week 12 and the last on-drug visit of >719 fmol/punch (ie, adequate adherence). Secondary outcomes included DBS TFV-DP concentrations of >1246 fmol/punch (ie, near-perfect adherence) and plasma FTC >350 ng/mL (consistent with dosing within the past 24 hours). Concentrations >719 fmol/punch of TFV-DP were found in 88.6% of participants at week 12 and 82.5% at week 48. For the primary endpoint, the study arms did not differ (72.0% in iTAB and 69.2% in SoC; P > .05). For the secondary composite endpoint of >1246 fmol/punch the iTAB arm was superior to SoC (33.5% vs 24.8%; P = .06), reaching statistical significance when adjusting for age (odds ratio, 1.56 [95% confidence interval, 1.00-2.42]; P < .05). At week 48, iTAB was superior to SoC for near-perfect adherence (51.0% vs 37.4%; P = .02). At week 12, iTAB was superior to SoC for dosing in past 24 hours by plasma FTC (47.5% vs 33.3%; P = .007), but not at weeks 24, 36, and 48 (all P > .05). Automated text messaging is a low-burden tool that improves durability of near-perfect PrEP adherence. NCT01761643.

Linear-No-Threshold Default Assumptions for Noncancer and Nongenotoxic Cancer Risks: A Mathematical and Biological Critique.

PubMed

Bogen, Kenneth T

2016-03-01

To improve U.S. Environmental Protection Agency (EPA) dose-response (DR) assessments for noncarcinogens and for nonlinear mode of action (MOA) carcinogens, the 2009 NRC Science and Decisions Panel recommended that the adjustment-factor approach traditionally applied to these endpoints should be replaced by a new default assumption that both endpoints have linear-no-threshold (LNT) population-wide DR relationships. The panel claimed this new approach is warranted because population DR is LNT when any new dose adds to a background dose that explains background levels of risk, and/or when there is substantial interindividual heterogeneity in susceptibility in the exposed human population. Mathematically, however, the first claim is either false or effectively meaningless and the second claim is false. Any dose-and population-response relationship that is statistically consistent with an LNT relationship may instead be an additive mixture of just two quasi-threshold DR relationships, which jointly exhibit low-dose S-shaped, quasi-threshold nonlinearity just below the lower end of the observed "linear" dose range. In this case, LNT extrapolation would necessarily overestimate increased risk by increasingly large relative magnitudes at diminishing values of above-background dose. The fact that chemically-induced apoptotic cell death occurs by unambiguously nonlinear, quasi-threshold DR mechanisms is apparent from recent data concerning this quintessential toxicity endpoint. The 2009 NRC Science and Decisions Panel claims and recommendations that default LNT assumptions be applied to DR assessment for noncarcinogens and nonlinear MOA carcinogens are therefore not justified either mathematically or biologically. © 2015 The Author. Risk Analysis published by Wiley Periodicals, Inc. on behalf of Society for Risk Analysis.

Particulate emissions from the combustion of birch, beech, and spruce logs cause different cytotoxic responses in A549 cells.

PubMed

Kasurinen, Stefanie; Jalava, Pasi I; Happo, Mikko S; Sippula, Olli; Uski, Oskari; Koponen, Hanna; Orasche, Jürgen; Zimmermann, Ralf; Jokiniemi, Jorma; Hirvonen, Maija-Riitta

2017-05-01

According to the World Health Organization particulate emissions from the combustion of solid fuels caused more than 110,000 premature deaths worldwide in 2010. Log wood combustion is the most prevalent form of residential biomass heating in developed countries, but it is unknown how the type of wood logs used in furnaces influences the chemical composition of the particulate emissions and their toxicological potential. We burned logs of birch, beech and spruce, which are used commonly as firewood in Central and Northern Europe in a modern masonry heater, and compared them to the particulate emissions from an automated pellet boiler fired with softwood pellets. We determined the chemical composition (elements, ions, and carbonaceous compounds) of the particulate emissions with a diameter of less than 1 µm and tested their cytotoxicity, genotoxicity, inflammatory potential, and ability to induce oxidative stress in a human lung epithelial cell line. The chemical composition of the samples differed significantly, especially with regard to the carbonaceous and metal contents. Also the toxic effects in our tested endpoints varied considerably between each of the three log wood combustion samples, as well as between the log wood combustion samples and the pellet combustion sample. The difference in the toxicological potential of the samples in the various endpoints indicates the involvement of different pathways of toxicity depending on the chemical composition. All three emission samples from the log wood combustions were considerably more toxic in all endpoints than the emissions from the pellet combustion. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1487-1499, 2017. © 2016 Wiley Periodicals, Inc.

Core Body Temperature as Adjunct to Endpoint Determination in Murine Median Lethal Dose Testing of Rattlesnake Venom

PubMed Central

Cates, Charles C; McCabe, James G; Lawson, Gregory W; Couto, Marcelo A

2014-01-01

Median lethal dose (LD50) testing in mice is the ‘gold standard’ for evaluating the lethality of snake venoms and the effectiveness of interventions. As part of a study to determine the murine LD50 of the venom of 3 species of rattlesnake, temperature data were collected in an attempt to more precisely define humane endpoints. We used an ‘up-and-down’ methodology of estimating the LD50 that involved serial intraperitoneal injection of predetermined concentrations of venom. By using a rectal thermistor probe, body temperature was taken once before administration and at various times after venom exposure. All but one mouse showed a marked, immediate, dose-dependent drop in temperature of approximately 2 to 6 °C at 15 to 45 min after administration. The lowest temperature sustained by any surviving mouse was 33.2 °C. Surviving mice generally returned to near-baseline temperatures within 2 h after venom administration, whereas mice that did not survive continued to show a gradual decline in temperature until death or euthanasia. Logistic regression modeling controlling for the effects of baseline core body temperature and venom type showed that core body temperature was a significant predictor of survival. Linear regression of the interaction of time and survival was used to estimate temperatures predictive of death at the earliest time point and demonstrated that venom type had a significant influence on temperature values. Overall, our data suggest that core body temperature is a useful adjunct to monitoring for endpoints in LD50 studies and may be a valuable predictor of survival in venom studies. PMID:25527024

Assuring consumer safety without animal testing: a feasibility case study for skin sensitisation.

PubMed

Maxwell, Gavin; Aleksic, Maja; Aptula, Aynur; Carmichael, Paul; Fentem, Julia; Gilmour, Nicola; Mackay, Cameron; Pease, Camilla; Pendlington, Ruth; Reynolds, Fiona; Scott, Daniel; Warner, Guy; Westmoreland, Carl

2008-11-01

Allergic Contact Dermatitis (ACD; chemical-induced skin sensitisation) represents a key consumer safety endpoint for the cosmetics industry. At present, animal tests (predominantly the mouse Local Lymph Node Assay) are used to generate skin sensitisation hazard data for use in consumer safety risk assessments. An animal testing ban on chemicals to be used in cosmetics will come into effect in the European Union (EU) from March 2009. This animal testing ban is also linked to an EU marketing ban on products containing any ingredients that have been subsequently tested in animals, from March 2009 or March 2013, depending on the toxicological endpoint of concern. Consequently, the testing of cosmetic ingredients in animals for their potential to induce skin sensitisation will be subject to an EU marketing ban, from March 2013 onwards. Our conceptual framework and strategy to deliver a non-animal approach to consumer safety risk assessment can be summarised as an evaluation of new technologies (e.g. 'omics', informatics), leading to the development of new non-animal (in silico and in vitro) predictive models for the generation and interpretation of new forms of hazard characterisation data, followed by the development of new risk assessment approaches to integrate these new forms of data and information in the context of human exposure. Following the principles of the conceptual framework, we have been investigating existing and developing new technologies, models and approaches, in order to explore the feasibility of delivering consumer safety risk assessment decisions in the absence of new animal data. We present here our progress in implementing this conceptual framework, with the skin sensitisation endpoint used as a case study. 2008 FRAME.

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

Mittal, Bharat B., E-mail: bmittal@nmh.org; Wang, Edward; Sejpal, Samir

Purpose: The current study examined the effect of recombinant human deoxyribonuclease (rhDNase) on quality of life (QOL) measures, clinical improvement, and DNA content of thick oropharyngeal secretions (OPS) in patients with head-and-neck (H and N) cancers. Methods and Materials: Thirty-six patients with local-regional advanced H and N cancer receiving chemoradiationtherapy (CRT) were randomized to receive either placebo or rhDNase. Endpoints included MD Anderson Symptom Inventory-Head and Neck (MDASI-HN) and Functional Assessment of Cancer Therapy–Head and Neck (FACT-NH) scores, along with clinical assessment and DNA concentration of OPS. Results: There were no statistically significant differences in patients' QOL outcomes over themore » study period. Both groups showed an increase in symptom and interference scores, although patients in the rhDNase group showed a greater decline in both scores during the 3 months posttreatment. Similarly, both groups showed a decline in physical and functional well being but recovered in the 3 months posttreatment follow-up, with the rhDNase group exhibiting speedier recovery. Patients in the rhDNase group exhibited significant clinical improvement in OPS, blindly assessed by a physician, compared with the placebo group (67% vs 27%, respectively; P=.046). The rhDNase group showed no change in OPS-DNA concentration, although the placebo group showed a significant increase in DNA concentration during the drug trial (P=.045). There was no differences in acute toxicities between the 2 groups. Conclusions: Our preliminary data suggest that rhDNase did not significantly improve study primary endpoints of QOL measures compared with the placebo group. However, there was a significant improvement in secondary endpoints of clinically assessed OPS and DNA concentration compared with placebo in H and N cancer patients treated with CRT. Further investigation in larger numbers of patients is warranted.« less

Some controversial multiple testing problems in regulatory applications.

PubMed

Hung, H M James; Wang, Sue-Jane

2009-01-01

Multiple testing problems in regulatory applications are often more challenging than the problems of handling a set of mathematical symbols representing multiple null hypotheses under testing. In the union-intersection setting, it is important to define a family of null hypotheses relevant to the clinical questions at issue. The distinction between primary endpoint and secondary endpoint needs to be considered properly in different clinical applications. Without proper consideration, the widely used sequential gate keeping strategies often impose too many logical restrictions to make sense, particularly to deal with the problem of testing multiple doses and multiple endpoints, the problem of testing a composite endpoint and its component endpoints, and the problem of testing superiority and noninferiority in the presence of multiple endpoints. Partitioning the null hypotheses involved in closed testing into clinical relevant orderings or sets can be a viable alternative to resolving the illogical problems requiring more attention from clinical trialists in defining the clinical hypotheses or clinical question(s) at the design stage. In the intersection-union setting there is little room for alleviating the stringency of the requirement that each endpoint must meet the same intended alpha level, unless the parameter space under the null hypothesis can be substantially restricted. Such restriction often requires insurmountable justification and usually cannot be supported by the internal data. Thus, a possible remedial approach to alleviate the possible conservatism as a result of this requirement is a group-sequential design strategy that starts with a conservative sample size planning and then utilizes an alpha spending function to possibly reach the conclusion early.

Definitions and validation criteria for biomarkers and surrogate endpoints: development and testing of a quantitative hierarchical levels of evidence schema.

PubMed

Lassere, Marissa N; Johnson, Kent R; Boers, Maarten; Tugwell, Peter; Brooks, Peter; Simon, Lee; Strand, Vibeke; Conaghan, Philip G; Ostergaard, Mikkel; Maksymowych, Walter P; Landewe, Robert; Bresnihan, Barry; Tak, Paul-Peter; Wakefield, Richard; Mease, Philip; Bingham, Clifton O; Hughes, Michael; Altman, Doug; Buyse, Marc; Galbraith, Sally; Wells, George

2007-03-01

There are clear advantages to using biomarkers and surrogate endpoints, but concerns about clinical and statistical validity and systematic methods to evaluate these aspects hinder their efficient application. Our objective was to review the literature on biomarkers and surrogates to develop a hierarchical schema that systematically evaluates and ranks the surrogacy status of biomarkers and surrogates; and to obtain feedback from stakeholders. After a systematic search of Medline and Embase on biomarkers, surrogate (outcomes, endpoints, markers, indicators), intermediate endpoints, and leading indicators, a quantitative surrogate validation schema was developed and subsequently evaluated at a stakeholder workshop. The search identified several classification schema and definitions. Components of these were incorporated into a new quantitative surrogate validation level of evidence schema that evaluates biomarkers along 4 domains: Target, Study Design, Statistical Strength, and Penalties. Scores derived from 3 domains the Target that the marker is being substituted for, the Design of the (best) evidence, and the Statistical strength are additive. Penalties are then applied if there is serious counterevidence. A total score (0 to 15) determines the level of evidence, with Level 1 the strongest and Level 5 the weakest. It was proposed that the term "surrogate" be restricted to markers attaining Levels 1 or 2 only. Most stakeholders agreed that this operationalization of the National Institutes of Health definitions of biomarker, surrogate endpoint, and clinical endpoint was useful. Further development and application of this schema provides incentives and guidance for effective biomarker and surrogate endpoint research, and more efficient drug discovery, development, and approval.

Effect of pre-fixation delay and freezing on mink testicular endpoints for environmental research.

PubMed

Spörndly-Nees, Ellinor; Ekstedt, Elisabeth; Magnusson, Ulf; Fakhrzadeh, Azadeh; Luengo Hendriks, Cris L; Holm, Lena

2015-01-01

There is growing interest in using wild animals to monitor the real-life cocktail effect of environmental chemicals on male reproduction. However, practical difficulties, such as long distances to the laboratory, generally prolong the time between euthanisation and specimen handling. For instance, tissue fixation is often performed on frozen material or on material where deterioration has started, which may affect tissue morphology. This study examined the effect of pre-fixation delay and freezing on mink testicular endpoints in order to determine robust endpoints in suboptimally handled specimens. Sexually mature farmed mink (n=30) selected at culling were divided into six groups and subjected to different time intervals between euthanisation and fixation or freezing: 0 hours (fixed immediately post mortem), 6 hours, 18 hours, 30 hours, 42 hours, or frozen 6 hours post mortem and thawed overnight. Unaffected endpoints when pre-fixation storage was extended to 30 hours included: area and diameter of the seminiferous tubules, length and weight of the testes, and acrosomes marked with Gata-4. Epithelial height, Sertoli cells marked with Gata-4 and cell morphology were affected endpoints after 6 hours of storage. Freezing the tissue prior to fixation severely altered cell morphology and reduced testicular weight, tubular diameter and area. Morphological changes seen after 6 hours included shredded germ cells and excess cytoplasm in seminiferous tubular lumen, chromatin rearrangements and increased germ cell death. Extended delay before fixation and freezing affected many endpoints in the mink testicular tissue. Some of these endpoints may mimic chemically induced effects, which is important to consider when evaluating specimens from wild animals for environmental toxicity.

Maximum type I error rate inflation from sample size reassessment when investigators are blind to treatment labels.

PubMed

Żebrowska, Magdalena; Posch, Martin; Magirr, Dominic

2016-05-30

Consider a parallel group trial for the comparison of an experimental treatment to a control, where the second-stage sample size may depend on the blinded primary endpoint data as well as on additional blinded data from a secondary endpoint. For the setting of normally distributed endpoints, we demonstrate that this may lead to an inflation of the type I error rate if the null hypothesis holds for the primary but not the secondary endpoint. We derive upper bounds for the inflation of the type I error rate, both for trials that employ random allocation and for those that use block randomization. We illustrate the worst-case sample size reassessment rule in a case study. For both randomization strategies, the maximum type I error rate increases with the effect size in the secondary endpoint and the correlation between endpoints. The maximum inflation increases with smaller block sizes if information on the block size is used in the reassessment rule. Based on our findings, we do not question the well-established use of blinded sample size reassessment methods with nuisance parameter estimates computed from the blinded interim data of the primary endpoint. However, we demonstrate that the type I error rate control of these methods relies on the application of specific, binding, pre-planned and fully algorithmic sample size reassessment rules and does not extend to general or unplanned sample size adjustments based on blinded data. © 2015 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. © 2015 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

 Alkaline phosphatase normalization is a biomarker of improved survival in primary sclerosing cholangitis.

PubMed

Hilscher, Moira; Enders, Felicity B; Carey, Elizabeth J; Lindor, Keith D; Tabibian, James H

2016-01-01

 Introduction. Recent studies suggest that serum alkaline phosphatase may represent a prognostic biomarker in patients with primary sclerosing cholangitis. However, this association remains poorly understood. Therefore, the aim of this study was to investigate the prognostic significance and clinical correlates of alkaline phosphatase normalization in primary sclerosing cholangitis. This was a retrospective cohort study of patients with a new diagnosis of primary sclerosing cholangitis made at an academic medical center. The primary endpoint was time to hepatobiliaryneoplasia, liver transplantation, or liver-related death. Secondary endpoints included occurrence of and time to alkaline phosphatase normalization. Patients who did and did not achieve normalization were compared with respect to clinical characteristics and endpoint-free survival, and the association between normalization and the primary endpoint was assessed with univariate and multivariate Cox proportional-hazards analyses. Eighty six patients were included in the study, with a total of 755 patient-years of follow-up. Thirty-eight patients (44%) experienced alkaline phosphatase normalization within 12 months of diagnosis. Alkaline phosphatase normalization was associated with longer primary endpoint-free survival (p = 0.0032) and decreased risk of requiring liver transplantation (p = 0.033). Persistent normalization was associated with even fewer adverse endpoints as well as longer survival. In multivariate analyses, alkaline phosphatase normalization (adjusted hazard ratio 0.21, p = 0.012) and baseline bilirubin (adjusted hazard ratio 4.87, p = 0.029) were the only significant predictors of primary endpoint-free survival. Alkaline phosphatase normalization, particularly if persistent, represents a robust biomarker of improved long-term survival and decreased risk of requiring liver transplantation in patients with primary sclerosing cholangitis.

Relevance of Changes in Serum Creatinine During a Heart Failure Trial of Decongestive Strategies: Insights From the DOSE Trial.

PubMed

Brisco, Meredith A; Zile, Michael R; Hanberg, Jennifer S; Wilson, F Perry; Parikh, Chirag R; Coca, Steven G; Tang, W H Wilson; Testani, Jeffrey M

2016-10-01

Worsening renal function (WRF) is a common endpoint in decompensated heart failure clinical trials because of associations between WRF and adverse outcomes. However, WRF has not universally been identified as a poor prognostic sign, challenging the validity of WRF as a surrogate endpoint. Our aim was to describe the associations between changes in creatinine and adverse outcomes in a clinical trial of decongestive therapies. We investigated the association between changes in creatinine and the composite endpoint of death, rehospitalization or emergency room visit within 60 days in 301 patients in the Diuretic Optimization Strategies Evaluation (DOSE) trial. WRF was defined as an increase in creatinine >0.3 mg/dL and improvement in renal function (IRF) as a decrease >0.3 mg/dL. When examining linear changes in creatinine from baseline to 72 hours (the coprimary endpoint of DOSE), increasing creatinine was associated with lower risk for the composite outcome (HR = 0.81 per 0.3 mg/dL increase, 95% CI 0.67-0.98, P = .026). Compared with patients with stable renal function (n = 219), WRF (n = 54) was not associated with the composite endpoint (HR = 1.17, 95% CI = 0.77-1.78, P = .47). However, compared with stable renal function, there was a strong relationship between IRF (n = 28) and the composite endpoint (HR = 2.52, 95% CI = 1.57-4.03, P < .001). The coprimary endpoint of the DOSE trial, a linear increase in creatinine, was paradoxically associated with improved outcomes. This was driven by absence of risk attributable to WRF and a strong risk associated with IRF. These results argue against using changes in serum creatinine as a surrogate endpoint in trials of decongestive strategies. Copyright © 2016 Elsevier Inc. All rights reserved.

Evaluation of a multi-endpoint assay in rats, combining the bone-marrow micronucleus test, the Comet assay and the flow-cytometric peripheral blood micronucleus test.

PubMed

Bowen, Damian E; Whitwell, James H; Lillford, Lucinda; Henderson, Debbie; Kidd, Darren; Mc Garry, Sarah; Pearce, Gareth; Beevers, Carol; Kirkland, David J

2011-05-18

With the publication of revised draft ICH guidelines (Draft ICH S2), there is scope and potential to establish a combined multi-end point in vivo assay to alleviate the need for multiple in vivo assays, thereby reducing time, cost and use of animals. Presented here are the results of an evaluation trial in which the bone-marrow and peripheral blood (via MicroFlow(®) flow cytometry) micronucleus tests (looking at potential chromosome breakage and whole chromosome loss) in developing erythrocytes or young reticulocytes were combined with the Comet assay (measuring DNA strand-breakage), in stomach, liver and blood lymphocytes. This allowed a variety of potential target tissues (site of contact, site of metabolism and peripheral distribution) to be assessed for DNA damage. This combination approach was performed with minimal changes to the standard and regulatory recommended sampling times for the stand-alone assays. A series of eight in vivo genotoxins (2-acetylaminofluorene, benzo[a]pyrene, carbendazim, cyclophosphamide, dimethylnitrosamine, ethyl methanesulfonate, ethyl nitrosourea and mitomycin C), which are known to act via different modes of action (direct- and indirect-acting clastogens, alkylating agents, gene mutagens, cross-linking and aneugenic compounds) were tested. Male rats were dosed at 0, 24 and 45 h, and bone marrow and peripheral blood (micronucleus endpoint), liver, whole blood and stomach (Comet endpoint) were sampled at three hours after the last dose. Comet and micronucleus responses were as expected based on available data for conventional (acute) stand-alone assays. All compounds were detected as genotoxic in at least one of the endpoints. The importance of evaluating both endpoints was highlighted by the uniquely positive responses for certain chemicals (benzo[a]pyrene and 2-acetylaminofluorene) with the Comet endpoint and certain other chemicals (carbendazim and mitomycin C) with the micronucleus endpoint. The data generated from these investigations demonstrate the suitability of the multi-endpoint design. 2011 Elsevier B.V. All rights reserved.

Is serial determination of inspiratory muscle strength a useful prognostic marker in chronic heart failure?

PubMed

Frankenstein, Lutz; Meyer, Franz Joachim; Sigg, Caroline; Nelles, Manfred; Schellberg, Dieter; Remppis, Andrew; Katus, Hugo A; Zugck, Christian

2008-04-01

Little data exists on the prognostic role of inspiratory muscle strength (PImax) in chronic heart failure (CHF). Training studies, however, frequently use it as a therapeutic target and surrogate marker for prognosis. The prognostic value of changes of PImax that allow this extrapolation is unknown. Patients with stable CHF were prospectively included and 1-year and all-time event rates recorded for endpoint analysis. In 158 patients (85% men; New York Heart Association functional class: 2.4+/-0.6), PImax was measured along with clinical evaluations at two visits, the initial visit and the second visit, 6.4+/-1.4 months apart. The mean follow-up was 59+/-34 months. Overall, 59 patients (37%) reached the primary endpoint of death or hospitalization (endpoint positive), and overall mortality rate (secondary endpoint) was 26% (42 patients). PImax did not differ between endpoint-negative and endpoint-positive patients, both at the initial and at the second visit (8.3+/-5.6 vs. 7.3+/-3.4 kPa and 8.8+/-6.0 vs. 7.9+/-3.6 kPa, respectively; P=NS), and both groups showed increased PImax (0.6+/-2.6 vs. 0.6+/-2.8 kPa; P=NS). Cox analyses found neither the absolute nor the relative change of PImax to be significant predictors for the primary and secondary endpoints (P=NS for both), both for the 1-year and for the all-time event rates. Endpoint rates did not differ between patients showing increasing or decreasing PImax (P=NS; relative risk (RR): 0.77; 95% confidence interval: 0.47-1.27). Trials focusing on inspiratory muscle function should use the actual levels of PImax as a surrogate marker to represent prognostic information, rather than relative or absolute changes. This is the first study to investigate the prognostic information of the changes of PImax over time, regarding both short-term and long-term morbidity and mortality in patients with stable CHF.

Gene expression profiles in auricle skin as a possible additional endpoint for determination of sensitizers: A multi-endpoint evaluation of the local lymph node assay.

PubMed

Tsuchiyama, Hiromi; Maeda, Akihisa; Nakajima, Mayumi; Kitsukawa, Mika; Takahashi, Kei; Miyoshi, Tomoya; Mutsuga, Mayu; Asaoka, Yoshiji; Miyamoto, Yohei; Oshida, Keiyu

2017-10-05

The murine local lymph node assay (LLNA) is widely used to test chemicals to induce skin sensitization. Exposure of mouse auricle skin to a sensitizer results in proliferation of local lymph node T cells, which has been measured by in vivo incorporation of H 3 -methyl thymidine or 5-bromo-2'-deoxyuridine (BrdU). The stimulation index (SI), the ratio of the mean proliferation in each treated group to that in the concurrent vehicle control group, is frequently used as a regulatory-authorized endpoint for LLNA. However, some non-sensitizing irritants, such as sodium dodecyl sulfate (SDS) or methyl salicylate (MS), have been reported as false-positives by this endpoint. In search of a potential endpoint to enhance the specificity of existing endpoints, we evaluated 3 contact sensitizers; (hexyl cinnamic aldehyde [HCA], oxazolone [OXA], and 2,4-dinitrochlorobenzene [DNCB]), 1 respiratory sensitizer (toluene 2,4-diisocyanate [TDI]), and 2 non-sensitizing irritants (MS and SDS) by several endpoints in LLNA. Each test substance was applied to both ears of female CBA/Ca mice daily for 3 consecutive days. The ears and auricle lymph node cells were analyzed on day 5 for endpoints including the SI value, lymph node cell count, cytokine release from lymph node cells, and histopathological changes and gene expression profiles in auricle skin. The SI values indicated that all the test substances induced significant proliferation of lymph node cells. The lymph node cell counts showed no significant changes by the non-sensitizers assessed. The inflammatory findings of histopathology were similar among the auricle skins treated by sensitizers and irritants. Gene expression profiles of cytokines IFN-γ, IL-4, and IL-17 in auricle skin were similar to the cytokine release profiles in draining lymph node cells. In addition, the gene expression of the chemokine CXCL1 and/or CXCL2 showed that it has the potential to discriminate sensitizers and non-sensitizing irritants. Our results suggest that multi-endpoint analysis in the LLNA leads to a better determination of the sensitizing potential of test substances. We also show that the gene expression of CXCL1 and/or CXCL2, which is involved in elicitation of contact hypersensitivity (CHS), can be a possible additional endpoint for discrimination of sensitizing compounds in LLNA. Copyright © 2017 Elsevier B.V. All rights reserved.

Relative biological effectiveness of light ions in human tumoural cell lines: role of protein p53

NASA Technical Reports Server (NTRS)

Baggio, L.; Cavinato, M.; Cherubini, R.; Conzato, M.; Cucinotta, F.; Favaretto, S.; Gerardi, S.; Lora, S.; Stoppa, P.; Williams, J. R.

2002-01-01

Protons and alpha particles of high linear energy transfer (LET) have shown an increased relative biological effectiveness (RBE) with respect to X/gamma rays for several cellular and molecular endpoints in different in vitro cell systems. To contribute to understanding the biochemical mechanisms involved in the increased effectiveness of high LET radiation, an extensive study has been designed. The present work reports the preliminary result of this study on two human tumoural cell lines, DLD1 and HCT116, (with different p53 status), which indicate that for these cell lines, p53 does not appear to take a part in the response to radiation induced DNA damage, suggesting an alternative p53-independent pathway and a cell biochemical mechanism dependent on the cell type.

Effects of graded load of artificial gravity on cardiovascular functions in humans.

PubMed

Iwase, Satoshi; Fu, Qi; Narita, Kenichi; Morimoto, Eiichi; Takada, Hiroki; Mano, Tadaaki

2002-12-01

An artificial gravity and ergometric exercise loading device for human use was manufactured. It has the capacity of a max 2 G-load at the heart level, and a max 150 W of work-load. Eight subjects (six completed) were subjected to four repeated trials with or without 20 W ergometric exercise. Anti-G score, defined as the G-load x running time to the endpoint, was significantly higher in the exercise trials than standing trials. Heart rate (HR), mean arterial pressure (MAP), thoracic fluid index (TFI) were significantly superior during the exercise trials. Artificial gravity by centrifuge at 1.2 or 1.4 G with 40 or 60 W of ergometric workload may be an excellent countermeasure against cardiovascular deconditioning after long exposure to microgravity.

End-point controller design for an experimental two-link flexible manipulator using convex optimization

NASA Technical Reports Server (NTRS)

Oakley, Celia M.; Barratt, Craig H.

1990-01-01

Recent results in linear controller design are used to design an end-point controller for an experimental two-link flexible manipulator. A nominal 14-state linear-quadratic-Gaussian (LQG) controller was augmented with a 528-tap finite-impulse-response (FIR) filter designed using convex optimization techniques. The resulting 278-state controller produced improved end-point trajectory tracking and disturbance rejection in simulation and experimentally in real time.

Enabling communication concurrency through flexible MPI endpoints

DOE PAGES

Dinan, James; Grant, Ryan E.; Balaji, Pavan; ...

2014-09-23

MPI defines a one-to-one relationship between MPI processes and ranks. This model captures many use cases effectively; however, it also limits communication concurrency and interoperability between MPI and programming models that utilize threads. Our paper describes the MPI endpoints extension, which relaxes the longstanding one-to-one relationship between MPI processes and ranks. Using endpoints, an MPI implementation can map separate communication contexts to threads, allowing them to drive communication independently. Also, endpoints enable threads to be addressable in MPI operations, enhancing interoperability between MPI and other programming models. Furthermore, these characteristics are illustrated through several examples and an empirical study thatmore » contrasts current multithreaded communication performance with the need for high degrees of communication concurrency to achieve peak communication performance.« less

Enabling communication concurrency through flexible MPI endpoints

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

Dinan, James; Grant, Ryan E.; Balaji, Pavan

MPI defines a one-to-one relationship between MPI processes and ranks. This model captures many use cases effectively; however, it also limits communication concurrency and interoperability between MPI and programming models that utilize threads. Our paper describes the MPI endpoints extension, which relaxes the longstanding one-to-one relationship between MPI processes and ranks. Using endpoints, an MPI implementation can map separate communication contexts to threads, allowing them to drive communication independently. Also, endpoints enable threads to be addressable in MPI operations, enhancing interoperability between MPI and other programming models. Furthermore, these characteristics are illustrated through several examples and an empirical study thatmore » contrasts current multithreaded communication performance with the need for high degrees of communication concurrency to achieve peak communication performance.« less

Enabling communication concurrency through flexible MPI endpoints

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

Dinan, James; Grant, Ryan E.; Balaji, Pavan

MPI defines a one-to-one relationship between MPI processes and ranks. This model captures many use cases effectively; however, it also limits communication concurrency and interoperability between MPI and programming models that utilize threads. This paper describes the MPI endpoints extension, which relaxes the longstanding one-to-one relationship between MPI processes and ranks. Using endpoints, an MPI implementation can map separate communication contexts to threads, allowing them to drive communication independently. Endpoints also enable threads to be addressable in MPI operations, enhancing interoperability between MPI and other programming models. These characteristics are illustrated through several examples and an empirical study that contrastsmore » current multithreaded communication performance with the need for high degrees of communication concurrency to achieve peak communication performance.« less

RIFM fragrance ingredient safety assessment, isobornyl isovalerate, CAS registry number 7779-73-9.

PubMed

Api, A M; Belsito, D; Bhatia, S; Bruze, M; Calow, P; Dagli, M L; Dekant, W; Fryer, A D; Kromidas, L; La Cava, S; Lapczynski, A; Liebler, D C; O'Brien, D; Parakhia, R; Penning, T M; Politano, V T; Ritacco, G; Salvito, D; Schultz, T W; Shen, J; Sipes, I G; Wall, B; Wilcox, D K

2017-12-01

This material was evaluated for genotoxicity, repeated dose toxicity, developmental toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization potential, as well as, environmental safety. Data from the suitable read across analog isobornyl acetate (CAS # 125-12-2) show that this material is not genotoxic, provided a MOE > 100 for the repeated dose, developmental and reproductive endpoints, and does not have skin sensitization potential. The local respiratory toxicity endpoint was completed using the TTC (threshold of Toxicological Concern) for a Cramer Class II material (0.47 mg/day). The phototoxicity/photoallergenicity endpoint was completed based on suitable UV spectra. The environmental endpoint was completed as described in the RIFM Framework. Copyright © 2016 Elsevier Ltd. All rights reserved.

The oral, live attenuated enterotoxigenic Escherichia coli vaccine ACE527 reduces the incidence and severity of diarrhea in a human challenge model of diarrheal disease.

PubMed

Darsley, Michael J; Chakraborty, Subhra; DeNearing, Barbara; Sack, David A; Feller, Andrea; Buchwaldt, Charlotte; Bourgeois, A Louis; Walker, Richard; Harro, Clayton D

2012-12-01

An oral, live attenuated, three-strain recombinant bacterial vaccine, ACE527, was demonstrated to generate strong immune responses to colonization factor and toxin antigens of enterotoxigenic Escherichia coli (ETEC) in human volunteers. The vaccine was safe and well tolerated at doses of up to 10(11) CFU, administered in each of two doses given 21 days apart. These observations have now been extended in a phase 2b study with a total of 70 subjects. Fifty-six of these subjects were challenged 28 days after the second dose of vaccine with the highly virulent ETEC strain H10407 to obtain preliminary indicators of efficacy against disease and to support further development of the vaccine for both travelers and infants in countries where ETEC is endemic. The vaccine had a significant impact on intestinal colonization by the challenge strain, as measured by quantitative fecal culture 2 days after challenge, demonstrating the induction of a functional immune response to the CFA/I antigen. The incidence and severity of diarrhea were also reduced in vaccinees as measured by a number of secondary and ad hoc endpoints, although the 27% reduction seen in the primary endpoint, moderate to severe diarrhea, was not statistically significant. Together, these observations support the hypothesis that the ACE527 vaccine has a dual mode of action, targeting both colonization factors and the heat-labile enterotoxin (LT), and suggest that it should be further developed for more advanced trials to evaluate its impact on the burden of ETEC disease in field settings.

International Cartilage Repair Society (ICRS) Recommended Guidelines for Histological Endpoints for Cartilage Repair Studies in Animal Models and Clinical Trials

PubMed Central

Hoemann, Caroline; Kandel, Rita; Roberts, Sally; Saris, Daniel B.F.; Creemers, Laura; Mainil-Varlet, Pierre; Méthot, Stephane; Hollander, Anthony P.; Buschmann, Michael D.

2011-01-01

Cartilage repair strategies aim to resurface a lesion with osteochondral tissue resembling native cartilage, but a variety of repair tissues are usually observed. Histology is an important structural outcome that could serve as an interim measure of efficacy in randomized controlled clinical studies. The purpose of this article is to propose guidelines for standardized histoprocessing and unbiased evaluation of animal tissues and human biopsies. Methods were compiled from a literature review, and illustrative data were added. In animal models, treatments are usually administered to acute defects created in healthy tissues, and the entire joint can be analyzed at multiple postoperative time points. In human clinical therapy, treatments are applied to developed lesions, and biopsies are obtained, usually from a subset of patients, at a specific time point. In striving to standardize evaluation of structural endpoints in cartilage repair studies, 5 variables should be controlled: 1) location of biopsy/sample section, 2) timing of biopsy/sample recovery, 3) histoprocessing, 4) staining, and 5) blinded evaluation with a proper control group. Histological scores, quantitative histomorphometry of repair tissue thickness, percentage of tissue staining for collagens and glycosaminoglycan, polarized light microscopy for collagen fibril organization, and subchondral bone integration/structure are all relevant outcome measures that can be collected and used to assess the efficacy of novel therapeutics. Standardized histology methods could improve statistical analyses, help interpret and validate noninvasive imaging outcomes, and permit cross-comparison between studies. Currently, there are no suitable substitutes for histology in evaluating repair tissue quality and cartilaginous character. PMID:26069577

Comparison of Mucosal Markers of Human Immunodeficiency Virus Susceptibility in Healthy Premenopausal Versus Postmenopausal Women.

PubMed

Thurman, Andrea Ries; Yousefieh, Nazita; Chandra, Neelima; Kimble, Thomas; Asin, Susana; Rollenhagen, Christiane; Anderson, Sharon M; Herold, Betsy C; Freiermuth, Jamie L; Starkman, Brian S; Mesquita, Pedro M M; Richardson-Harman, Nicola; Cunningham, Tina; Hillier, Sharon; Rabe, Lorna; Schwartz, Jill L; Doncel, Gustavo F

2017-08-01

The objective of this study was to characterize cervicovaginal (CV) mucosal factors modulating susceptibility to human immunodeficiency virus (HIV) acquisition in healthy premenopausal (PRE) and postmenopausal (POST) women before and after treatment with estradiol (E2). We compared CV mucosal epithelial histology and immune cells, vaginal microbiota, antimicrobial activity of and soluble mucosal protein concentrations in the CV fluid lavage (CVL), and p24 antigen production after ex vivo infection of ectocervical tissues with HIV-1 BaL among PRE women (n = 20) in the follicular and luteal phases of the menstrual cycle and POST women (n = 17) at baseline and after ∼1 month of treatment with 0.01% vaginal E2 cream. Compared to PRE women, we measured higher levels of p24 antigen after ex vivo infection in tissues from POST women. POST women had a significantly thinner vaginal epithelium with decreased tight junction proteins and a higher density of mucosal immune T cells and lower levels of CD1a antigen-presenting cells, antimicrobial peptides, and inflammatory cytokines in the CVL (p values <.05). POST women had higher vaginal pH and lower vaginal Lactobacilli (p values <.05) than PRE women. After vaginal E2 therapy, CV endpoints and ex vivo HIV replication in POST tissues were similar to those observed in PRE tissues. The CV mucosa in POST women is thinned and compromised, with increased HIV-target immune cells and decreased antimicrobial factors, being more susceptible to HIV infection. After POST women receive topical E2 treatment, mucosal endpoints are similar to PRE levels.

The discriminative effects of the kappa-opioid hallucinogen salvinorin A in nonhuman primates: dissociation from classic hallucinogen effects.

PubMed

Butelman, Eduardo R; Rus, Szymon; Prisinzano, Thomas E; Kreek, Mary Jeanne

2010-06-01

The widely available hallucinogen salvinorin A is a unique example of a plant-derived compound selective for kappa-opioid receptors and may produce effects distinct from those of other compounds with classic hallucinogenic or dissociative properties which are also abused in humans. The objective of this study is to characterize the salvinorin A discriminative cue in nonhuman primates with high kappa-receptor genetic homology to humans. Adult rhesus monkeys (n = 3) were trained to discriminate salvinorin A (0.015 mg/kg, s.c.) from vehicle, in a food-reinforced operant discrimination assay. Parallel studies, using unconditioned behavioral endpoints (facial relaxation and ptosis) also evaluated the kappa-opioid receptor mediation of salvinorin A in vivo function. Monkeys trained to discriminate salvinorin A generalized structurally diverse, centrally penetrating kappa-agonists (bremazocine, U69,593, and U50,488). By contrast, mu- and delta-opioid agonists (fentanyl and SNC80, respectively) were not generalized, nor were the serotonergic 5HT2 hallucinogen psilocybin or the dissociative N-methyl-D-aspartic acid antagonist, ketamine. The discriminative effects of salvinorin A were blocked by the opioid antagonist quadazocine (0.32 mg/kg), but not by the 5HT2 antagonist ketanserin (0.1 mg/kg). Consistent with these findings, salvinorin and kappa-agonists (e.g., U69,593) produce effects in the unconditioned endpoints (e.g., ptosis), whereas psilocybin was inactive. These findings support the conclusion that the interoceptive/discriminative cue produced by salvinorin A is mediated by agonism at kappa-receptors and is mechanistically distinct from that produced by a classic serotonergic hallucinogen.

A Double Blind, Randomized, Neoadjuvant Study of the Tissue effects of POMx Pills in Men with Prostate Cancer Prior to Radical Prostatectomy

PubMed Central

Freedland, Stephen J.; Carducci, Michael; Kroeger, Nils; Partin, Alan; Rao, Jian-yu; Jin, Yusheng; Kerkoutian, Susan; Wu, Hong; Li, Yunfeng; Creel, Patricia; Mundy, Kelly; Gurganus, Robin; Fedor, Helen; King, Serina A.; Zhang, Yanjun; Heber, David; Pantuck, Allan J.

2013-01-01

Pomegranates slow prostate cancer xenograft growth and prolong PSA doubling times in single-arm human studies. Pomegranates’ effects on human prostate tissue are understudied. We hypothesized orally administered pomegranate extract (POMx; PomWonderful, Los Angeles, CA) would lower tissue 8-hydroxy-2-deoxyguanosine (8-OHdG), an oxidative stress biomarker. 70 men were randomized to 2 tablets POMx or placebo daily up to 4 weeks prior to radical prostatectomy. Tissue was analyzed for intra-prostatic Urolithin A, a pomegranate metabolite, benign and malignant 8-OHdG, and cancer pS6 kinase, NFκB, and Ki67. Primary end-point was differences in 8-OHdG powered to detect 30% reduction. POMx was associated with 16% lower benign tissue 8-OHdG (p=0.095), which was not statistically significant. POMx was well-tolerated with no treatment-related withdrawals. There were no differences in baseline clinicopathological features between arms. Urolithin A was detected in 21/33 patient in the POMx group vs. 12/35 in the placebo group (p=0.031). Cancer pS6 kinase, NFκB, Ki67, and serum PSA changes were similar between arms. POMx prior to surgery results in pomegranate metabolite accumulation in prostate tissues. Our primary end-point in this modest-sized short-term trial was negative. Future larger longer studies are needed to more definitely test whether POMx reduces prostate oxidative stress as well as further animal testing to better understand the multiple mechanisms through which POMx may alter prostate cancer biology. PMID:23985577

Learning algorithms for human-machine interfaces.

PubMed

Danziger, Zachary; Fishbach, Alon; Mussa-Ivaldi, Ferdinando A

2009-05-01

The goal of this study is to create and examine machine learning algorithms that adapt in a controlled and cadenced way to foster a harmonious learning environment between the user and the controlled device. To evaluate these algorithms, we have developed a simple experimental framework. Subjects wear an instrumented data glove that records finger motions. The high-dimensional glove signals remotely control the joint angles of a simulated planar two-link arm on a computer screen, which is used to acquire targets. A machine learning algorithm was applied to adaptively change the transformation between finger motion and the simulated robot arm. This algorithm was either LMS gradient descent or the Moore-Penrose (MP) pseudoinverse transformation. Both algorithms modified the glove-to-joint angle map so as to reduce the endpoint errors measured in past performance. The MP group performed worse than the control group (subjects not exposed to any machine learning), while the LMS group outperformed the control subjects. However, the LMS subjects failed to achieve better generalization than the control subjects, and after extensive training converged to the same level of performance as the control subjects. These results highlight the limitations of coadaptive learning using only endpoint error reduction.

mBAND analysis for high- and low-LET radiation-induced chromosome aberrations: a review.

PubMed

Hada, Megumi; Wu, Honglu; Cucinotta, Francis A

2011-06-03

During long-term space travel or cancer therapy, humans are exposed to high linear energy transfer (LET) energetic heavy ions. High-LET radiation is much more effective than low-LET radiation in causing various biological effects, including cell inactivation, genetic mutations, cataracts and cancer induction. Most of these biological endpoints are closely related to chromosomal damage, and cytogenetic damage can be utilized as a biomarker for radiation insults. Epidemiological data, mainly from survivors of the atomic bomb detonations in Japan, have enabled risk estimation from low-LET radiation exposures. The identification of a cytogenetic signature that distinguishes high- from low-LET exposure remains a long-term goal in radiobiology. Recently developed fluorescence in situ hybridization (FISH)-painting methodologies have revealed unique endpoints related to radiation quality. Heavy-ions induce a high fraction of complex-type exchanges, and possibly unique chromosome rearrangements. This review will concentrate on recent data obtained with multicolor banding in situ hybridization (mBAND) methods in mammalian cells exposed to low- and high-LET radiations. Chromosome analysis with mBAND technique allows detection of both inter- and intrachromosomal exchanges, and also distribution of the breakpoints of aberrations. 2011 Elsevier B.V. All rights reserved.

Ultrasound enhanced thrombolysis: Clinical evidence

NASA Astrophysics Data System (ADS)

Alexandrov, Andrei V.

2005-04-01

Phase II CLOTBUST randomized clinical trial (Houston, Barcelona, Edmonton, Calgary) evaluated patients with acute ischemic stroke due to intracranial occlusion and treated with intravenous tissue plasminogen activator (TPA) within 3 h of symptom onset. Randomization: monitoring with pulsed wave 2 MHz transcranial Doppler (TCD) (Target) or placebo monitoring (Control). Safety: symptomatic bleeding to the brain (sICH). Primary end-point: complete recanalization on TCD or dramatic clinical recovery by the total NIHSS score <3, or improvement by >10 NIHSS points within 2 hours after TPA bolus. All projected 126 patients were randomized 1:1 to target (median NIHSS 16) or control (NIHSS 17). sICH: 4.8% Target, 4.8% Controls. Primary end-point was achieved by 31 (49%, Target) versus 19 (30%, Control), p<0.03. At 3 months, 22 (42% Target) and 14 (29% Control) patients achieved favorable outcomes. Continuous TCD monitoring of intracranial occlusion safely augments TPA-induced arterial recanalization, and 2 MHz diagnostic ultrasound has a positive biological activity that aids systemic thrombolytic therapy. For the first time in clinical medicine, the CLOTBUST trial provides the evidence that ultrasound enhances thrombolytic activity of a drug in humans thereby confirming intense multi-disciplinary experimental research conducted worldwide for the past 30 years.

Quantitative Relationship Between AUEC of Absolute Neutrophil Count and Duration of Severe Neutropenia for G-CSF in Breast Cancer Patients.

PubMed

Li, Liang; Ma, Lian; Schrieber, Sarah J; Rahman, Nam Atiqur; Deisseroth, Albert; Farrell, Ann T; Wang, Yaning; Sinha, Vikram; Marathe, Anshu

2018-02-02

The aim of the study was to evaluate the quantitative relationship between duration of severe neutropenia (DSN, the efficacy endpoint) and area under effect curve of absolute neutrophil counts (ANC-AUEC, the pharmacodynamic endpoint), based on data from filgrastim products, a human granulocyte colony-stimulating factor (G-CSF). Clinical data from filgrastim product comparator and test arms of two randomized, parallel-group, phase III studies in breast cancer patients treated with myelosuppressive chemotherapy were utilized. A zero-inflated Poisson regression model best described the negative correlation between DSN and ANC-AUEC. The models predicted that with 10 × 10 9 day/L of increase in ANC-AUEC, the mean DSN would decrease from 1.1 days to 0.93 day in Trial 1 and from 1.2 days to 1.0 day in Trial 2. The findings of the analysis provide useful information regarding the relationship between ANC and DSN that can be used for dose selection and optimization of clinical trial design for G-CSF. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.

Induction of micronuclei in human fibroblasts across the Bragg curve of energetic heavy ions

NASA Technical Reports Server (NTRS)

Hada, Megumi; Rusek, Adam; Cucinotta, Francis A.; Wu, Honglu

2006-01-01

The space environment consists of a varying field of radiation particles including high energy ions, with spacecraft shielding material providing the major protection to astronauts from harmful exposure. Unlike low-L or X-rays, the presence of shielding does not always reduce the radiation risks for energetic charged particle exposure. Although the dose delivered by the charged particle increases sharply as the particle approaches the Bragg peak, the Bragg curve does not necessarily represent the biological damage along the particle traversal. The "biological Bragg curve" is dependent on the energy and the type of the primary particle, and may vary for different biological endpoints. To investigate "biological Bragg curves", we analyzed micronuclei (MN) induction along the particle traversal of Si and Fe ions at incident energies of 300 MeV/nucleon and 1 GeV/nucleon. A quantitative biological response curve did not reveal an increased yield of MN at the location of the Bragg peak. However, the ratio of mono-to bi-nucleated cells, which indicates inhibition in cell progression, increased at the Bragg peak location. These results confirm the hypothesis that "over kill" at the Bragg peak will affect the outcome of other biological endpoints.

Use of Zebrafish Larvae as a Multi-Endpoint Platform to Characterize the Toxicity Profile of Silica Nanoparticles.

PubMed

Pham, Duc-Hung; De Roo, Bert; Nguyen, Xuan-Bac; Vervaele, Mattias; Kecskés, Angela; Ny, Annelii; Copmans, Daniëlle; Vriens, Hanne; Locquet, Jean-Pierre; Hoet, Peter; de Witte, Peter A M

2016-11-22

Nanomaterials are being extensively produced and applied in society. Human and environmental exposures are, therefore, inevitable and so increased attention is being given to nanotoxicity. While silica nanoparticles (NP) are one of the top five nanomaterials found in consumer and biomedical products, their toxicity profile is poorly characterized. In this study, we investigated the toxicity of silica nanoparticles with diameters 20, 50 and 80 nm using an in vivo zebrafish platform that analyzes multiple endpoints related to developmental, cardio-, hepato-, and neurotoxicity. Results show that except for an acceleration in hatching time and alterations in the behavior of zebrafish embryos/larvae, silica NPs did not elicit any developmental defects, nor any cardio- and hepatotoxicity. The behavioral alterations were consistent for both embryonic photomotor and larval locomotor response and were dependent on the concentration and the size of silica NPs. As embryos and larvae exhibited a normal touch response and early hatching did not affect larval locomotor response, the behavior changes observed are most likely the consequence of modified neuroactivity. Overall, our results suggest that silica NPs do not cause any developmental, cardio- or hepatotoxicity, but they pose a potential risk for the neurobehavioral system.

A structured approach to Exposure Based Waiving of human health endpoints under REACH developed in the OSIRIS project.

PubMed

Marquart, Hans; Meijster, Tim; Van de Bovenkamp, Marja; Ter Burg, Wouter; Spaan, Suzanne; Van Engelen, Jacqueline

2012-03-01

Exposure Based Waiving (EBW) is one of the options in REACH when there is insufficient hazard data on a specific endpoint. Rules for adaptation of test requirements are specified and a general option for EBW is given via Appendix XI of REACH, allowing waiving of repeated dose toxicity studies, reproductive toxicity studies and carcinogenicity studies under a number of conditions if exposure is very low. A decision tree is described that was developed in the European project OSIRIS (Optimised Strategies for Risk Assessment of Industrial Chemicals through Integration of Non-Test and Test Information) to help decide in what cases EBW can be justified. The decision tree uses specific criteria as well as more general questions. For the latter, guidance on interpretation and resulting conclusions is provided. Criteria and guidance are partly based on an expert elicitation process. Among the specific criteria a number of proposed Thresholds of Toxicological Concern are used. The decision tree, expanded with specific parts on absorption, distribution, metabolism and excretion that are not described in this paper, is implemented in the OSIRIS webtool on integrated testing strategies. Copyright © 2011 Elsevier Inc. All rights reserved.

An Overview of the Effects of Dioxins and Dioxin-like Compounds on Vertebrates, as Documented in Human and Ecological Epidemiology

PubMed Central

White, Sally S.; Birnbaum, Linda S.

2009-01-01

Dioxins and dioxin-like compounds are primary examples of persistent organic pollutants that induce toxicity in both wildlife and humans. Over the past 200 years these compounds have been almost exclusively generated by human activity and have left a string of disasters in the wake of their accidental release. Most recently, the contamination of the Irish pork supply with dioxins resulted in an international recall of all Irish pork products. Epidemiologic data on human and ecological dioxin exposures have revealed a common pattern of biological response among vertebrate species, which is mediated through activation of the Aryl hydrocarbon Receptor (AhR). These AhR-mediated effects include profound consequences on the vertebrate individual exposed in early-life, with respect to myriad developmental endpoints including neurologic, immunologic, and reproductive parameters. Humans appear to be susceptible to these effects, in a manner similar to that of the laboratory and wildlife species which have demonstrated such outcomes. Furthermore, epidemiologic data suggest that there is little or no margin of exposure for humans, with respect to these developmental effects. Given these concerns, prudent public health policy should include the continued reduction of exposures. PMID:19953395

Motor adaptation to Coriolis force perturbations of reaching movements: endpoint but not trajectory adaptation transfers to the nonexposed arm

NASA Technical Reports Server (NTRS)

Dizio, P.; Lackner, J. R.

1995-01-01

1. Reaching movements made in a rotating room generate Coriolis forces that are directly proportional to the cross product of the room's angular velocity and the arm's linear velocity. Such Coriolis forces are inertial forces not involving mechanical contact with the arm. 2. We measured the trajectories of arm movements made in darkness to a visual target that was extinguished at the onset of each reach. Prerotation subjects pointed with both the right and left arms in alternating sets of eight movements. During rotation at 10 rpm, the subjects reached only with the right arm. Postrotation, the subjects pointed with the left and right arms, starting with the left, in alternating sets of eight movements. 3. The initial perrotary reaching movements of the right arm were highly deviated both in movement path and endpoint relative to the prerotation reaches of the right arm. With additional movements, subjects rapidly regained straight movement paths and accurate endpoints despite the absence of visual or tactile feedback about reaching accuracy. The initial postrotation reaches of the left arm followed straight paths to the wrong endpoint. The initial postrotation reaches of the right arm had paths with mirror image curvature to the initial perrotation reaches of the right arm but went to the correct endpoint. 4. These observations are inconsistent with current equilibrium point models of movement control. Such theories predict accurate reaches under our experimental conditions. Our observations further show independent implementation of movement and posture, as evidenced by transfer of endpoint adaptation to the nonexposed arm without transfer of path adaptation. Endpoint control may occur at a relatively central stage that represents general constraints such as gravitoinertial force background or egocentric direction relative to both arms, and control of path may occur at a more peripheral stage that represents moments of inertia and muscle dynamics unique to each limb. 5. Endpoint and path adaptation occur despite the absence both of mechanical contact cues about the perturbing force and visual or tactile cues about movement accuracy. These findings point to the importance of muscle spindle signals, monitoring of motor commands, and possibly joint and tendon receptors in a detailed trajectory monitoring process. Muscle spindle primary and secondary afferent signals may differentially influence adaptation of movement shape and endpoint, respectively.