A data-driven weighting scheme for multivariate phenotypic endpoints recapitulates zebrafish developmental cascades

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

Zhang, Guozhu, E-mail: gzhang6@ncsu.edu

Zebrafish have become a key alternative model for studying health effects of environmental stressors, partly due to their genetic similarity to humans, fast generation time, and the efficiency of generating high-dimensional systematic data. Studies aiming to characterize adverse health effects in zebrafish typically include several phenotypic measurements (endpoints). While there is a solid biomedical basis for capturing a comprehensive set of endpoints, making summary judgments regarding health effects requires thoughtful integration across endpoints. Here, we introduce a Bayesian method to quantify the informativeness of 17 distinct zebrafish endpoints as a data-driven weighting scheme for a multi-endpoint summary measure, called weightedmore » Aggregate Entropy (wAggE). We implement wAggE using high-throughput screening (HTS) data from zebrafish exposed to five concentrations of all 1060 ToxCast chemicals. Our results show that our empirical weighting scheme provides better performance in terms of the Receiver Operating Characteristic (ROC) curve for identifying significant morphological effects and improves robustness over traditional curve-fitting approaches. From a biological perspective, our results suggest that developmental cascade effects triggered by chemical exposure can be recapitulated by analyzing the relationships among endpoints. Thus, wAggE offers a powerful approach for analysis of multivariate phenotypes that can reveal underlying etiological processes. - Highlights: • Introduced a data-driven weighting scheme for multiple phenotypic endpoints. • Weighted Aggregate Entropy (wAggE) implies differential importance of endpoints. • Endpoint relationships reveal developmental cascade effects triggered by exposure. • wAggE is generalizable to multi-endpoint data of different shapes and scales.« less

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.

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.

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

Ecological risk assessment of bisphenol A in surface waters of China based on both traditional and reproductive endpoints.

PubMed

Guo, Lei; Li, Zhengyan; Gao, Pei; Hu, Hong; Gibson, Mark

2015-11-01

Bisphenol A (BPA) occurs widely in natural waters with both traditional and reproductive toxicity to various aquatic species. The water quality criteria (WQC), however, have not been established in China, which hinders the ecological risk assessment for the pollutant. This study therefore aims to derive the water quality criteria for BPA based on both acute and chronic toxicity endpoints and to assess the ecological risk in surface waters of China. A total of 15 acute toxicity values tested with aquatic species resident in China were found in published literature, which were simulated with the species sensitivity distribution (SSD) model for the derivation of criterion maximum concentration (CMC). 18 chronic toxicity values with traditional endpoints were simulated for the derivation of traditional criterion continuous concentration (CCC) and 12 chronic toxicity values with reproductive endpoints were for reproductive CCC. Based on the derived WQC, the ecological risk of BPA in surface waters of China was assessed with risk quotient (RQ) method. The results showed that the CMC, traditional CCC and reproductive CCC were 1518μgL(-1), 2.19μgL(-1) and 0.86μgL(-1), respectively. The acute risk of BPA was negligible with RQ values much lower than 0.1. The chronic risk was however much higher with RQ values of between 0.01-3.76 and 0.03-9.57 based on traditional and reproductive CCC, respectively. The chronic RQ values on reproductive endpoints were about threefold as high as those on traditional endpoints, indicating that ecological risk assessment based on traditional effects may not guarantee the safety of aquatic biota. Copyright © 2015 Elsevier Ltd. All rights reserved.

Modeling hard clinical end-point data in economic analyses.

PubMed

Kansal, Anuraag R; Zheng, Ying; Palencia, Roberto; Ruffolo, Antonio; Hass, Bastian; Sorensen, Sonja V

2013-11-01

The availability of hard clinical end-point data, such as that on cardiovascular (CV) events among patients with type 2 diabetes mellitus, is increasing, and as a result there is growing interest in using hard end-point data of this type in economic analyses. This study investigated published approaches for modeling hard end-points from clinical trials and evaluated their applicability in health economic models with different disease features. A review of cost-effectiveness models of interventions in clinically significant therapeutic areas (CV diseases, cancer, and chronic lower respiratory diseases) was conducted in PubMed and Embase using a defined search strategy. Only studies integrating hard end-point data from randomized clinical trials were considered. For each study included, clinical input characteristics and modeling approach were summarized and evaluated. A total of 33 articles (23 CV, eight cancer, two respiratory) were accepted for detailed analysis. Decision trees, Markov models, discrete event simulations, and hybrids were used. Event rates were incorporated either as constant rates, time-dependent risks, or risk equations based on patient characteristics. Risks dependent on time and/or patient characteristics were used where major event rates were >1%/year in models with fewer health states (<7). Models of infrequent events or with numerous health states generally preferred constant event rates. The detailed modeling information and terminology varied, sometimes requiring interpretation. Key considerations for cost-effectiveness models incorporating hard end-point data include the frequency and characteristics of the relevant clinical events and how the trial data is reported. When event risk is low, simplification of both the model structure and event rate modeling is recommended. When event risk is common, such as in high risk populations, more detailed modeling approaches, including individual simulations or explicitly time-dependent event rates

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

A Prospective, Randomized, Open-Label, Blinded, Endpoint Study Exploring Platelet Response to Half-Dose Prasugrel and Ticagrelor in Patients with the Acute Coronary Syndrome: HOPE-TAILOR Study.

PubMed

Jin, Cai De; Kim, Moo Hyun; Bang, Junghee; Serebruany, Victor

The optimal dosing of novel oral P2Y12 receptor platelet inhibitors such as prasugrel or ticagrelor is unclear and especially challenging in East Asians. We hypothesize that half-dose prasugrel and ticagrelor may be sufficient for long-term maintenance management in Korean patients with the acute coronary syndrome (ACS) compared with conventional dosages. HOPE-TAILOR (Half Dose of Prasugrel and Ticagrelor in Platelet Response after Acute Coronary Syndromes) is a prospective, randomized, open-label, blinded, endpoint (PROBE) single-center, clinical trial. A total of 100 patients with ACS undergoing drug-eluting stent implantation will be randomly assigned to prasugrel, ticagrelor, or clopidogrel, and the patients in each treatment group will receive 1-month therapy with 100 mg q.d. aspirin plus prasugrel 10 mg q.d., ticagrelor 90 mg b.i.d., or clopidogrel 75 mg q.d., followed by half-dose prasugrel 5 mg q.d. or ticagrelor 45 mg b.i.d. for maintenance treatment but without clopidogrel dose reduction. The primary endpoint will be optimal platelet reactivity 3 months after coronary intervention, defined by VerifyNow Analyzer (PRU: 85-208) and vasodilator-stimulated phosphoprotein P2Y12 flow cytometry assay (platelet reactivity indices: 16-50%). Clinical outcomes will also be assessed, including major efficacy (composite of cardiac death, nonfatal myocardial infarction, repeat revascularization, or stroke) and safety (bleeding ≥2 according to the Bleeding Academic Research Consortium). HOPE-TAILOR is a prospective, randomized, open-label, blinded, endpoint study to explore the efficacy and safety of novel P2Y12 receptor inhibitors administered orally at half the dose in Korean patients with ACS. The results will be available late in 2017. © 2017 S. Karger AG, Basel.

Self-Reported Mental Health Predicts Acute Respiratory Infection.

PubMed

Maxwell, Lizzie; Barrett, Bruce; Chase, Joseph; Brown, Roger; Ewers, Tola

2015-06-01

Poor mental health conditions, including stress and depression, have been recognized as a risk factor for the development of acute respiratory infection. Very few studies have considered the role of general mental health in acute respiratory infection occurrence. The aim of this analysis is to determine if overall mental health, as assessed by the mental component of the Short Form 12 Health Survey, predicts incidence, duration, or severity of acute respiratory infection. Data utilized for this analysis came from the National Institute of Health-funded Meditation or Exercise for Preventing Acute Respiratory Infection (MEPARI) and MEPARI-2 randomized controlled trials examining the effects of meditation or exercise on acute respiratory infection among adults aged > 30 years in Madison, Wisconsin. A Kendall tau rank correlation compared the Short Form 12 mental component, completed by participants at baseline, with acute respiratory infection incidence, duration, and area-under-the-curve (global) severity, as assessed by the Wisconsin Upper Respiratory Symptom Survey. Participants were recruited from Madison, Wis, using advertisements in local media. Short Form 12 mental health scores significantly predicted incidence (P = 0.037) of acute respiratory infection, but not duration (P = 0.077) or severity (P = 0.073). The Positive and Negative Affect Schedule (PANAS) negative emotion measure significantly predicted global severity (P = 0.036), but not incidence (P = 0.081) or duration (P = 0.125). Mindful Attention Awareness Scale scores significantly predicted incidence of acute respiratory infection (P = 0.040), but not duration (P = 0.053) or severity (P = 0.70). The PHQ-9, PSS-10, and PANAS positive measures did not show significant predictive associations with any of the acute respiratory infection outcomes. Self-reported overall mental health, as measured by the mental component of Short Form 12, predicts acute respiratory infection incidence.

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.

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

[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.

The Use of a Binary Composite Endpoint and Sample Size Requirement: Influence of Endpoints Overlap.

PubMed

Marsal, Josep-Ramon; Ferreira-González, Ignacio; Bertran, Sandra; Ribera, Aida; Permanyer-Miralda, Gaietà; García-Dorado, David; Gómez, Guadalupe

2017-05-01

Although composite endpoints (CE) are common in clinical trials, the impact of the relationship between the components of a binary CE on the sample size requirement (SSR) has not been addressed. We performed a computational study considering 2 treatments and a CE with 2 components: the relevant endpoint (RE) and the additional endpoint (AE). We assessed the strength of the components' interrelation by the degree of relative overlap between them, which was stratified into 5 groups. Within each stratum, SSR was computed for multiple scenarios by varying the events proportion and the effect of the therapy. A lower SSR using CE was defined as the best scenario for using the CE. In 25 of 66 scenarios the degree of relative overlap determined the benefit of using CE instead of the RE. Adding an AE with greater effect than the RE leads to lower SSR using the CE regardless of the AE proportion and the relative overlap. The influence of overlapping decreases when the effect on RE increases. Adding an AE with lower effect than the RE constitutes the most uncertain situation. In summary, the interrelationship between CE components, assessed by the relative overlap, can help to define the SSR in specific situations and it should be considered for SSR computation. © The Author 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Standardized endpoint definitions for transcatheter aortic valve implantation clinical trials: a consensus report from the Valve Academic Research Consortium†

PubMed Central

Leon, Martin B.; Piazza, Nicolo; Nikolsky, Eugenia; Blackstone, Eugene H.; Cutlip, Donald E.; Kappetein, Arie Pieter; Krucoff, Mitchell W.; Mack, Michael; Mehran, Roxana; Miller, Craig; Morel, Marie-angèle; Petersen, John; Popma, Jeffrey J.; Takkenberg, Johanna J.M.; Vahanian, Alec; van Es, Gerrit-Anne; Vranckx, Pascal; Webb, John G.; Windecker, Stephan; Serruys, Patrick W.

2011-01-01

Objectives To propose standardized consensus definitions for important clinical endpoints in transcatheter aortic valve implantation (TAVI), investigations in an effort to improve the quality of clinical research and to enable meaningful comparisons between clinical trials. To make these consensus definitions accessible to all stakeholders in TAVI clinical research through a peer reviewed publication, on behalf of the public health. Background Transcatheter aortic valve implantation may provide a worthwhile less invasive treatment in many patients with severe aortic stenosis and since its introduction to the medical community in 2002, there has been an explosive growth in procedures. The integration of TAVI into daily clinical practice should be guided by academic activities, which requires a harmonized and structured process for data collection, interpretation, and reporting during well-conducted clinical trials. Methods and results The Valve Academic Research Consortium established an independent collaboration between Academic Research organizations and specialty societies (cardiology and cardiac surgery) in the USA and Europe. Two meetings, in San Francisco, California (September 2009) and in Amsterdam, the Netherlands (December 2009), including key physician experts, and representatives from the US Food and Drug Administration (FDA) and device manufacturers, were focused on creating consistent endpoint definitions and consensus recommendations for implementation in TAVI clinical research programs. Important considerations in developing endpoint definitions included (i) respect for the historical legacy of surgical valve guidelines; (ii) identification of pathophysiological mechanisms associated with clinical events; (iii) emphasis on clinical relevance. Consensus criteria were developed for the following endpoints: mortality, myocardial infarction, stroke, bleeding, acute kidney injury, vascular complications, and prosthetic valve performance. Composite

Dose and dose rate extrapolation factors for malignant and non-malignant health endpoints after exposure to gamma and neutron radiation.

PubMed

Tran, Van; Little, Mark P

2017-11-01

Murine experiments were conducted at the JANUS reactor in Argonne National Laboratory from 1970 to 1992 to study the effect of acute and protracted radiation dose from gamma rays and fission neutron whole body exposure. The present study reports the reanalysis of the JANUS data on 36,718 mice, of which 16,973 mice were irradiated with neutrons, 13,638 were irradiated with gamma rays, and 6107 were controls. Mice were mostly Mus musculus, but one experiment used Peromyscus leucopus. For both types of radiation exposure, a Cox proportional hazards model was used, using age as timescale, and stratifying on sex and experiment. The optimal model was one with linear and quadratic terms in cumulative lagged dose, with adjustments to both linear and quadratic dose terms for low-dose rate irradiation (<5 mGy/h) and with adjustments to the dose for age at exposure and sex. After gamma ray exposure there is significant non-linearity (generally with upward curvature) for all tumours, lymphoreticular, respiratory, connective tissue and gastrointestinal tumours, also for all non-tumour, other non-tumour, non-malignant pulmonary and non-malignant renal diseases (p < 0.001). Associated with this the low-dose extrapolation factor, measuring the overestimation in low-dose risk resulting from linear extrapolation is significantly elevated for lymphoreticular tumours 1.16 (95% CI 1.06, 1.31), elevated also for a number of non-malignant endpoints, specifically all non-tumour diseases, 1.63 (95% CI 1.43, 2.00), non-malignant pulmonary disease, 1.70 (95% CI 1.17, 2.76) and other non-tumour diseases, 1.47 (95% CI 1.29, 1.82). However, for a rather larger group of malignant endpoints the low-dose extrapolation factor is significantly less than 1 (implying downward curvature), with central estimates generally ranging from 0.2 to 0.8, in particular for tumours of the respiratory system, vasculature, ovary, kidney/urinary bladder and testis. For neutron exposure most endpoints, malignant

Meat juice: An alternative matrix for assessing animal health by measuring acute phase proteins. Correlations of pig-MAP and haptoglobin concentrations in pig meat juice and plasma.

PubMed

Piñeiro, M; Gymnich, S; Knura, S; Piñeiro, C; Petersen, B

2009-10-01

Quantification of acute phase proteins (APPs) in blood can be used for monitoring animal health and welfare on farms, and could be also of interest for the detection of diseased animals during the meat inspection process. However serum or plasma is not always available for end-point analysis at slaughter. Meat juice might provide an adequate, alternative matrix that can be easily obtained for post-mortem analysis at abattoirs. The concentrations of pig Major Acute phase Protein (pig-MAP) and haptoglobin, two of the main APPs in pigs, were determined in approximately 300 paired samples of plasma and meat juice from the diaphragm (pars costalis), obtained after freezing and thawing the muscle. APPs concentrations in meat juice were closely correlated to those in plasma (r=0.695 for haptoglobin, r=0.858 for pig-MAP, p<0.001). These results open new possibilities for the assessment of animal health in pig production, with implications for food safety and meat quality.

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.

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

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

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.

Association between in-hospital acute hypertensive episodes and outcomes in older trauma patients.

PubMed

Saliba, Lina; Stawicki, Stanislaw Peter; Thongrong, Cattleya; Bergese, Sergio Daniel; Papadimos, Thomas John; Gerlach, Anthony Thomas

2014-08-01

Although chronic hypertension is associated with long-term complications, few studies directly examine the effects of in-hospital acute hypertensive episodes in trauma patients. The aim was to determine whether there is an association between in-hospital acute hypertension and morbidity. We included trauma patients between 45 and 89 years who presented to a level I trauma center between January and September 2008. Patients were classified as either experiencing or not experiencing acute hypertensive episode(s) as defined by systolic blood pressure ≥180, or diastolic blood pressure ≥110 mmHg, or at least two readings of systolic blood pressure ≥160 or diastolic blood pressure ≥100 mmHg. The primary outcome was a composite endpoint of myocardial infarction, stroke, venous thromboembolism, new-onset atrial fibrillation, or acute kidney injury. At least one acute hypertensive episode occurred in 42.6% (69/162) of patients. A total of 10.5% patients developed the composite endpoint, 17.4% in the acute hypertensive episode group compared to 5.4% in the non-hypertensive group, p = 0.012. Patients in the acute hypertensive group were more likely to require an intensive care unit admission compared to the non-hypertensive group (33.3 versus 14.0%, p = 0.004). Of the 17 patients who developed an acute hypertensive episode and met the primary endpoint, 10 were on home antihypertensive medications. Of those, four were restarted on all medications initially, three on some, two were started on new medications, and one was not resumed on home medications. Development of acute hypertensive episode(s) in older trauma patients was associated with an increase in the composite endpoint. Prospective studies are needed.

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

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

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

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 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.

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.

Meeting Report: Measuring Endocrine-Sensitive Endpoints within the First Years of Life

PubMed Central

Arbuckle, Tye E.; Hauser, Russ; Swan, Shanna H.; Mao, Catherine S.; Longnecker, Matthew P.; Main, Katharina M.; Whyatt, Robin M.; Mendola, Pauline; Legrand, Melissa; Rovet, Joanne; Till, Christine; Wade, Mike; Jarrell, John; Matthews, Stephen; Van Vliet, Guy; Bornehag, Carl-Gustaf; Mieusset, Roger

2008-01-01

An international workshop titled “Assessing Endocrine-Related Endpoints within the First Years of Life” was held 30 April–1 May 2007, in Ottawa, Ontario, Canada. Representatives from a number of pregnancy cohort studies in North America and Europe presented options for measuring various endocrine-sensitive endpoints in early life and discussed issues related to performing and using those measures. The workshop focused on measuring reproductive tract developmental endpoints [e.g., anogenital distance (AGD)], endocrine status, and infant anthropometry. To the extent possible, workshop participants strove to develop or recommend standardized measurements that would allow comparisons and pooling of data across studies. The recommended outcomes include thigh fat fold, breast size, vaginal cytology, AGD, location of the testis, testicular size, and growth of the penis, with most of the discussion focusing on the genital exam. Although a number of outcome measures recommended during the genital exam have been associated with exposure to endocrine-disrupting chemicals, little is known about how predictive these effects are of later reproductive health or other chronic health conditions. PMID:18629319

[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.

Improved Endpoints for Cancer Immunotherapy Trials

PubMed Central

Eggermont, Alexander M. M.; Janetzki, Sylvia; Hodi, F. Stephen; Ibrahim, Ramy; Anderson, Aparna; Humphrey, Rachel; Blumenstein, Brent; Wolchok, Jedd

2010-01-01

Unlike chemotherapy, which acts directly on the tumor, cancer immunotherapies exert their effects on the immune system and demonstrate new kinetics that involve building a cellular immune response, followed by changes in tumor burden or patient survival. Thus, adequate design and evaluation of some immunotherapy clinical trials require a new development paradigm that includes reconsideration of established endpoints. Between 2004 and 2009, several initiatives facilitated by the Cancer Immunotherapy Consortium of the Cancer Research Institute and partner organizations systematically evaluated an immunotherapy-focused clinical development paradigm and created the principles for redefining trial endpoints. On this basis, a body of clinical and laboratory data was generated that supports three novel endpoint recommendations. First, cellular immune response assays generate highly variable results. Assay harmonization in multicenter trials may minimize variability and help to establish cellular immune response as a reproducible biomarker, thus allowing investigation of its relationship with clinical outcomes. Second, immunotherapy may induce novel patterns of antitumor response not captured by Response Evaluation Criteria in Solid Tumors or World Health Organization criteria. New immune-related response criteria were defined to more comprehensively capture all response patterns. Third, delayed separation of Kaplan–Meier curves in randomized immunotherapy trials can affect results. Altered statistical models describing hazard ratios as a function of time and recognizing differences before and after separation of curves may allow improved planning of phase III trials. These recommendations may improve our tools for cancer immunotherapy trials and may offer a more realistic and useful model for clinical investigation. PMID:20826737

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

Power Calculations to Select Instruments for Clinical Trial Secondary Endpoints. A Case Study of Instrument Selection for Post-Traumatic Stress Symptoms in Subjects with Acute Respiratory Distress Syndrome.

PubMed

Sjoding, Michael W; Schoenfeld, David A; Brown, Samuel M; Hough, Catherine L; Yealy, Donald M; Moss, Marc; Angus, Derek C; Iwashyna, Theodore J

2017-01-01

After the sample size of a randomized clinical trial (RCT) is set by the power requirement of its primary endpoint, investigators select secondary endpoints while unable to further adjust sample size. How the sensitivity and specificity of an instrument used to measure these outcomes, together with their expected underlying event rates, affect an RCT's power to measure significant differences in these outcomes is poorly understood. Motivated by the design of an RCT of neuromuscular blockade in acute respiratory distress syndrome, we examined how power to detect a difference in secondary endpoints varies with the sensitivity and specificity of the instrument used to measure such outcomes. We derived a general formula and Stata code for calculating an RCT's power to detect differences in binary outcomes when such outcomes are measured with imperfect sensitivity and specificity. The formula informed the choice of instrument for measuring post-traumatic stress-like symptoms in the Reevaluation of Systemic Early Neuromuscular Blockade RCT ( www.clinicaltrials.gov identifier NCT02509078). On the basis of published sensitivities and specificities, the Impact of Events Scale-Revised was predicted to measure a 36% symptom rate, whereas the Post-Traumatic Stress Symptoms instrument was predicted to measure a 23% rate, if the true underlying rate of post-traumatic stress symptoms were 25%. Despite its lower sensitivity, the briefer Post-Traumatic Stress Symptoms instrument provided superior power to detect a difference in rates between trial arms, owing to its higher specificity. Examining instruments' power to detect differences in outcomes may guide their selection when multiple instruments exist, each with different sensitivities and specificities.

Predictors of mental health-related acute service utilisation and treatment costs in the 12 months following an acute psychiatric admission.

PubMed

Siskind, Dan; Harris, Meredith; Diminic, Sandra; Carstensen, Georgia; Robinson, Gail; Whiteford, Harvey

2014-11-01

A key step in informing mental health resource allocation is to identify the predictors of service utilisation and costs. This project aims to identify the predictors of mental health-related acute service utilisation and treatment costs in the year following an acute public psychiatric hospital admission. A dataset containing administrative and routinely measured outcome data for 1 year before and after an acute psychiatric admission for 1757 public mental health patients was analysed. Multivariate regression models were developed to identify patient- and treatment-related predictors of four measures of service utilisation or cost: (a) duration of index admission; and, in the year after discharge from the index admission (b) acute psychiatric inpatient bed-days; (c) emergency department (ED) presentations; and (d) total acute mental health service costs. Split-sample cross-validation was used. A diagnosis of psychosis, problems with living conditions and prior acute psychiatric inpatient bed-days predicted a longer duration of index admission, while prior ED presentations and self-harm predicted a shorter duration. A greater number of acute psychiatric inpatient bed-days in the year post-discharge were predicted by psychosis diagnosis, problems with living conditions and prior acute psychiatric inpatient admissions. The number of future ED presentations was predicted by past ED presentations. For total acute care costs, diagnosis of psychosis was the strongest predictor. Illness acuity and prior acute psychiatric inpatient admission also predicted higher costs, while self-harm predicted lower costs. The development of effective models for predicting acute mental health treatment costs using existing administrative data is an essential step towards a workable activity-based funding model for mental health. Future studies would benefit from the inclusion of a wider range of variables, including ethnicity, clinical complexity, cognition, mental health legal status

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

Validated surrogate endpoints needed for peri-implantitis.

PubMed

Lee, Dong Won

2011-01-01

Pubmed, Cochrane and Lilac databases, Google, Google Scholar, hand searching of websites of major dental journals. The reference list of five recently published systematic reviews on peri-implantitis treatment were also screened for potential studies. Randomised controlled trials and non-randomised studies in English, German, French, Spanish and Italian on peri-implantitis treatment in humans were included. Case series, case reports and cross sectional or non-therapy studies were excluded from the assessment of endpoints. No minimum follow up time was set for studies that were included. Data were extracted in duplicate by two reviewers and disagreements were resolved by consensus. True endpoints for peri-implantitis treatment were considered only if they provided evidence of tangible benefit to the patient. The outcome variables regarded as true endpoints were implant failure, aesthetic assessment and variables related to quality of life, but these were only considered if they were clearly identified as an objective of the research, not as an outcome of treatment. Surrogate endpoints were considered as those measurements of clinical outcomes such as probing pocket depth and clinical attachment level. Fourteen studies were included in this review with data on implant failure presented solely as consequence of peri-implantitis therapy. No true endpoint was described for any study on peri-implantitis. Mean pocket probing depth, clinical attachment level and bleeding on probing were the three surrogate endpoints cited most often in the literature. All endpoints used in the trials reviewed are surrogates of clinical events, such as implant failure. Clinical surrogate endpoints should be validated to assess the real effect of these measures on true endpoints.

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

Successful Repeat Catheter Ablation of Recurrent Longstanding Persistent Atrial Fibrillation With Rotor Elimination as the Procedural Endpoint: A Case Series.

PubMed

Sommer, Philipp; Kircher, Simon; Rolf, Sascha; John, Silke; Arya, Arash; Dinov, Borislav; Richter, Sergio; Bollmann, Andreas; Hindricks, Gerhard

2016-03-01

There remains a lack of consensus regarding the ideal ablation strategy for atrial fibrillation (AF), particularly in patients with persistent or longstanding persistent AF. Given increasing evidence from clinical imaging studies that rotors sustain AF, rotor elimination may be a desirable procedural endpoint. However, there is no description to date of the clinical outcomes using rotor elimination during ablation as the procedural endpoint. Moreover, a series of studies question whether procedural AF termination is a desirable endpoint for ablation after many forms of AF ablation. We report a single-center experience of rotor elimination during AF ablation using Focal Impulse and Rotor Mapping (FIRM), describing 20 consecutive patients with case descriptions of 3 patients with recurrent longstanding persistent AF after prior ablation. In all cases, endocardial mapping using a 64-electrode basket catheter was performed to identify rotors, which were eliminated using radiofrequency catheter ablation. After it was verified that all identified rotors were eliminated, standard ablation consisting of PV isolation was performed. Notably, persistent AF terminated in only 1/20 (5%) patients. However, after a follow-up of 6 months, single-procedure freedom from AF was 80% (16/20 patients) with only 1 patient on antiarrhythmic drugs. All three patients in the highlighted series are AF free despite the lack of acute procedural AF termination. Patients with persistent AF including those with unsuccessful prior ablation can be treated successfully by rotor targeted ablation, using the elimination of all rotors rather than acute AF termination as the procedural endpoint. © 2015 Wiley Periodicals, Inc.

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...

Power Calculations to Select Instruments for Clinical Trial Secondary Endpoints. A Case Study of Instrument Selection for Post-Traumatic Stress Symptoms in Subjects with Acute Respiratory Distress Syndrome

PubMed Central

Schoenfeld, David A.; Brown, Samuel M.; Hough, Catherine L.; Yealy, Donald M.; Moss, Marc; Angus, Derek C.; Iwashyna, Theodore J.

2017-01-01

Rationale: After the sample size of a randomized clinical trial (RCT) is set by the power requirement of its primary endpoint, investigators select secondary endpoints while unable to further adjust sample size. How the sensitivity and specificity of an instrument used to measure these outcomes, together with their expected underlying event rates, affect an RCT’s power to measure significant differences in these outcomes is poorly understood. Objectives: Motivated by the design of an RCT of neuromuscular blockade in acute respiratory distress syndrome, we examined how power to detect a difference in secondary endpoints varies with the sensitivity and specificity of the instrument used to measure such outcomes. Methods: We derived a general formula and Stata code for calculating an RCT’s power to detect differences in binary outcomes when such outcomes are measured with imperfect sensitivity and specificity. The formula informed the choice of instrument for measuring post-traumatic stress–like symptoms in the Reevaluation of Systemic Early Neuromuscular Blockade RCT (www.clinicaltrials.gov identifier NCT02509078). Measurements and Main Results: On the basis of published sensitivities and specificities, the Impact of Events Scale-Revised was predicted to measure a 36% symptom rate, whereas the Post-Traumatic Stress Symptoms instrument was predicted to measure a 23% rate, if the true underlying rate of post-traumatic stress symptoms were 25%. Despite its lower sensitivity, the briefer Post-Traumatic Stress Symptoms instrument provided superior power to detect a difference in rates between trial arms, owing to its higher specificity. Conclusions: Examining instruments’ power to detect differences in outcomes may guide their selection when multiple instruments exist, each with different sensitivities and specificities. PMID:27788018

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.

Changing the endpoints for determining effective obesity management.

PubMed

Ross, Robert; Blair, Steve; de Lannoy, Louise; Després, Jean-Pierre; Lavie, Carl J

2015-01-01

Health authorities worldwide recommend weight loss as a primary endpoint for effective obesity management. Despite a growing public awareness of the importance of weight loss and the spending of billions of dollars by Americans in attempts to lose weight, obesity prevalence continues to rise. In this report we argue that effective obesity management in today's environment will require a shift in focus from weight loss as the primary endpoint, to improvements in the causal behaviors; diet and exercise/physical activity (PA). We reason that increases in PA combined with a balanced diet are associated with improvement in many of the intermediate risk factors including cardiorespiratory fitness (CRF) associated with obesity despite minimal or no weight loss. Consistent with this notion, we suggest that a focus on healthy behaviors for the prevention of additional weight gain may be an effective way of managing obesity in the short term. Copyright © 2014 Elsevier Inc. All rights reserved.

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...

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

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

Use of nutrigenomics endpoints in dietary interventions.

PubMed

Hendriks, Henk F J

2013-08-01

In this paper, the nutrigenomics approach is discussed as a research tool to study the physiological effects of nutrition and consequently how nutrition affects health and disease (endpoints). Nutrigenomics is the study of the effects of foods and food constituents on gene expression; the analyses include analysis of mRNA, proteins and metabolites. Nutrigenomics may be useful in dealing with the challenges that nutrition research is facing; by integrating the description of numerous active genes and metabolic pathways stronger evidence and new biomarkers for subtle nutritional effects may be obtained. Also, a new definition of disease and health may be needed. The use of tests challenging homoeostasis is being proposed to help define health. Challenge tests may be able to demonstrate in a better way subtle beneficial effects of nutrition on health. The paper describes some basic concepts relevant to nutrition research as well as some of the possibilities that are offered by nutrigenomics technology. Some of its applications are described.

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.

Endpoint Model of Exclusive Processes

NASA Astrophysics Data System (ADS)

Dagaonkar, Sumeet; Jain, Pankaj; Ralston, John P.

2018-07-01

The endpoint model explains the scaling laws observed in exclusive hadronic reactions at large momentum transfer in all experimentally important regimes. The model, originally conceived by Feynman and others, assumes a single valence quark carries most of the hadron momentum. The quark wave function is directly related to the momentum transfer dependence of the reaction. After extracting the momentum dependence of the quark wave function from one process, it explains all the others. Endpoint quark-counting rules relate the number of quarks in a hadron to the power-law. A universal linear endpoint behavior explains the proton electromagnetic form factors F1 and F2, proton-proton scattering at fixed-angle, the t-dependence of proton-proton scattering at large s>> t, and Compton scattering at fixed t. The model appears to be the only comprehensive mechanism consistent with all experimental information.

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.

Old model organisms and new behavioral end-points: Swimming alteration as an ecotoxicological response.

PubMed

Faimali, Marco; Gambardella, Chiara; Costa, Elisa; Piazza, Veronica; Morgana, Silvia; Estévez-Calvar, Noelia; Garaventa, Francesca

2017-07-01

Behavioral responses of aquatic organisms have received much less attention than developmental or reproductive ones due to the scarce presence of user-friendly tools for their acquisition. The technological development of data acquisition systems for quantifying behavior in the aquatic environment and the increase of studies on the understanding the relationship between the behavior of aquatic organisms and the physiological/ecological activities have generated renewed interest in using behavioral responses also in marine ecotoxicology. Recent reviews on freshwater environment show that behavioral end-points are comparatively fast and sensitive, and warrant further attention as tools for assessing the toxicological effects of environmental contaminants. In this mini-review, we perform a systematic analysis of the most recent works that have used marine invertebrate swimming alteration as behavioral end-point in ecotoxicological studies by assessing the differences between behavioral and acute responses in a wide range of species, in order to compare their sensitivity. Copyright © 2016. Published by Elsevier Ltd.

Acute Health Impact of Air Pollution in China

NASA Astrophysics Data System (ADS)

Feng, T.; Zhao, Y.; Zheng, M.

2014-12-01

Air pollution not only has long term health impact, but can affect health through acute exposure. This paper, using air pollution index (API) as overall evaluation of air quality, blood pressure and vital capacity as health outcomes, focuses on the acute health impact of air pollution in China. Current result suggests that after controlling smoking history, occupational exposure, income and education, API is positively associated with blood pressure and negatively associated with vital capacity. The associations became stronger for people with hypertension or pulmonary functional diseases, which indicates that these people are more sensitive to air pollution. Among three pollutants which API measures, that is inhalable particles (PM10), sulfur dioxide (SO2) and nitrogen dioxide (NO2), PM10 is most statistically associated with blood pressure increase and vital capacity decrease. Further study will focusing on the following two questions. The first question is how various time lags affect the associations among API, blood pressure and vital capacity. The second question is how differently people in various cohorts reacts to acute exposure to air pollution. The differences in reactions of blood pressure and vital capacity between people in urban and rural areas, genders, various age cohorts, distinct income and education groups will be further studied.

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.

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.

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.

SOLITAIRE™ with the intention for thrombectomy (SWIFT) trial: design of a randomized, controlled, multicenter study comparing the SOLITAIRE™ Flow Restoration device and the MERCI Retriever in acute ischaemic stroke.

PubMed

Saver, J L; Jahan, R; Levy, E I; Jovin, T G; Baxter, B; Nogueira, R; Clark, W; Budzik, R; Zaidat, O O

2014-07-01

Self-expanding stent retrievers are a promising new device class designed for rapid flow restoration in acute cerebral ischaemia. The SOLITAIRE™ Flow Restoration device (SOLITAIRE) has shown high rates of recanalization in preclinical models and in uncontrolled clinical series. (1) To demonstrate non-inferiority of SOLITAIRE compared with a legally marketed device, the MERCI Retrieval System®; (2) To demonstrate safety, feasibility, and efficacy of SOLITAIRE in subjects requiring mechanical thrombectomy diagnosed with acute ischaemic stroke. DESIGN : Multicenter, randomized, prospective, controlled trial with blinded primary end-point ascertainment. Key entry criteria include: age 22-85; National Institute of Health Stroke Scale (NIHSS) ≥8 and <30; clinical and imaging findings consistent with acute ischaemic stroke; patient ineligible or failed intravenous tissue plasminogen activator; accessible occlusion in M1 or M2 middle cerebral artery, internal carotid artery, basilar artery, or vertebral artery; and patient able to be treated within 8 h of onset. Sites first participate in a roll-in phase, treating two patients with the SOLITAIRE device, before proceeding to the randomized phase. In patients unresponsive to the initially assigned therapy, after the angiographic component of the primary end-point is ascertained (reperfusion with the initial assigned device), rescue therapy with other reperfusion techniques is permitted. The primary efficacy end-point is successful recanalization with the assigned study device (no use of rescue therapy) and with no symptomatic intracranial haemorrhage. Successful recanalization is defined as achieving Thrombolysis In Myocardial Ischemia 2 or 3 flow in all treatable vessels. The primary safety end-point is the incidence of device-related and procedure-related serious adverse events. A major secondary efficacy end-point is time to achieve initial recanalization. Additional secondary end-points include clinical outcomes

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

Ecosystem services as assessment endpoints for ecological risk assessment.

PubMed

Munns, Wayne R; Rea, Anne W; Suter, Glenn W; Martin, Lawrence; Blake-Hedges, Lynne; Crk, Tanja; Davis, Christine; Ferreira, Gina; Jordan, Steve; Mahoney, Michele; Barron, Mace G

2016-07-01

Ecosystem services are defined as the outputs of ecological processes that contribute to human welfare or have the potential to do so in the future. Those outputs include food and drinking water, clean air and water, and pollinated crops. The need to protect the services provided by natural systems has been recognized previously, but ecosystem services have not been formally incorporated into ecological risk assessment practice in a general way in the United States. Endpoints used conventionally in ecological risk assessment, derived directly from the state of the ecosystem (e.g., biophysical structure and processes), and endpoints based on ecosystem services serve different purposes. Conventional endpoints are ecologically important and susceptible entities and attributes that are protected under US laws and regulations. Ecosystem service endpoints are a conceptual and analytical step beyond conventional endpoints and are intended to complement conventional endpoints by linking and extending endpoints to goods and services with more obvious benefit to humans. Conventional endpoints can be related to ecosystem services even when the latter are not considered explicitly during problem formulation. To advance the use of ecosystem service endpoints in ecological risk assessment, the US Environmental Protection Agency's Risk Assessment Forum has added generic endpoints based on ecosystem services (ES-GEAE) to the original 2003 set of generic ecological assessment endpoints (GEAEs). Like conventional GEAEs, ES-GEAEs are defined by an entity and an attribute. Also like conventional GEAEs, ES-GEAEs are broadly described and will need to be made specific when applied to individual assessments. Adoption of ecosystem services as a type of assessment endpoint is intended to improve the value of risk assessment to environmental decision making, linking ecological risk to human well-being, and providing an improved means of communicating those risks. Integr Environ Assess Manag

Acute pulmonary and innate immunity health effects in mice inhaling cookstove emissions

EPA Science Inventory

Background: Burning of solid-fuels in rudimentary stoves generates harmful emissions that contribute to poor indoor air quality and have detrimental impacts on human health. Acute health effects include respiratory and eye irritation, cough, acute lower respiratory infection and ...

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...

Closeness, chaos and crisis: the attractions of working in acute mental health care.

PubMed

Deacon, M; Warne, T; McAndrew, S

2006-12-01

This paper makes a case for the attractiveness of acute mental health inpatient nursing (acute nursing) and argues that an altered perception of this work is essential if we are to provide the most acutely mentally ill and vulnerable people with a stable and expert nursing workforce. The discussion draws on an ethnographic study conducted in an inner-city psychiatric unit in England and the advantages of this method for understanding nursing work are described. Within our findings, we set out two overarching themes: the contextual realities of the contemporary acute ward and features of attraction that encourage nurses to work in the acute care setting. The former includes nurses' responsibility for the total ward environment and the latter the 'comfort of closeness' and 'surviving and thriving in chaos and crisis'. In conclusion, we argue that despite the unpopularity of the acute inpatient mental health environment, the highly sophisticated skills employed by acute nurses actually ensure the promotion of health for the majority of service users.

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

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

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.

Choice of saccade endpoint under risk

PubMed Central

Ackermann, John F.; Landy, Michael S.

2013-01-01

Eye movements function to bring detailed information onto the high-resolution region of the retina. Previous research has shown that human observers select fixation points that maximize information acquisition and minimize target location uncertainty. In this study, we ask whether human observers choose the saccade endpoint that maximizes gain when there are explicit rewards associated with correctly detecting the target. Observers performed an 8-alternative forced-choice detection task for a contrast-defined target in noise. After a single saccade, observers indicated the target location. Each potential target location had an associated reward that was known to the observer. In some conditions, the reward at one location was higher than at the other locations. We compared human saccade endpoints to those of an ideal observer that maximizes expected gain given the respective human observer's visibility map, i.e., d′ for target detection as a function of retinal location. Varying the location of the highest reward had a significant effect on human observers' distribution of saccade endpoints. Both human and ideal observers show a high density of saccades made toward the highest rewarded and actual target locations. But humans' overall spatial distributions of saccade endpoints differed significantly from the ideal observer as they made a greater number of saccade to locations far from the highest rewarded and actual target locations. Suboptimal choice of saccade endpoint, possibly in combination with suboptimal integration of information across saccades, had a significant effect on human observers' ability to correctly detect the target and maximize gain. PMID:24023277

Evaluating Candidate Principal Surrogate Endpoints

PubMed Central

Gilbert, Peter B.; Hudgens, Michael G.

2009-01-01

Summary Frangakis and Rubin (2002, Biometrics 58, 21–29) proposed a new definition of a surrogate endpoint (a “principal” surrogate) based on causal effects. We introduce an estimand for evaluating a principal surrogate, the causal effect predictiveness (CEP) surface, which quantifies how well causal treatment effects on the biomarker predict causal treatment effects on the clinical endpoint. Although the CEP surface is not identifiable due to missing potential outcomes, it can be identified by incorporating a baseline covariate(s) that predicts the biomarker. Given case–cohort sampling of such a baseline predictor and the biomarker in a large blinded randomized clinical trial, we develop an estimated likelihood method for estimating the CEP surface. This estimation assesses the “surrogate value” of the biomarker for reliably predicting clinical treatment effects for the same or similar setting as the trial. A CEP surface plot provides a way to compare the surrogate value of multiple biomarkers. The approach is illustrated by the problem of assessing an immune response to a vaccine as a surrogate endpoint for infection. PMID:18363776

Endpoint titration and immunotherapy.

PubMed

King, H C

1985-11-01

Inhalant allergy, or "atopy" as it is now termed, is the best understood form of allergy today. In some circles, it is the only recognized form of allergy. While an overall picture of its effects on the body and a reasonable approach to its treatment now exist, many problems remain to be solved and much improvement in its treatment will probably occur within the next several years. Many new approaches to treatment of aeroallergens are now available; however, all are compared with the skin test, which is and has been the baseline for testing and treatment. Endpoint titration provides a quantitative means for undertaking treatment of aeroallergen sensitivity. In no other way does it differ from the forms of skin testing that have been widely used for generations. The practitioners of endpoint titration feel that this difference is highly significant in simplifying, validating, and shortening the necessary period of therapy. While the concept of endpoint titration is not difficult, it is by definition a quantitative form of testing and requires a degree of expertise in performing it correctly. While a good understanding of the method may be gained from the literature, adequate hands-on experience should be obtained by any physician prior to instituting the technique as a treatment modality. Once mastered, it becomes a reliable baseline for all forms of inhalant allergy care.

Responsiveness of efficacy endpoints in clinical trials with over the counter analgesics for headache.

PubMed

Aicher, Bernhard; Peil, Hubertus; Peil, Barbara; Diener, Hans-Christoph

2012-10-01

calculations confirmed an adequate responsiveness for all continuous endpoints. The following cut-off points for differentiating between satisfied and non-satisfied patients were deduced from the data in the pre- and treatment phase, respectively: 'time to 50% pain relief' 1:10 and 1:31 h:min, 'time until reduction of pain intensity to 10 mm' 2:40 and 3:00 h:min, '%SPIDweighted' 68 and 64%, 'PID at 2 hours' 35 and 35 mm. The sensitivity and specificity based on these cut-off points ranged from 70 to 79%. The binary endpoint 'pain-free at 2 hours' showed a clearly higher specificity (80 and 87%) than sensitivity (65 and 61%) in the pre- and treatment phase, respectively. When global assessment of efficacy by the patient was used as external criterion, ROC curve calculations confirmed a high responsiveness for all efficacy endpoints included in this study. Clinically relevant differences between patients satisfied and non-satisfied with the treatment were observed. The endpoint '%SPIDweighted' proved slightly but consistently superior to the other endpoints. SPID and %SPIDweighted are not easy to interpret and the time course of pain reduction is of high importance for the patients in the treatment of acute pain, including headache. The endpoint 'pain-free at 2 hours' showed the expected high specificity, but at the cost of a concurrently low sensitivity and clearly makes less use of the available information than the endpoint 'time to 50% pain reduction', which combines the highly relevant aspects of time course and extent of pain reduction. Responsiveness, the ability of an outcome measure to detect clinically important changes in a specific condition of a patient, should be added in future revisions of IHS guidelines for clinical trials in headache disorders.

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.

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.

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.

Safety and Efficacy Endpoints for Mesenchymal Stromal Cell Therapy in Renal Transplant Recipients.

PubMed

Bank, J R; Rabelink, T J; de Fijter, J W; Reinders, M E J

2015-01-01

Despite excellent short-term graft survival after renal transplantation, the long-term graft outcome remains compromised. It has become evident that a combination of sustained alloreactivity and calcineurin-inhibitor- (CNI-) related nephrotoxicity results in fibrosis and consequently dysfunction of the graft. New immunosuppressive regimens that can minimize or eliminate side effects, while maintaining efficacy, are required to improve long-term graft survival. In this perspective mesenchymal stromal cells (MSCs) are an interesting candidate, since MSCs have immunosuppressive and regenerative properties. The first clinical trials with MSCs in renal transplantation showed safety and feasibility and displayed promising results. Recently, the first phase II studies have been started. One of the most difficult and challenging aspects in those early phase trials is to define accurate endpoints that can measure safety and efficacy of MSC treatment. Since both graft losses and acute rejection rates declined, alternative surrogate markers such as renal function, histological findings, and immunological markers are used to measure efficacy and to provide mechanistic insight. In this review, we will discuss the current status of MSCs in renal transplantation with a focus on the endpoints used in the different experimental and clinical studies.

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.

Investigating the efficacy of a whole team, psychologically informed, acute mental health service approach.

PubMed

Araci, David; Clarke, Isabel

2017-08-01

Service user demand and service changes, from hospital based, to community and hospital mix, within acute adult mental health services, focus the need for psychologically informed, holistic, approaches. (1) Describe and report feasibility of a psychologically led Intensive Support Programme (ISP) to meet this need. (2) Present results of a pilot evaluation of this programme. ISP was implemented in four acute mental health services of the Southern Health NHS Trust, available to both inpatient and outpatient acute services. Evaluation of the service one month after data collection, illustrates operation and level of uptake across different professional roles. The programme was evaluated by assessing psychological distress (CORE-10) and confidence in self-management (Mental Health Confidence Scale) of participating service users before and after intervention. The service evaluation demonstrated extensive roll out of this programme across acute services of an extensive NHS Trust. Repeated measure t-tests demonstrated significant decrease in distress (p < 0.0005) and significant increase in confidence in self-management of mental health (p < 0.0005). Evaluation shows that ISP can be delivered in routine care in an acute mental health service and results in improvement in self management skills and facilitation of recovery.

Acute maternal social dysfunction, health perception and psychological distress after ultrasonographic detection of a fetal structural anomaly.

PubMed

Kaasen, A; Helbig, A; Malt, U F; Naes, T; Skari, H; Haugen, G

2010-08-01

To predict acute psychological distress in pregnant women following detection of a fetal structural anomaly by ultrasonography, and to relate these findings to a comparison group. A prospective, observational study. Tertiary referral centre for fetal medicine. One hundred and eighty pregnant women with a fetal structural anomaly detected by ultrasound (study group) and 111 with normal ultrasound findings (comparison group) were included within a week following sonographic examination after gestational age 12 weeks (inclusion period: May 2006 to February 2009). Social dysfunction and health perception were assessed by the corresponding subscales of the General Health Questionnaire (GHQ-28). Psychological distress was assessed using the Impact of Events Scale (IES-22), Edinburgh Postnatal Depression Scale (EPDS) and the anxiety and depression subscales of the GHQ-28. Fetal anomalies were classified according to severity and diagnostic or prognostic ambiguity at the time of assessment. Social dysfunction, health perception and psychological distress (intrusion, avoidance, arousal, anxiety, depression). The least severe anomalies with no diagnostic or prognostic ambiguity induced the lowest levels of IES intrusive distress (P = 0.025). Women included after 22 weeks of gestation (24%) reported significantly higher GHQ distress than women included earlier in pregnancy (P = 0.003). The study group had significantly higher levels of psychosocial distress than the comparison group on all psychometric endpoints. Psychological distress was predicted by gestational age at the time of assessment, severity of the fetal anomaly, and ambiguity concerning diagnosis or prognosis.

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

Self-Reported Acute Health Effects and Exposure to Companion Animals.

PubMed

Krueger, W S; Hilborn, E D; Dufour, A P; Sams, E A; Wade, T J

2016-06-01

To understand the etiological burden of disease associated with acute health symptoms [e.g. gastrointestinal (GI), respiratory, dermatological], it is important to understand how common exposures influence these symptoms. Exposures to familiar and unfamiliar animals can result in a variety of health symptoms related to infection, irritation and allergy; however, few studies have examined this association in a large-scale cohort setting. Cross-sectional data collected from 50 507 participants in the United States enrolled from 2003 to 2009 were used to examine associations between animal contact and acute health symptoms during a 10-12 day period. Fixed-effects multivariable logistic regression estimated adjusted odds ratios (AORs) and 95% confident intervals (CI) for associations between animal exposures and outcomes of GI illness, respiratory illness and skin/eye symptoms. Two-thirds of the study population (63.2%) reported direct contact with animals, of which 7.7% had contact with at least one unfamiliar animal. Participants exposed to unfamiliar animals had significantly higher odds of self-reporting all three acute health symptoms, when compared to non-animal-exposed participants (GI: AOR = 1.4, CI = 1.2-1.7; respiratory: AOR = 1.5, CI = 1.2-1.8; and skin/eye: AOR = 1.9, CI = 1.6-2.3), as well as when compared to participants who only had contact with familiar animals. Specific contact with dogs, cats or pet birds was also significantly associated with at least one acute health symptom; AORs ranged from 1.1 to 1.5, when compared to participants not exposed to each animal. These results indicate that contact with animals, especially unfamiliar animals, was significantly associated with GI, respiratory and skin/eye symptoms. Such associations could be attributable to zoonotic infections and allergic reactions. Etiological models for acute health symptoms should consider contact with companion animals, particularly exposure to unfamiliar animals

Optimizing Outcome Assessment in Multicenter TBI Trials: Perspectives From TRACK-TBI and the TBI Endpoints Development Initiative.

PubMed

Bodien, Yelena G; McCrea, Michael; Dikmen, Sureyya; Temkin, Nancy; Boase, Kim; Machamer, Joan; Taylor, Sabrina R; Sherer, Mark; Levin, Harvey; Kramer, Joel H; Corrigan, John D; McAllister, Thomas W; Whyte, John; Manley, Geoffrey T; Giacino, Joseph T

Traumatic brain injury (TBI) is a global public health problem that affects the long-term cognitive, physical, and psychological health of patients, while also having a major impact on family and caregivers. In stark contrast to the effective trials that have been conducted in other neurological diseases, nearly 30 studies of interventions employed during acute hospital care for TBI have failed to identify treatments that improve outcome. Many factors may confound the ability to detect true and meaningful treatment effects. One promising area for improving the precision of intervention studies is to optimize the validity of the outcome assessment battery by using well-designed tools and data collection strategies to reduce variability in the outcome data. The Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study, conducted at 18 sites across the United States, implemented a multidimensional outcome assessment battery with 22 measures aimed at characterizing TBI outcome up to 1 year postinjury. In parallel, through the TBI Endpoints Development (TED) Initiative, federal agencies and investigators have partnered to identify the most valid, reliable, and sensitive outcome assessments for TBI. Here, we present lessons learned from the TRACK-TBI and TED initiatives aimed at optimizing the validity of outcome assessment in TBI.

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

77 FR 46444 - Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics (GREAT); Public Workshop

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-03

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-N-0001] Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics (GREAT); Public Workshop AGENCY: Food and Drug Administration, HHS. ACTION: Notice of public workshop. SUMMARY: The Food and Drug Administration...

Health Care Seeking Behavior of Persons with Acute Chagas Disease in Rural Argentina: A Qualitative View.

PubMed

Llovet, Ignacio; Dinardi, Graciela; Canevari, Cecilia; Torabi, Nahal

2016-01-01

Chagas disease (CD) is a tropical parasitic disease largely underdiagnosed and mostly asymptomatic affecting marginalized rural populations. Argentina regularly reports acute cases of CD, mostly young individuals under 14 years old. There is a void of knowledge of health care seeking behavior in subjects experiencing a CD acute condition. Early treatment of the acute case is crucial to limit subsequent development of disease. The article explores how the health outcome of persons with acute CD may be conditioned by their health care seeking behavior. The study, with a qualitative approach, was carried out in rural areas of Santiago del Estero Province, a high risk endemic region for vector transmission of CD. Narratives of 25 in-depth interviews carried out in 2005 and 2006 are analyzed identifying patterns of health care seeking behavior followed by acute cases. Through the retrospective recall of paths for diagnoses, weaknesses of disease information, knowledge at the household level, and underperformance at the provincial health care system level are detected. The misdiagnoses were a major factor in delaying a health care response. The study results expose lost opportunities for the health care system to effectively record CD acute cases.

Health Care Seeking Behavior of Persons with Acute Chagas Disease in Rural Argentina: A Qualitative View

PubMed Central

Dinardi, Graciela; Canevari, Cecilia; Torabi, Nahal

2016-01-01

Chagas disease (CD) is a tropical parasitic disease largely underdiagnosed and mostly asymptomatic affecting marginalized rural populations. Argentina regularly reports acute cases of CD, mostly young individuals under 14 years old. There is a void of knowledge of health care seeking behavior in subjects experiencing a CD acute condition. Early treatment of the acute case is crucial to limit subsequent development of disease. The article explores how the health outcome of persons with acute CD may be conditioned by their health care seeking behavior. The study, with a qualitative approach, was carried out in rural areas of Santiago del Estero Province, a high risk endemic region for vector transmission of CD. Narratives of 25 in-depth interviews carried out in 2005 and 2006 are analyzed identifying patterns of health care seeking behavior followed by acute cases. Through the retrospective recall of paths for diagnoses, weaknesses of disease information, knowledge at the household level, and underperformance at the provincial health care system level are detected. The misdiagnoses were a major factor in delaying a health care response. The study results expose lost opportunities for the health care system to effectively record CD acute cases. PMID:27829843

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

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

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.

Aldosterone, mortality, and acute ischaemic events in coronary artery disease patients outside the setting of acute myocardial infarction or heart failure.

PubMed

Ivanes, Fabrice; Susen, Sophie; Mouquet, Frédéric; Pigny, Pascal; Cuilleret, François; Sautière, Karine; Collet, Jean-Philippe; Beygui, Farzin; Hennache, Bernadette; Ennezat, Pierre Vladimir; Juthier, Françis; Richard, Florence; Dallongeville, Jean; Hillaert, Marieke A; Doevendans, Pieter A; Jude, Brigitte; Bertrand, Michel; Montalescot, Gilles; Van Belle, Eric

2012-01-01

Recent studies have demonstrated that aldosterone levels measured in patients with heart failure or acute myocardial infarction (MI) are associated with long-term mortality, but the association with aldosterone levels in patients with coronary artery disease (CAD) outside these specific settings remains unknown. In addition, no clear mechanism has been elucidated to explain these observations. The present study was designed to evaluate the relationship between the level of aldosterone and the risk of death and acute ischaemic events in CAD patients with a preserved left ventricular (LV) function and no acute MI. In 799 consecutive CAD patients referred for elective coronary angioplasty measurements were obtained before the procedure for: aldosterone (median = 25 pg/mL), brain natriuretic peptide (BNP) (median = 35 pg/mL), hsC-reactive protein (median = 4.17 mg/L), and left ventricular ejection fraction (mean = 58%). Patients with acute MI or coronary syndrome (ACS) who required urgent revascularization were not included in the study. The primary endpoint, cardiovascular death, occurred in 41 patients during a median follow-up period of 14.9 months. Secondary endpoints-total mortality, acute ischaemic events (acute MI or ischaemic stroke), and the composite of death and acute ischaemic events-were observed in 52, 54, and 94 patients, respectively. Plasma aldosterone was found to be related to BMI, hypertension and NYHA class, and inversely related to age, creatinine clearance, and use of beta-blockers. Multivariate Cox model analysis demonstrated that aldosterone was independently associated with cardiovascular mortality (P = 0.001), total mortality (P = 0.001), acute ischaemic events (P = 0.01), and the composite of death and acute ischaemic events (P = 0.004). Reclassification analysis, using integrated discrimination improvement (IDI) and net reclassification improvement (NRI), demonstrated incremental predictive value of aldosterone (P < 0.0001). Our results

Zebrafish (Danio rerio) Models To Assess Acute, Developmental, And Neurodevelopmental Toxicity

EPA Science Inventory

Zebrafish (Danio rerio) acute, developmental, and neurodevelopmental model systems have been developed to assess both known and unknown environmental contaminants. Developmental toxicity is assessed using death and dysmorphology as endpoints, whereas neurodevelopmental toxicity ...

Self-reported acute health symptoms and exposure to companion animals#

EPA Science Inventory

Self-reported acute health symptoms and exposure to companion animalsWhitney S. Krueger1,2, Elizabeth D. Hilborn2, Timothy J. Wade21Oak Ridge Institute for Science and Education, Oak Ridge, Tennessee, USA2Environmental Public Health Division, Office of Research and Development, U...

Catastrophic health expenditure on acute coronary events in Asia: a prospective study.

PubMed

Jan, Stephen; Lee, Stephen W-L; Sawhney, Jitendra P S; Ong, Tiong K; Chin, Chee Tang; Kim, Hyo-Soo; Krittayaphong, Rungroj; Nhan, Vo T; Itoh, Yohji; Huo, Yong

2016-03-01

To estimate out-of-pocket costs and the incidence of catastrophic health expenditure in people admitted to hospital with acute coronary syndromes in Asia. Participants were enrolled between June 2011 and May 2012 into this observational study in China, India, Malaysia, Republic of Korea, Singapore, Thailand and Viet Nam. Sites were required to enrol a minimum of 10 consecutive participants who had been hospitalized for an acute coronary syndrome. Catastrophic health expenditure was defined as out-of-pocket costs of initial hospitalization > 30% of annual baseline household income, and it was assessed six weeks after discharge. We assessed associations between health expenditure and age, sex, diagnosis of the index coronary event and health insurance status of the participant, using logistic regression models. Of 12,922 participants, 9370 (73%) had complete data on expenditure. The mean out-of-pocket cost was 3237 United States dollars. Catastrophic health expenditure was reported by 66% (1984/3007) of those without insurance versus 52% (3296/6366) of those with health insurance (P < 0.05). The occurrence of catastrophic expenditure ranged from 80% (1055/1327) in uninsured and 56% (3212/5692) of insured participants in China, to 0% (0/41) in Malaysia. Large variation exists across Asia in catastrophic health expenditure resulting from hospitalization for acute coronary syndromes. While insurance offers some protection, substantial numbers of people with health insurance still incur financial catastrophe.

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...

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.

The utility of outpatient commitment: acute medical care access and protecting health.

PubMed

Segal, Steven P; Hayes, Stephania L; Rimes, Lachlan

2018-06-01

This study considers whether, in an easy access single-payer health care system, patients placed on outpatient commitment-community treatment orders (CTOs) in Victoria Australia-are more likely to access acute medical care addressing physical illness than voluntary patients with and without severe mental illness. For years 2000 to 2010, the study compared acute medical care access of 27,585  severely mentally ill psychiatrically hospitalized patients (11,424 with and 16,161 without CTO exposure) and 12,229 never psychiatrically hospitalized outpatients (individuals with less morbidity risk as they were not considered to have severe mental illness). Logistic regression was used to determine the influence of the CTO on the likelihood of receiving a diagnosis of physical illness requiring acute care. Validating their shared and elevated morbidity risk, 53% of each hospitalized cohort accessed acute care compared to 32% of outpatients during the decade. While not under mental health system supervision, however, the likelihood that a CTO patient would receive a physical illness diagnosis was 31% lower than for non-CTO patients, and no different from lower morbidity-risk outpatients without severe mental illness. While, under mental health system supervision, the likelihood that CTO patients would receive a physical illness diagnosis was 40% greater than non-CTO patients and 5.02 times more likely than outpatients were. Each CTO episode was associated with a 4.6% increase in the likelihood of a member of the CTO group receiving a diagnosis. Mental health system involvement and CTO supervision appeared to facilitate access to physical health care in acute care settings for patients with severe mental illness, a group that has, in the past, been subject to excess morbidity and mortality.

Transitioning from acute to primary health care nursing: an integrative review of the literature.

PubMed

Ashley, Christine; Halcomb, Elizabeth; Brown, Angela

2016-08-01

This paper seeks to explore the transition experiences of acute care nurses entering employment in primary health care settings. Internationally the provision of care in primary health care settings is increasing. Nurses are moving from acute care settings to meet the growing demand for a primary health care workforce. While there is significant research relating to new graduate transition experiences, little is known about the transition experience from acute care into primary health care employment. An integrative review, guided by Whittemore and Knafl's (2005) approach, was undertaken. Following a systematic literature search eight studies met the inclusion criteria. Papers which met the study criteria were identified and assessed against the inclusion and exclusion criteria. Papers were then subjected to methodological quality appraisal. Thematic analysis was undertaken to identify key themes within the data. Eight papers met the selection criteria. All described nurses transitioning to either community or home nursing settings. Three themes were identified: (1) a conceptual understanding of transition, (2) role losses and gains and (3) barriers and enablers. There is a lack of research specifically exploring the transitioning of acute care nurses to primary health care settings. To better understand this process, and to support the growth of the primary health care workforce there is an urgent need for further well-designed research. There is an increasing demand for the employment of nurses in primary health care settings. To recruit experienced nurses it is logical that many nurses will transition into primary health care from employment in the acute sector. To optimise retention and enhance the transition experience of these nurses it is important to understand the transition experience. © 2016 John Wiley & Sons Ltd.

Key stakeholder perceptions regarding acute care psychiatry in distressed publicly funded mental health care markets.

PubMed

Frueh, B Christopher; Grubaugh, Anouk L; Lo Sasso, Anthony T; Jones, Walter J; Oldham, John M; Lindrooth, Richard C

2012-01-01

The role of acute care inpatient psychiatry, public and private, has changed dramatically since the 1960s, especially as recent market forces affecting the private sector have had ripple effects on publicly funded mental health care. Key stakeholders' experiences, perceptions, and opinions regarding the role of acute care psychiatry in distressed markets of publicly funded mental health care were examined. A qualitative research study was conducted using semi-structured thematic interviews with 52 senior mental health system administrators, clinical directors and managers, and nonclinical policy specialists. Participants were selected from markets in six regions of the United States that experienced recent significant closures of acute care psychiatric beds. Qualitative data analyses yielded findings that clustered around three sets of higher order themes: structure of care, service delivery barriers, and outcomes. Structure of care suggests that acute care psychiatry is seen as part of a continuum of services; service delivery barriers inhibit effective delivery of services and are perceived to include economic, regulatory, and political factors; outcomes include fragmentation of mental health care services across the continuum, the shift of mental health care to the criminal justice system, and market-specific issues affecting mental health care. Findings delineate key stakeholders' perceptions regarding the role acute care psychiatry plays in the continuum of care for publicly funded mental health and suggest that public mental health care is inefficacious. Results carry implications for policy makers regarding strategies/policies to improve optimal utilization of scarce resources for mental health care, including greater focus on psychotherapy.

Key stakeholder perceptions regarding acute care psychiatry in distressed publicly funded mental health care markets

PubMed Central

Frueh, B. Christopher; Grubaugh, Anouk L.; Lo Sasso, Anthony T.; Jones, Walter J.; Oldham, John M.; Lindrooth, Richard C.

2017-01-01

The role of acute care inpatient psychiatry, public and private, has changed dramatically since the 1960s, especially as recent market forces affecting the private sector have had ripple effects on publicly funded mental health care. Key stakeholders’ experiences, perceptions, and opinions regarding the role of acute care psychiatry in distressed markets of publicly funded mental health care were examined. A qualitative research study was conducted using semi-structured thematic interviews with 52 senior mental health system administrators, clinical directors and managers, and nonclinical policy specialists. Participants were selected from markets in six regions of the United States that experienced recent significant closures of acute care psychiatric beds. Qualitative data analyses yielded findings that clustered around three sets of higher order themes: structure of care, service delivery barriers, and outcomes. Structure of care suggests that acute care psychiatry is seen as part of a continuum of services; service delivery barriers inhibit effective delivery of services and are perceived to include economic, regulatory, and political factors; outcomes include fragmentation of mental health care services across the continuum, the shift of mental health care to the criminal justice system, and market-specific issues affecting mental health care. Findings delineate key stakeholders’ perceptions regarding the role acute care psychiatry plays in the continuum of care for publicly funded mental health and suggest that public mental health care is inefficacious. Results carry implications for policy makers regarding strategies/policies to improve optimal utilization of scarce resources for mental health care, including greater focus on psychotherapy. PMID:22409204

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.

A probabilistic assessment of health risks associated with short-term exposure to tropospheric ozone

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

Whitfield, R.G; Biller, W.F.; Jusko, M.J.

1996-06-01

The work described in this report is part of a larger risk assessment sponsored by the U.S. Environmental Protection Agency. Earlier efforts developed exposure-response relationships for acute health effects among populations engaged in heavy exertion. Those efforts also developed a probabilistic national ambient air quality standards exposure model and a general methodology for integrating probabilistic exposure-response relation- ships and exposure estimates to calculate overall risk results. Recently published data make it possible to model additional health endpoints (for exposure at moderate exertion), including hospital admissions. New air quality and exposure estimates for alternative national ambient air quality standards for ozonemore » are combined with exposure-response models to produce the risk results for hospital admissions and acute health effects. Sample results explain the methodology and introduce risk output formats.« less

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.

Prognostic implications of epicardial fat volume quantification in acute pericarditis.

PubMed

Lazaros, George; Antonopoulos, Alexios S; Oikonomou, Evangelos K; Vasileiou, Panagiotis; Oikonomou, Evangelos; Stroumpouli, Evangelia; Karavidas, Apostolos; Antoniades, Charalambos; Tousoulis, Dimitris

2017-02-01

The pathophysiology of acute pericarditis remains largely unknown, and biomarkers are needed to identify patients susceptible to complications. As adipose tissue has a pivotal role in cardiovascular disease pathogenesis, we hypothesized that quantification of epicardial fat volume (EFV) provides prognostic information in patients with acute pericarditis. Fifty (n = 50) patients with first diagnosis of acute pericarditis were enrolled in this study. Patients underwent a cardiac computerized tomography (CT) scan to quantify EFV on a dedicated workstation. Patients were followed up in hospital for atrial fibrillation (AF) development and up to 18 months for the composite clinical endpoint of development of constrictive, recurrent or incessant pericarditis or poor response to nonsteroidal anti-inflammatory drugs. Patients presenting with chest pain had lower EFV vs. patients without chest pain (167·2 ± 21·7 vs. 105·1 ± 11·1 cm 3 , respectively, P < 0·01); EFV (but not body mass index) was strongly positively correlated with pericardial effusion size (r = 0·395, P = 0·007) and associated with in-hospital AF. At follow-up, patients that reached the composite clinical endpoint had lower EFV (P < 0·05). After adjustment for age, EFV was associated with lower odds ratio for the composite clinical endpoint point of poor response to NSAIDs or the development of constrictive, recurrent or incessant pericarditis during follow-up (per 20 cm 3 increase in EFV: OR = 0·802 [0·656-0·981], P < 0·05). We report for the first time a significant association of EFV with the clinical features and the outcome of patients with acute pericarditis. Measurement of EFV by CT may have important prognostic implications in these patients. © 2016 Stichting European Society for Clinical Investigation Journal Foundation.

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

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.

Catastrophic health expenditure on acute coronary events in Asia: a prospective study

PubMed Central

Lee, Stephen W-L; Sawhney, Jitendra PS; Ong, Tiong K; Chin, Chee Tang; Kim, Hyo-Soo; Krittayaphong, Rungroj; Nhan, Vo T; Itoh, Yohji; Huo, Yong

2016-01-01

Abstract Objective To estimate out-of-pocket costs and the incidence of catastrophic health expenditure in people admitted to hospital with acute coronary syndromes in Asia. Methods Participants were enrolled between June 2011 and May 2012 into this observational study in China, India, Malaysia, Republic of Korea, Singapore, Thailand and Viet Nam. Sites were required to enrol a minimum of 10 consecutive participants who had been hospitalized for an acute coronary syndrome. Catastrophic health expenditure was defined as out-of-pocket costs of initial hospitalization > 30% of annual baseline household income, and it was assessed six weeks after discharge. We assessed associations between health expenditure and age, sex, diagnosis of the index coronary event and health insurance status of the participant, using logistic regression models. Findings Of 12 922 participants, 9370 (73%) had complete data on expenditure. The mean out-of-pocket cost was 3237 United States dollars. Catastrophic health expenditure was reported by 66% (1984/3007) of those without insurance versus 52% (3296/6366) of those with health insurance (P < 0.05). The occurrence of catastrophic expenditure ranged from 80% (1055/1327) in uninsured and 56% (3212/5692) of insured participants in China, to 0% (0/41) in Malaysia. Conclusion Large variation exists across Asia in catastrophic health expenditure resulting from hospitalization for acute coronary syndromes. While insurance offers some protection, substantial numbers of people with health insurance still incur financial catastrophe. PMID:26966330

Blood and Marrow Transplant Clinical Trials Network Report on the Development of Novel Endpoints and Selection of Promising Approaches for Graft-versus-Host Disease Prevention Trials.

PubMed

Pasquini, Marcelo C; Logan, Brent; Jones, Richard J; Alousi, Amin M; Appelbaum, Frederick R; Bolaños-Meade, Javier; Flowers, Mary E D; Giralt, Sergio; Horowitz, Mary M; Jacobsohn, David; Koreth, John; Levine, John E; Luznik, Leo; Maziarz, Richard; Mendizabal, Adam; Pavletic, Steven; Perales, Miguel-Angel; Porter, David; Reshef, Ran; Weisdorf, Daniel; Antin, Joseph H

2018-06-01

Graft-versus-host disease (GVHD) is a common complication after hematopoietic cell transplantation (HCT) and associated with significant morbidity and mortality. Preventing GVHD without chronic therapy or increasing relapse is a desired goal. Here we report a benchmark analysis to evaluate the performance of 6 GVHD prevention strategies tested at single institutions compared with a large multicenter outcomes database as a control. Each intervention was compared with the control for the incidence of acute and chronic GVHD and overall survival and against novel composite endpoints: acute and chronic GVHD, relapse-free survival (GRFS), and chronic GVHD, relapse-free survival (CRFS). Modeling GRFS and CRFS using the benchmark analysis further informed the design of 2 clinical trials testing GVHD prophylaxis interventions. This study demonstrates the potential benefit of using an outcomes database to select promising interventions for multicenter clinical trials and proposes novel composite endpoints for use in GVHD prevention trials. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

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.

Public Health Response Systems In-Action: Learning from Local Health Departments’ Experiences with Acute and Emergency Incidents

PubMed Central

Hunter, Jennifer C.; Yang, Jane E.; Crawley, Adam W.; Biesiadecki, Laura; Aragón, Tomás J.

2013-01-01

As part of their core mission, public health agencies attend to a wide range of disease and health threats, including those that require routine, acute, and emergency responses. While each incident is unique, the number and type of response activities are finite; therefore, through comparative analysis, we can learn about commonalities in the response patterns that could improve predictions and expectations regarding the resources and capabilities required to respond to future acute events. In this study, we interviewed representatives from more than 120 local health departments regarding their recent experiences with real-world acute public health incidents, such as infectious disease outbreaks, severe weather events, chemical spills, and bioterrorism threats. We collected highly structured data on key aspects of the incident and the public health response, particularly focusing on the public health activities initiated and community partners engaged in the response efforts. As a result, we are able to make comparisons across event types, create response profiles, and identify functional and structural response patterns that have import for future public health preparedness and response. Our study contributes to clarifying the complexity of public health response systems and our analysis reveals the ways in which these systems are adaptive to the character of the threat, resulting in differential activation of functions and partners based on the type of incident. Continued and rigorous examination of the experiences of health departments throughout the nation will refine our very understanding of what the public health response system is, will enable the identification of organizational and event inputs to performance, and will allow for the construction of rich, relevant, and practical models of response operations that can be employed to strengthen public health systems. PMID:24236137

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

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.

Surrogate Endpoints in Suicide Research

ERIC Educational Resources Information Center

Wortzel, Hal S.; Gutierrez, Peter M.; Homaifar, Beeta Y.; Breshears, Ryan E.; Harwood, Jeri E.

2010-01-01

Surrogate endpoints frequently substitute for rare outcomes in research. The ability to learn about completed suicides by investigating more readily available and proximate outcomes, such as suicide attempts, has obvious appeal. However, concerns with surrogates from the statistical science perspective exist, and mounting evidence from…

Recurrent acute otitis media detracts from health-related quality of life.

PubMed

Kujala, T; Alho, O-P; Kristo, A; Uhari, M; Renko, M; Pokka, T; Koivunen, P

2017-02-01

Acute otitis media causes discomfort to children and inconvenience to their parents. This study evaluated the quality of life in children with recurrent acute otitis media aged less than 24 months. Quality of life was evaluated in 149 children aged 10 to 24 months who were referred to the Oulu University Hospital on account of recurrent acute otitis media. The children were treated with or without surgery. Age-matched controls were selected randomly from the general child population. Parents completed the Child Health Questionnaire. The children with recurrent acute otitis media had a significantly poorer quality of life than control children. The control children with a history of a few acute otitis media episodes had a significantly poorer quality of life than those without any such history. The quality of life of the children with recurrent acute otitis media improved during the one-year follow up, regardless of the treatment, but did not reach the same level as healthy children. Acute otitis media detracted from quality of life when a generic measure was used. The mode of treatment used to prevent further recurrences of acute otitis media did not influence quality of life improvement.

Perioperative antibiotic prophylaxis in the treatment of acute cholecystitis (PEANUTS II trial): study protocol for a randomized controlled trial.

PubMed

Loozen, Charlotte S; van Santvoort, Hjalmar C; van Geloven, Antoinette A W; Nieuwenhuijzen, Grard A P; de Reuver, Philip R; Besselink, Mark H G; Vlaminckx, Bart; Kelder, Johannes C; Knibbe, Catherijne A J; Boerma, Djamila

2017-08-23

The additional value of perioperative antibiotic prophylaxis in preventing infectious complications after emergency cholecystectomy for acute cholecystitis is a much-debated subject in the surgical community. Evidence-based guidelines are lacking, and consequently the use of antibiotic prophylaxis varies greatly among surgeons and hospitals. Recently, high-level evidence became available demonstrating that postoperative antibiotic prophylaxis in patients with acute cholecystitis does not reduce the risk of infectious complications. Preoperative antibiotic prophylaxis in relation to the risk of infectious complications, however, has never been studied. The PEANUTS II trial is a randomized, controlled, multicenter, open-label noninferiority trial whose aim is to determine the utility of preoperative antibiotic prophylaxis in patients undergoing emergency cholecystectomy for acute calculous cholecystitis. Patients with mild or moderate acute cholecystitis, as defined according the Tokyo Guidelines, will be randomly assigned to a single preoperative dose of antibiotic prophylaxis (2000 mg of first-generation cephalosporin delivered intravenously) or no antibiotic prophylaxis before emergency cholecystectomy. The primary endpoint is a composite endpoint consisting of all postoperative infectious complications occurring during the first 30 days after surgery. Secondary endpoints include all the individual components of the primary endpoint, all other complications, duration of hospital stay, and total costs. The hypothesis is that the absence of antibiotic prophylaxis is noninferior to the presence of antibiotic prophylaxis. A noninferiority margin of 10% is assumed. With a 1-sided risk of 2.5% and a power of 80%, a total of 454 subjects will have to be included. Analysis will be performed according to the intention-to-treat principle. The PEANUTS II trial will provide evidence-based advice concerning the utility of antibiotic prophylaxis in patients undergoing

Design Considerations for Post-Acute Care mHealth: Patient Perspectives.

PubMed

Sanger, Patrick; Hartzler, Andrea; Lober, William B; Evans, Heather L; Pratt, Wanda

2014-01-01

Many current mobile health applications ("apps") and most previous research have been directed at management of chronic illnesses. However, little is known about patient preferences and design considerations for apps intended to help in a post-acute setting. Our team is developing an mHealth platform to engage patients in wound tracking to identify and manage surgical site infections (SSI) after hospital discharge. Post-discharge SSIs are a major source of morbidity and expense, and occur at a critical care transition when patients are physically and emotionally stressed. Through interviews with surgical patients who experienced SSI, we derived design considerations for such a post-acute care app. Key design qualities include: meeting basic accessibility, usability and security needs; encouraging patient-centeredness; facilitating better, more predictable communication; and supporting personalized management by providers. We illustrate our application of these guiding design considerations and propose a new framework for mHealth design based on illness duration and intensity.

Building on a national health information technology strategic plan for long-term and post-acute care: comments by the Long Term Post Acute Care Health Information Technology Collaborative.

PubMed

Alexander, Gregory L; Alwan, Majd; Batshon, Lynne; Bloom, Shawn M; Brennan, Richard D; Derr, John F; Dougherty, Michelle; Gruhn, Peter; Kirby, Annessa; Manard, Barbara; Raiford, Robin; Serio, Ingrid Johnson

2011-07-01

The LTPAC (Long Term Post Acute Care) Health Information Technology (HIT) Collaborative consists of an alliance of long-term services and post-acute care stakeholders. Members of the collaborative are actively promoting HIT innovations in long-term care settings because IT adoption for health care institutions in the United States has become a high priority. One method used to actively promote HIT is providing expert comments on important documents addressing HIT adoption. Recently, the Office of the National Coordinator for HIT released a draft of the Federal Health Information Technology Strategic Plan 2011-2015 for public comment. The following brief is intended to inform about recommendations and comments made by the Collaborative on the strategic plan. Copyright 2011, SLACK Incorporated.

Effects of short- and long-term exposures to copper on lethal and reproductive endpoints of the harpacticoid copepod Tigriopus fulvus.

PubMed

Biandolino, Francesca; Parlapiano, Isabella; Faraponova, Olga; Prato, Ermelinda

2018-01-01

The long-term exposure provides a realistic measurement of the effects of toxicants on aquatic organisms. The harpacticoid copepod Tigriopus fulvus has a wide geographical distribution and is considered as an ideal model organism for ecotoxicological studies for its good sensitivity to different toxicants. In this study, acute, sub-chronic and chronic toxicity tests based on lethal and reproductive responses of Tigriopus fulvus to copper were performed. The number of moults during larval development was chosen as an endpoint for sub-chronic test. Sex ratio, inhibitory effect on larval development, hatching time, fecundity, brood number, nauplii/brood, total newborn production, etc, were calculated in the chronic test (28d). Lethal effect of copper to nauplii showed the LC50-48h of 310 ± 72µgCu/L (mean ± sd). It was observed a significant inhibition of larval development at sublethal copper concentrations, after 4 and 7 d. After 4d, the EC50 value obtained for the endpoint in "moult naupliar reduction" was of 55.8 ± 2.5µgCu/L (mean ± sd). The EC50 for the inhibition of naupliar development into copepodite stage, was of 21.7 ± 4.4µgCu/L (mean ± sd), after 7 days. Among the different traits tested, copper did not affect sex ratio and growth, while fecundity and total nauplii production were the most sensitive endpoints. The reproductive endpoints offer the advantage of being detectable at very low pollutant concentrations. Copyright © 2017 Elsevier Inc. All rights reserved.

Quantitative Structure--Activity Relationship Modeling of Rat Acute Toxicity by Oral Exposure

EPA Science Inventory

Background: Few Quantitative Structure-Activity Relationship (QSAR) studies have successfully modeled large, diverse rodent toxicity endpoints. Objective: In this study, a combinatorial QSAR approach has been employed for the creation of robust and predictive models of acute toxi...

[The endpoint detection of cough signal in continuous speech].

PubMed

Yang, Guoqing; Mo, Hongqiang; Li, Wen; Lian, Lianfang; Zheng, Zeguang

2010-06-01

The endpoint detection of cough signal in continuous speech has been researched in order to improve the efficiency and veracity of manual recognition or computer-based automatic recognition. First, using the short time zero crossing ratio(ZCR) for identifying the suspicious coughs and getting the threshold of short time energy based on acoustic characteristics of cough. Then, the short time energy is combined with short time ZCR in order to implement the endpoint detection of cough in continuous speech. To evaluate the effect of the method, first, the virtual number of coughs in each recording was identified by two experienced doctors using the graphical user interface (GUI). Second, the recordings were analyzed by automatic endpoint detection program under Matlab7.0. Finally, the comparison between these two results showed: The error rate of undetected cough is 2.18%, and 98.13% of noise, silence and speech were removed. The way of setting short time energy threshold is robust. The endpoint detection program can remove most speech and noise, thus maintaining a lower rate of error.

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

Association Between Acute Medical Exacerbations and Consuming or Producing Web-Based Health Information: Analysis From Pew Survey Data.

PubMed

Gidwani, Risha; Zulman, Donna

2015-06-23

The Internet is an increasingly important resource for individuals who seek information from both health professionals and peers. While the demographic and health characteristics of persons who use health information technology has been well described, less is known about the relationship between these health characteristics and level of engagement with health information technology. Even less is known about whether persons who produce Web-based health information differ in health status from persons who consume such content. We explored the health characteristics of persons who engage with the Internet for the purposes of consuming or producing Web-based health information, and specifically, whether healthier versus sicker persons engage with health information technology in different ways. We analyzed data from the 2012 Pew Health survey, a landline and cell phone survey of 3104 adults in the United States. Using multiple logistic regression with sampling weights, we examined the association between sociodemographic and health characteristics and the consumption or production of Web-based health information. Sociodemographic variables included age, sex, race, and education. Health characteristics included self-reported health status, presence of chronic condition(s), and having an acute medical exacerbation. Acute medical exacerbations were defined as an emergency department visit, hospitalization, or other serious medical emergency in the last 12 months. The majority of the sample reported good or excellent health (79.7%), although 50.3% reported having at least one chronic condition. About a fifth (20.2%) of the sample experienced an acute medical exacerbation in the past year. Education was the sociodemographic characteristic most strongly associated with consuming Web-based health information. The strongest health-related predictors of consuming Web-based health information were an acute medical exacerbation (OR 2.39, P<.001) and having a chronic condition

Acute cholecystitis in high risk surgical patients: percutaneous cholecystostomy versus laparoscopic cholecystectomy (CHOCOLATE trial): Study protocol for a randomized controlled trial

PubMed Central

2012-01-01

Background Laparoscopic cholecystectomy in acute calculous cholecystitis in high risk patients can lead to significant morbidity and mortality. Percutaneous cholecystostomy may be an alternative treatment option but the current literature does not provide the surgical community with evidence based advice. Methods/Design The CHOCOLATE trial is a randomised controlled, parallel-group, superiority multicenter trial. High risk patients, defined as APACHE-II score 7-14, with acute calculous cholecystitis will be randomised to laparoscopic cholecystectomy or percutaneous cholecystostomy. During a two year period 284 patients will be enrolled from 30 high volume teaching hospitals. The primary endpoint is a composite endpoint of major complications within three months following randomization and need for re-intervention and mortality during the follow-up period of one year. Secondary endpoints include all other complications, duration of hospital admission, difficulty of procedures and total costs. Discussion The CHOCOLATE trial is designed to provide the surgical community with an evidence based guideline in the treatment of acute calculous cholecystitis in high risk patients. Trial Registration Netherlands Trial Register (NTR): NTR2666 PMID:22236534

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

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

The acute gastrointestinal subsyndrome of the acute radiation syndrome: a rhesus macaque model.

PubMed

MacVittie, Thomas J; Farese, Ann M; Bennett, Alexander; Gelfond, Daniel; Shea-Donohue, Terez; Tudor, Gregory; Booth, Catherine; McFarland, Emylee; Jackson, William

2012-10-01

The development of medical countermeasures against the acute gastrointestinal subsyndrome of the acute radiation syndrome in humans requires well characterized and validated animal models. These models must adhere to the criteria of the U.S. Food and Drug Administration's Animal Rule and consider the natural history and clinical context of the human radiation response and treatment in the nuclear terrorist scenario. The models must define the radiation dose- and time-dependent relationships for mortality and major signs of morbidity, including concurrent damage in other organs, such as the bone marrow, that may contribute to the overall mortality and morbidity. There are no such models of the gastrointestinal syndrome in response to total-body irradiation in the nonhuman primate. Herein, these parameters are defined for the rhesus macaque exposed to potentially lethal doses of radiation and administered medical management. Rhesus macaques (n = 69) were exposed bilaterally to 6 MV linear accelerator-derived photon total body irradiation to midline tissue (thorax) doses ranging from 10.0 to 14.0 Gy at 0.80 Gy min(-1). Following irradiation, all animals were administered supportive care consisting of fluids, anti-emetics, anti-diarrheal medication, antibiotics, blood transfusions, analgesics, and nutrition. The primary endpoint was survival at 15 d post-irradiation. Secondary endpoints included indices of dehydration, diarrhea, weight loss, hematological parameters, cellular histology of the small and large intestine, and mean survival time of decedents. Mortality within the 15-d in vivo study defined the acute gastrointestinal syndrome and provided an LD30/15 of 10.76 Gy, LD50/15 of 11.33 Gy, and an LD70/15 of 11.90 Gy. Intestinal crypt and villus loss were dose- and time-dependent with an apparent nadir 7 d post-irradiation and recovery noted thereafter. Severe myelosuppression and thrombocytopenia were noted in all animals, requiring the administration of

Worrying About Terrorism and Other Acute Environmental Health Hazard Events

PubMed Central

Babcock-Dunning, Lauren

2012-01-01

Objectives. To better understand why some people worry more about terrorism compared with others, we measured how much US residents worried about a terrorist event in their area and examined the association of their fears with their concerns about acute and chronic hazards and other correlates. Methods. In 2008 (n = 600) and 2010 (n = 651), we performed a random-digit dialing national landline telephone survey. We asked about worries about terrorism and 5 other environmental health hazard issues. We also collected demographic and socioeconomic data. Results. Only 15% worried “a great deal” about a terrorist event in their area and 18% to 33% were greatly concerned about other environmental issues. Fear about acute hazard events was a stronger predictor of a great deal of concern about terrorism than were age, race/ethnicity, gender, educational achievement, and other correlates. Conclusions. Those who worried most about acute environmental health hazard events were most likely to worry about terrorism. Also, those who were older, poorer, Blacks, or Latinos, or who lived in populous urban areas felt they were most vulnerable to terrorist attacks. We recommend methods to involve US citizens as part of disaster planning. PMID:22397346

Worrying about terrorism and other acute environmental health hazard events.

PubMed

Greenberg, Michael; Babcock-Dunning, Lauren

2012-04-01

To better understand why some people worry more about terrorism compared with others, we measured how much US residents worried about a terrorist event in their area and examined the association of their fears with their concerns about acute and chronic hazards and other correlates. In 2008 (n = 600) and 2010 (n = 651), we performed a random-digit dialing national landline telephone survey. We asked about worries about terrorism and 5 other environmental health hazard issues. We also collected demographic and socioeconomic data. Only 15% worried "a great deal" about a terrorist event in their area and 18% to 33% were greatly concerned about other environmental issues. Fear about acute hazard events was a stronger predictor of a great deal of concern about terrorism than were age, race/ethnicity, gender, educational achievement, and other correlates. Those who worried most about acute environmental health hazard events were most likely to worry about terrorism. Also, those who were older, poorer, Blacks, or Latinos, or who lived in populous urban areas felt they were most vulnerable to terrorist attacks. We recommend methods to involve US citizens as part of disaster planning.

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

Nutrient reference value: non-communicable disease endpoints--a conference report.

PubMed

Lupton, J R; Blumberg, J B; L'Abbe, M; LeDoux, M; Rice, H B; von Schacky, C; Yaktine, A; Griffiths, J C

2016-03-01

scientific evidence does exist to confirm a relationship between the intake of a specific bioactive constituent and enhanced health conditions or reduced risk of a chronic disease. Further, research on the putative mechanisms of action of various classes of bioactives is supported by national and pan-national government agencies, and academic institutions, as well as functional food and dietary supplement manufacturers. Consumers are becoming educated and are seeking to purchase products containing bioactives, yet there is no evaluative process in place to let the public know how strong the science is behind the benefits or the quantitative amounts needed to achieve these beneficial health effects or to avoid exceeding the upper level (UL). When one lacks an essential nutrient, overt deficiency with concomitant physiological determents and eventually death are expected. The absence of bioactive substances from the diet results in suboptimal health, e.g., poor cellular and/or physiological function, which is relative and not absolute. Regrettably at this time, there is no DRI process to evaluate bioactives, although a recent workshop convened by the National Institutes of Health (Options for Consideration of Chronic Disease Endpoints for Dietary Reference Intakes (DRIs); March 10-11, 2015; http://health.gov/dietaryguidelines/dri/ ) did explore the process to develop DVs for nutrients, the lack of which result in increased risk of chronic disease (non-communicable disease) endpoints. A final report is expected soon. This conference (CRN-International Scientific Symposium; "Nutrient Reference Value-Non-Communicable Disease (NRV-NCD) Endpoints," 20 November in Kronberg, Germany; http://www.crn-i.ch/2015symposium/ ) explores concepts related to the Codex NRV process, the public health opportunities in setting NRVs for bioactive constituents, and further research and details on the specific class of bioactives, n-3 long-chain polyunsaturated fatty acids (also termed omega-3 fatty

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

Ethnographic research into nursing in acute adult mental health units: a review.

PubMed

Cleary, Michelle; Hunt, Glenn E; Horsfall, Jan; Deacon, Maureen

2011-01-01

Acute inpatient mental health units are busy and sometimes chaotic settings, with high bed occupancy rates. These settings include acutely unwell patients, busy staff, and a milieu characterised by unpredictable interactions and events. This paper is a report of a literature review conducted to identify, analyse, and synthesize ethnographic research in adult acute inpatient mental health units. Several electronic databases were searched using relevant keywords to identify studies published from 1990-present. Additional searches were conducted using reference lists. Ethnographic studies published in English were included if they investigated acute inpatient care in adult settings. Papers were excluded if the unit under study was not exclusively for patients in the acute phase of their mental illness, or where the original study was not fully ethnographic. Ten research studies meeting our criteria were found (21 papers). Findings were grouped into the following overarching categories: (1) Micro-skills; (2) Collectivity; (3) Pragmatism; and (4) Reframing of nursing activities. The results of this ethnographic review reveal the complexity, patient-orientation, and productivity of some nursing interventions that may not have been observed or understood without the use of this research method. Additional quality research should focus on redefining clinical priorities and philosophies to ensure everyday care is aligned constructively with the expectations of stakeholders and is consistent with policy and the realities of the organisational setting. We have more to learn from each other with regard to the effective nursing care of inpatients who are acutely disturbed.

Self-reported acute health symptoms and exposure to companion animals

EPA Science Inventory

Background: In order to understand the etiological burden of disease associated with acute health symptoms (e.g. gastrointestinal [GI], respiratory, dermatological), it is important to understand how common exposures influence these symptoms. Exposures to familiar and unfamiliar ...

Point-of-care C-reactive protein testing to reduce inappropriate use of antibiotics for non-severe acute respiratory infections in Vietnamese primary health care: a randomised controlled trial.

PubMed

Do, Nga T T; Ta, Ngan T D; Tran, Ninh T H; Than, Hung M; Vu, Bich T N; Hoang, Long B; van Doorn, H Rogier; Vu, Dung T V; Cals, Jochen W L; Chandna, Arjun; Lubell, Yoel; Nadjm, Behzad; Thwaites, Guy; Wolbers, Marcel; Nguyen, Kinh V; Wertheim, Heiman F L

2016-09-01

Inappropriate antibiotic use for acute respiratory tract infections is common in primary health care, but distinguishing serious from self-limiting infections is difficult, particularly in low-resource settings. We assessed whether C-reactive protein point-of-care testing can safely reduce antibiotic use in patients with non-severe acute respiratory tract infections in Vietnam. We did a multicentre open-label randomised controlled trial in ten primary health-care centres in northern Vietnam. Patients aged 1-65 years with at least one focal and one systemic symptom of acute respiratory tract infection were assigned 1:1 to receive either C-reactive protein point-of-care testing or routine care, following which antibiotic prescribing decisions were made. Patients with severe acute respiratory tract infection were excluded. Enrolled patients were reassessed on day 3, 4, or 5, and on day 14 a structured telephone interview was done blind to the intervention. Randomised assignments were concealed from prescribers and patients but not masked as the test result was used to assist treatment decisions. The primary outcome was antibiotic use within 14 days of follow-up. All analyses were prespecified in the protocol and the statistical analysis plan. All analyses were done on the intention-to-treat population and the analysis of the primary endpoint was repeated in the per-protocol population. This trial is registered under number NCT01918579. Between March 17, 2014, and July 3, 2015, 2037 patients (1028 children and 1009 adults) were enrolled and randomised. One adult patient withdrew immediately after randomisation. 1017 patients were assigned to receive C-reactive protein point-of-care testing, and 1019 patients were assigned to receive routine care. 115 patients in the C-reactive protein point-of-care group and 72 patients in the routine care group were excluded in the intention-to-treat analysis due to missing primary endpoint. The number of patients who used antibiotics

Reduction of animal suffering in rabies vaccine potency testing by introduction of humane endpoints.

PubMed

Takayama-Ito, Mutsuyo; Lim, Chang-Kweng; Nakamichi, Kazuo; Kakiuchi, Satsuki; Horiya, Madoka; Posadas-Herrera, Guillermo; Kurane, Ichiro; Saijo, Masayuki

2017-03-01

Potency controls of inactivated rabies vaccines for human use are confirmed by the National Institutes of Health challenge test in which lethal infection with severe neurological symptoms should be observed in approximately half of the mice inoculated with the rabies virus. Weight loss, decreased body temperature, and the presence of rabies-associated neurological signs have been proposed as humane endpoints. The potential for reduction of animal suffering by introducing humane endpoints in the potency test for inactivated rabies vaccine for human use was investigated. The clinical signs were scored and body weight was monitored. The average times to death following inoculation were 10.49 and 10.99 days post-inoculation (dpi) by the potency and challenge control tests, respectively, whereas the average times to showing Score-2 signs (paralysis, trembling, and coma) were 6.26 and 6.55 dpi, respectively. Body weight loss of more than 15% appeared at 5.82 and 6.42 dpi. The data provided here support the introduction of obvious neuronal signs combined with a body weight loss of ≥15% as a humane endpoint to reduce the time of animal suffering by approximately 4 days. Copyright © 2017 International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

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.

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.

A novel study design for antibiotic trials in acute exacerbations of COPD: MAESTRAL methodology

PubMed Central

Wilson, Robert; Anzueto, Antonio; Miravitlles, Marc; Arvis, Pierre; Faragó, Geneviève; Haverstock, Daniel; Trajanovic, Mila; Sethi, Sanjay

2011-01-01

Antibiotics, along with oral corticosteroids, are standard treatments for acute exacerbations of chronic obstructive pulmonary disease (AECOPD). The ultimate aims of treatment are to minimize the impact of the current exacerbation, and by ensuring complete resolution, reduce the risk of relapse. In the absence of superiority studies of antibiotics in AECOPD, evidence of the relative efficacy of different drugs is lacking, and so it is difficult for physicians to select the most effective antibiotic. This paper describes the protocol and rationale for MAESTRAL (moxifloxacin in AECBs [acute exacerbation of chronic bronchitis] trial; www.clinicaltrials.gov: NCT00656747), one of the first antibiotic comparator trials designed to show superiority of one antibiotic over another in AECOPD. It is a prospective, multinational, multicenter, randomized, double-blind controlled study of moxifloxacin (400 mg PO [ per os] once daily for 5 days) vs amoxicillin/clavulanic acid (875/125 mg PO twice daily for 7 days) in outpatients with COPD and chronic bronchitis suffering from an exacerbation. MAESTRAL uses an innovative primary endpoint of clinical failure: the requirement for additional or alternate treatment for the exacerbation at 8 weeks after the end of antibiotic therapy, powered for superiority. Patients enrolled are those at high-risk of treatment failure, and all are experiencing an Anthonisen type I exacerbation. Patients are stratified according to oral corticosteroid use to control their effect across antibiotic treatment arms. Secondary endpoints include quality of life, symptom assessments and health care resource use. PMID:21760724

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.

ERic Acute StrokE Recanalization: A study using predictive analytics to assess a new device for mechanical thrombectomy.

PubMed

Siemonsen, Susanne; Forkert, Nils D; Bernhardt, Martina; Thomalla, Götz; Bendszus, Martin; Fiehler, Jens

2017-08-01

Aim and hypothesis Using a new study design, we investigate whether next-generation mechanical thrombectomy devices improve clinical outcomes in ischemic stroke patients. We hypothesize that this new methodology is superior to intravenous tissue plasminogen activator therapy alone. Methods and design ERic Acute StrokE Recanalization is an investigator-initiated prospective single-arm, multicenter, controlled, open label study to compare the safety and effectiveness of a new recanalization device and distal access catheter in acute ischemic stroke patients with symptoms attributable to acute ischemic stroke and vessel occlusion of the internal cerebral artery or middle cerebral artery. Study outcome The primary effectiveness endpoint is the volume of saved tissue. Volume of saved tissue is defined as difference of the actual infarct volume and the brain volume that is predicted to develop infarction by using an optimized high-level machine learning model that is trained on data from a historical cohort treated with IV tissue plasminogen activator. Sample size estimates Based on own preliminary data, 45 patients fulfilling all inclusion criteria need to complete the study to show an efficacy >38% with a power of 80% and a one-sided alpha error risk of 0.05 (based on a one sample t-test). Discussion ERic Acute StrokE Recanalization is the first prospective study in interventional stroke therapy to use predictive analytics as primary and secondary endpoint. Such trial design cannot replace randomized controlled trials with clinical endpoints. However, ERic Acute StrokE Recanalization could serve as an exemplary trial design for evaluating nonpivotal neurovascular interventions.

Reproductive endpoints of Rhinella arenarum (Anura, Bufonidae): Populations that persist in agroecosystems and their use for the environmental health assessment.

PubMed

Babini, María Selene; de Lourdes Bionda, Clarisa; Salinas, Zulma Anahí; Salas, Nancy Edith; Martino, Adolfo Ludovico

2018-06-15

Degradation of the environment by agriculture affects the persistence and health of the amphibian populations. Characteristics related to reproduction of anuran can be used to evaluate the status of populations and as endpoints in environmental health assessment. In this in situ study the aspects related to the amplexus and ovipositions of the bioindicator species Rhinella arenarum that inhabits agroecosystems were analyzed. The hypothesis of this study is that perturbations of agroecosystems have a negative impact on the size of reproductive adults, on the size of ovipositions and eggs, and on the survival of eggs and embryos. Study area is located in the rural landscape of central Argentina. Four sampling sites were selected: C1, C2 and C3 are ponds on agroecosystems; and SM is a reference site that is not affected by agriculture or livestock. Abundance of amplexus pairs, oviposition and tadpoles per site was recorded. Individuals´ snout-vent length (SVL) in amplexus was measured. The fecundity was calculated like number of eggs per oviposition. The eggs' Gosner stage, the diameter eggs and the frequency of dead and abnormal eggs were recorded by oviposition. Killing-power between egg-embryo and egg-tadpole was calculated. The higher phosphate concentration was detected in all agroecosystems and nitrate was detected in C1 and C2. Conductivity, salinity and SDT were higher in C1 site Male SVL from the SM site was lower than the other sites while the largest SVL was of female from the C3 site. The higher frequencies of sprouted eggs and of dead eggs were recorded in the C2 site. Egg diameter was associated with SM and correlated negatively to SVL of the male and female. No correlation between female SVL and oviposition size was recorded. Killing-power in the passage from egg to tadpole classes was higher in the three agroecosystems. The hypothesis of this study was corroborated in part. Reproductive adults in agroecosystems did not have smaller body size. However

Comparing the acute sensitivity of growth and photosynthetic endpoints in three Lemna species exposed to four herbicides.

PubMed

Park, Jihae; Brown, Murray T; Depuydt, Stephen; Kim, Jang K; Won, Dam-Soo; Han, Taejun

2017-01-01

An ecological impact assessment of four herbicides (atrazine, diuron, paraquat and simazine) was assessed using the aquatic floating vascular plants, Lemna gibba, Lemna minor and Lemna paucicostata as test organisms. The sensitivity of several ecologically relevant parameters (increase in frond area, root length after regrowth, maximum and effective quantum yield of PSII and maximum electron transport rate (ETR max ), were compared after a 72 h exposure to herbicides. The present test methods require relatively small sample volume (3 mL), shorter exposure times (72 h), simple and quick analytical procedures as compared with standard Lemna assays. Sensitivity ranking of endpoints, based on EC 50 values, differed depending on the herbicide. The most toxic herbicides were diuron and paraquat and the most sensitive endpoints were root length (6.0-12.3 μg L -1 ) and ETR max (4.7-10.3 μg L -1 ) for paraquat and effective quantum yield (6.8-10.4 μg L -1 ) for diuron. Growth and chlorophyll a fluorescence parameters in all three Lemna species were sensitive enough to detect toxic levels of diuron and paraquat in water samples in excess of allowable concentrations set by international standards. CV values of all EC 50 s obtained from the Lemna tests were in the range of 2.8-24.33%, indicating a high level of repeatability comparable to the desirable level of <30% for adoption of toxicity test methods as international standards. Our new Lemna methods may provide useful information for the assessment of toxicity risk of residual herbicides in aquatic ecosystems. Copyright © 2016 Elsevier Ltd. All rights reserved.

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.

Predictive Modeling of Apical Toxicity Endpoints Using Data ...

EPA Pesticide Factsheets

The US EPA and other regulatory agencies face a daunting challenge of evaluating potential toxicity for tens of thousands of environmental chemicals about which little is currently known. The EPA’s ToxCast program is testing a novel approach to this problem by screening compounds using a variety of in vitro assays and using the results to prioritize chemicals for further, more detailed testing. Phase I of ToxCast is testing 320 chemicals (mainly pesticide active ingredients) against ~400 cell-based and biochemical assays. In order to anchor these studies, we are using in vivo guideline study data for subchronic, chronic, cancer, reproductive and developmental endpoints. This data is compiled in the EPA toxicity reference database, ToxRefDB. The main goal of ToxCast is the discovery and validation of “signatures” linking in vitro assay data to in vivo toxicity endpoints. These signatures will be collections of assays that are correlated with particular endpoints. These assay collections should also help define molecular-and cellular-level mechanisms of toxicity. This talk will discuss our strategy to use a combination of statistical and machine learning methods, coupled with biochemical network or systems biology approaches. Our initial examples will focus signatures for endpoints from 2 year rodent cancer bioassays. Most of the data we have analyzed is in dose or concentration response series, so to effectively use this data we have developed novel appro

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

A double-blind, crossover, randomized comparison of granisetron and ramosetron for the prevention of acute and delayed cisplatin-induced emesis in patients with gastrointestinal cancer: is patient preference a better primary endpoint?

PubMed

Koizumi, Wasaburo; Tanabe, Satoshi; Nagaba, Shizuka; Higuchi, Katsuhiko; Nakayama, Norisuke; Saigenji, Katsunori; Nonaka, Miwa; Yago, Kazuo

2003-12-01

Serotonin receptor antagonists are recommended by the American Society of Clinical Oncology for the prevention of acute and delayed chemotherapy-induced emesis. However, the most effective agent in this class of antiemetic drugs for preventing emesis has not been clearly defined. We therefore performed a double-blind, crossover, randomized, controlled trial comparing the efficacy of granisetron and ramosetron, using patient preference as the primary endpoint. Thirty patients receiving two courses of combined chemotherapy (including > or =60 mg/m(2) cisplatin) for gastric or esophageal cancer were randomly assigned to the granisetron-ramosetron group (treatment phase 1: granisetron, 3 mg; treatment phase 2: ramosetron, 0.3 mg) or the ramosetron-granisetron group (treatment phase 1: ramosetron, 0.3 mg; treatment phase 2: granisetron, 3 mg). All patients received methylprednisolone sodium, 250 mg i.v., during each treatment phase. The efficacy of granisetron and ramosetron was similar in terms of the suppression of emesis and appetite status. However, the majority of patients (19/30, 63.3%) expressed a preference for granisetron, as compared with 9 patients (30.0%) who preferred ramosetron; 2 patients (6.7%) had no preference (chi(2) test: p = 0.008; Fisher's exact test: p = 0.015). (1) A significant proportion of patients prefer granisetron over ramosetron for the prevention of chemotherapy-induced emesis. (2) Granisetron and ramosetron possess similar effectiveness for the suppression of emesis. (3) The variable of 'patient preference' should be accepted as a primary endpoint of antiemetic drug efficacy. Copyright 2003 S. Karger AG, Basel

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...

Health insurance and payment systems for severe acute pancreatitis.

PubMed

Yoshida, Masahiro; Takada, Tadahiro; Hirata, Koichi; Mayumi, Toshihiko; Shikata, Satoru; Shirai, Kunihiro; Kimura, Yasutoshi; Wada, Keita; Amano, Hodaka; Arata, Shinju; Hirota, Masahiko; Takeda, Kazunori; Gabata, Toshifumi; Hirota, Morihisa; Yokoe, Masamichi; Kiriyama, Seiki; Sekimoto, Miho

2010-01-01

The medical insurance system of Japan is based on the Universal Medical Care System guaranteed by the provision of the Article 25 of the Constitution of Japan, which states that "All the people shall have the right to live a healthy, cultural and minimum standard of life." The health insurance system of Japan comprises the medical insurance system and the health care system for the long-lived. Medical care insurance includes the employees' health insurance (Social Insurance) that covers employees of private companies and their families and community insurance (National Health Insurance) that covers the self-employed. Each medical insurance system has its own medical care system for the retired and their families. The health care system for the long-lived covers people of over 75 years of age (over 65 years in people with a certain handicap). There is also a system under which all or part of the medical expenses is reimbursed by public expenditure or the cost of medical care not covered by health insurance is paid by the government. This system is referred to collectively as the "the public payment system of medical expenses." To support the realization of the purpose of this system, there is a treatment research enterprise for specified diseases (intractable diseases). Because of the high mortality rate, acute pancreatitis is specified as an intractable disease for the purpose of reducing its mortality rate, and treatment expenses of patients are paid in full by the government dating back to the day when the application was made for a certificate verifying that he or she has severe acute pancreatitis.

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.

The health economic burden that acute and chronic wounds impose on an average clinical commissioning group/health board in the UK.

PubMed

Guest, J F; Vowden, K; Vowden, P

2017-06-02

To estimate the patterns of care and related resource use attributable to managing acute and chronic wounds among a catchment population of a typical clinical commissioning group (CCG)/health board and corresponding National Health Service (NHS) costs in the UK. This was a sub-analysis of a retrospective cohort analysis of the records of 2000 patients in The Health Improvement Network (THIN) database. Patients' characteristics, wound-related health outcomes and health-care resource use were quantified for an average CCG/health board with a catchment population of 250,000 adults ≥18 years of age, and the corresponding NHS cost of patient management was estimated at 2013/2014 prices. An average CCG/health board was estimated to be managing 11,200 wounds in 2012/2013. Of these, 40% were considered to be acute wounds, 48% chronic and 12% lacking any specific diagnosis. The prevalence of acute, chronic and unspecified wounds was estimated to be growing at the rate of 9%, 12% and 13% per annum respectively. Our analysis indicated that the current rate of wound healing must increase by an average of at least 1% per annum across all wound types in order to slow down the increasing prevalence. Otherwise, an average CCG/health board is predicted to manage ~23,200 wounds per annum by 2019/2020 and is predicted to spend a discounted (the process of determining the present value of a payment that is to be received in the future) £50 million on managing these wounds and associated comorbidities. Real-world evidence highlights the substantial burden that acute and chronic wounds impose on an average CCG/health board. Strategies are required to improve the accuracy of diagnosis and healing rates.

Acute kidney injury: Global health alert

PubMed Central

Kam Tao Li, Philip; Burdmann, Emmanuel A; Mehta, Ravindra L

2013-01-01

Acute kidney injury (AKI) is increasingly prevalent in developing and developed countries and is associated with severe morbidity and mortality. Most etiologies of AKI can be prevented by interventions at the individual, community, regional and in-hospital levels. Effective measures must include community-wide efforts to increase an awareness of the devastating effects of AKI and provide guidance on preventive strategies, as well as early recognition and management. Efforts should be focused on minimizing causes of AKI, increasing awareness of the importance of serial measurements of serum creatinine in high risk patients, and documenting urine volume in acutely ill people to achieve early diagnosis; there is as yet no definitive role for alternative biomarkers. Protocols need to be developed to systematically manage prerenal conditions and specific infections. More accurate data about the true incidence and clinical impact of AKI will help to raise the importance of the disease in the community, increase awareness of AKI by governments, the public, general and family physicians and other health care professionals to help prevent the disease. Prevention is the key to avoid the heavy burden of mortality and morbidity associated with AKI. PMID:24475433

Acute Kidney Injury: Global Health Alert

PubMed Central

Tao Li, P. K.; Burdmann, E. A.; Mehta, R. L.

2013-01-01

Acute kidney injury (AKI) is increasingly prevalent in developing and developed countries and is associated with severe morbidity and mortality. Most etiologies of AKI can be prevented by interventions at the individual, community, regional and in-hospital levels. Effective measures must include community-wide efforts to increase an awareness of the devastating effects of AKI and provide guidance on preventive strategies, as well as early recognition and management. Efforts should be focused on minimizing causes of AKI, increasing awareness of the importance of serial measurements of serum creatinine in high risk patients, and documenting urine volume in acutely ill people to achieve early diagnosis; there is as yet no definitive role for alternative biomarkers. Protocols need to be developed to systematically manage prerenal conditions and specific infections. More accurate data about the true incidence and clinical impact of AKI will help to raise the importance of the disease in the community, increase awareness of AKI by governments, the public, general and family physicians and other health care professionals to help prevent the disease. Prevention is the key to avoid the heavy burden of mortality and morbidity associated with AKI. PMID:25013646

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

School-Based Mental Health Program Evaluation: Children's School Outcomes and Acute Mental Health Service Use

ERIC Educational Resources Information Center

Kang-Yi, Christina D.; Mandell, David S.; Hadley, Trevor

2013-01-01

Background: This study examined the impact of school-based mental health programs on children's school outcomes and the utilization of acute mental health services. Methods: The study sample included 468 Medicaid-enrolled children aged 6 to 17 years who were enrolled 1 of 2 school-based mental health programs (SBMHs) in a metropolitan area…

Early biliary decompression versus conservative treatment in acute biliary pancreatitis (APEC trial): study protocol for a randomized controlled trial.

PubMed

Schepers, Nicolien J; Bakker, Olaf J; Besselink, Marc G H; Bollen, Thomas L; Dijkgraaf, Marcel G W; van Eijck, Casper H J; Fockens, Paul; van Geenen, Erwin J M; van Grinsven, Janneke; Hallensleben, Nora D L; Hansen, Bettina E; van Santvoort, Hjalmar C; Timmer, Robin; Anten, Marie-Paule G F; Bolwerk, Clemens J M; van Delft, Foke; van Dullemen, Hendrik M; Erkelens, G Willemien; van Hooft, Jeanin E; Laheij, Robert; van der Hulst, René W M; Jansen, Jeroen M; Kubben, Frank J G M; Kuiken, Sjoerd D; Perk, Lars E; de Ridder, Rogier J J; Rijk, Marno C M; Römkens, Tessa E H; Schoon, Erik J; Schwartz, Matthijs P; Spanier, B W Marcel; Tan, Adriaan C I T L; Thijs, Willem J; Venneman, Niels G; Vleggaar, Frank P; van de Vrie, Wim; Witteman, Ben J; Gooszen, Hein G; Bruno, Marco J

2016-01-05

Acute pancreatitis is mostly caused by gallstones or sludge. Early decompression of the biliary tree by endoscopic retrograde cholangiography (ERC) with sphincterotomy may improve outcome in these patients. Whereas current guidelines recommend early ERC in patients with concomitant cholangitis, early ERC is not recommended in patients with mild biliary pancreatitis. Evidence on the role of routine early ERC with endoscopic sphincterotomy in patients without cholangitis but with biliary pancreatitis at high risk for complications is lacking. We hypothesize that early ERC with sphincterotomy improves outcome in these patients. The APEC trial is a randomized controlled, parallel group, superiority multicenter trial. Within 24 hours after presentation to the emergency department, patients with biliary pancreatitis without cholangitis and at high risk for complications, based on an Acute Physiology and Chronic Health Evaluation (APACHE-II) score of 8 or greater, Modified Glasgow score of 3 or greater, or serum C-reactive protein above 150 mg/L, will be randomized. In 27 hospitals of the Dutch Pancreatitis Study Group, 232 patients will be allocated to early ERC with sphincterotomy or to conservative treatment. The primary endpoint is a composite of major complications (that is, organ failure, pancreatic necrosis, pneumonia, bacteremia, cholangitis, pancreatic endocrine, or exocrine insufficiency) or death within 180 days after randomization. Secondary endpoints include ERC-related complications, infected necrotizing pancreatitis, length of hospital stay and an economical evaluation. The APEC trial investigates whether an early ERC with sphincterotomy reduces the composite endpoint of major complications or death compared with conservative treatment in patients with biliary pancreatitis at high risk of complications. Current Controlled Trials ISRCTN97372133 (date registration: 17-12-2012).

Experiences of stress among nurses in acute mental health settings.

PubMed

Currid, Thomas

To explore occupational stressors, the lived experience of stress and the meaning of this experience for staff working in acute mental health care. The study adopted a hermeneutic phenomenological approach to ascertain the lived experience of stress among eight qualified staff working in a mental health NHS trust in London. A semi-structured interview format was used. Interviews were transcribed verbatim and analysed using an interpretative phenomenological analysis framework. The occupational experience of nurses in this study indicates that staff are frequently subjected to violent and aggressive behaviour from patients. Such experiences adversely affect patient outcomes in that staff may be reluctant to engage with such individuals because of anxiety about being hurt or experiencing further intimidation. Environmental pressures coupled with high activity levels mean that staff have little time to focus on the task at hand or to plan future activities. As a result they find that when they go home they are unable to switch off from work. Further investment is needed in acute mental health settings and in staff who work in this area. If this does not happen, it is likely that the quality of service provision will deteriorate and nurses' health and wellbeing will suffer.

School Nurse Workload: A Scoping Review of Acute Care, Community Health, and Mental Health Nursing Workload Literature

ERIC Educational Resources Information Center

Endsley, Patricia

2017-01-01

The purpose of this scoping review was to survey the most recent (5 years) acute care, community health, and mental health nursing workload literature to understand themes and research avenues that may be applicable to school nursing workload research. The search for empirical and nonempirical literature was conducted using search engines such as…

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.

Developing a Cognition Endpoint for Traumatic Brain Injury Clinical Trials

PubMed Central

Crane, Paul K.; Dams-O'Connor, Kristen; Holdnack, James; Ivins, Brian J.; Lange, Rael T.; Manley, Geoffrey T.; McCrea, Michael; Iverson, Grant L.

2017-01-01

Abstract Cognitive impairment is a core clinical feature of traumatic brain injury (TBI). After TBI, cognition is a key determinant of post-injury productivity, outcome, and quality of life. As a final common pathway of diverse molecular and microstructural TBI mechanisms, cognition is an ideal endpoint in clinical trials involving many candidate drugs and nonpharmacological interventions. Cognition can be reliably measured with performance-based neuropsychological tests that have greater granularity than crude rating scales, such as the Glasgow Outcome Scale-Extended, which remain the standard for clinical trials. Remarkably, however, there is no well-defined, widely accepted, and validated cognition endpoint for TBI clinical trials. A single cognition endpoint that has excellent measurement precision across a wide functional range and is sensitive to the detection of small improvements (and declines) in cognitive functioning would enhance the power and precision of TBI clinical trials and accelerate drug development research. We outline methodologies for deriving a cognition composite score and a research program for validation. Finally, we discuss regulatory issues and the limitations of a cognition endpoint. PMID:27188248

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

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.

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.

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.

Association of Cost Sharing With Mental Health Care Use, Involuntary Commitment, and Acute Care.

PubMed

Ravesteijn, Bastian; Schachar, Eli B; Beekman, Aartjan T F; Janssen, Richard T J M; Jeurissen, Patrick P T

2017-09-01

A higher out-of-pocket price for mental health care may lead not only to cost savings but also to negative downstream consequences. To examine the association of higher patient cost sharing with mental health care use and downstream effects, such as involuntary commitment and acute mental health care use. This difference-in-differences study compared changes in mental health care use by adults, who experienced an increase in cost sharing, with changes in youths, who did not experience the increase and thus formed a control group. The study examined all 2 780 558 treatment records opened from January 1, 2010, through December 31, 2012, by 110 organizations that provide specialist mental health care in the Netherlands. Data analysis was performed from January 18, 2016, to May 9, 2017. On January 1, 2012, the Dutch national government increased the out-of-pocket price of mental health services for adults by up to €200 (US$226) per year for outpatient treatment and €150 (US$169) per month for inpatient treatment. The number of treatment records opened each day in regular specialist mental health care, involuntary commitment, and acute mental health care, and annual specialist mental health care spending. This study included 1 448 541 treatment records opened from 2010 to 2012 (mean [SD] age, 41.4 [16.7] years; 712 999 men and 735 542 women). The number of regular mental health care records opened for adults decreased abruptly and persistently by 13.4% (95% CI, -16.0% to -10.8%; P < .001) per day when cost sharing was increased in 2012. The decrease was substantial and significant for severe and mild disorders and larger in low-income than in high-income neighborhoods. Simultaneously, in 2012, daily record openings increased for involuntary commitment by 96.8% (95% CI, 87.7%-105.9%; P < .001) and for acute mental health care by 25.1% (95% CI, 20.8%-29.4%; P < .001). In contrast to our findings for adults, the use of regular care among youths

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.

Ecotoxicological evaluation of the additive butylated hydroxyanisole using a battery with six model systems and eighteen endpoints.

PubMed

Jos, Angeles; Repetto, Guillermo; Ríos, Juan Carlos; del Peso, Ana; Salguero, Manuel; Hazen, María José; Molero, María Luisa; Fernández-Freire, Paloma; Pérez-Martín, Jose Manuel; Labrador, Verónica; Cameán, Ana

2005-01-26

The occurrence and fate of additives in the aquatic environment is an emerging issue in environmental chemistry. This paper describes the ecotoxicological effects of the commonly used additive butylated hydroxyanisole (BHA) using a test battery, comprising of several different organisms and in vitro test systems, representing a proportion of the different trophic levels. The most sensitive system to BHA was the inhibition of bioluminescence in Vibrio fischeri bacteria, which resulted in an acute low observed adverse effect concentration (LOAEC) of 0.28 microM. The next most sensitive system was the immobilization of the cladoceran Daphnia magna followed by: the inhibition of the growth of the unicellular alga Chlorella vulgaris; the endpoints evaluated in Vero (mammalian) cells (total protein content, LDH activity, neutral red uptake and MTT metabolization), mitotic index and root growth inhibition in the terrestrial plant Allium cepa, and finally, the endpoints used on the RTG-2 salmonid fish cell line (neutral red uptake, total protein content, MTS metabolization, lactate dehydrogenase leakage and activity, and glucose-6-phosphate dehydrogenase activity). Morphological alterations in RTG-2 cells were also assessed and these included loss of cells, induction of cellular pleomorphism, hydropic degeneration and induction of apoptosis at high concentrations. The results from this study also indicated that micronuclei were not induced in A.cepa exposed to BHA. The differences in sensitivity for the diverse systems that were used (EC50 ranged from 1.2 to >500 microM) suggest the importance for a test battery approach in the evaluation of the ecological consequences of chemicals. According to the results, the levels of BHA reported in industrial wastewater would elicit adverse effects in the environment. This, coupled with its potential to bioaccumulate, makes BHA a pollutant of concern not only for acute exposures, but also for the long-term.

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

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.

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

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.

Acute and chronic disability among U.S. farmers and pesticide applicators: the National Health Interview Survey (NHIS).

PubMed

Gómez-Marín, O; Fleming, L E; Lee, D J; LeBlanc, W; Zheng, D; Ma, F; Jané, D; Pitman, T; Caban, A

2004-11-01

The National Health Interview Survey (NHIS) is a multipurpose household survey of the U.S. civilian non-institutionalized population conducted annually since 1957. From 1986 to 1994, over 450,000 U.S. workers, age 18 years and older, participated in a probability sampling of the entire non-institutionalized U.S. population; variables collected included a range of measures of acute and chronic disability. The objective of the present study was to assess predictors of health status, and acute and chronic disability for farmers and pesticide applicators (pesticide-exposed workers) compared to all other U.S. workers using the 1986-1994 NHIS. After adjustment for sample weights and design effects using SUDAAN, several measures of acute and chronic disability and health status were modeled with multiple logistic regression. Farmers (n = 9576) were significantly older compared to all other U.S. workers (n = 453,219) and pesticide applicators (n = 180). Farmers and pesticide applicators had a higher proportion of males, whites, and Hispanics and were less educated. After adjusting for age, gender, race-ethnicity, and education, compared to all other workers, farmers were significantly less likely to report acute and chronic disability and health conditions, while pesticide applicators were more likely to report chronic disability, health conditions, and poor health. Given the cross-sectional nature of the data and the significant job demands of farming, both leading to a relative healthy worker effect, the present results indicate that at any point in time, farmers report less acute and chronic disability, compared to other U.S. workers, whereas pesticide applicators report similar or poorer health.

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.

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.

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

Health Literacy and Mortality: A Cohort Study of Patients Hospitalized for Acute Heart Failure

PubMed Central

McNaughton, Candace D; Cawthon, Courtney; Kripalani, Sunil; Liu, Dandan; Storrow, Alan B; Roumie, Christianne L

2015-01-01

Background More than 30% of patients hospitalized for heart failure are rehospitalized or die within 90 days of discharge. Lower health literacy is associated with mortality among outpatients with chronic heart failure; little is known about this relationship after hospitalization for acute heart failure. Methods and Results Patients hospitalized for acute heart failure and discharged home between November 2010 and June 2013 were followed through December 31, 2013. Nurses administered the Brief Health Literacy Screen at admission; low health literacy was defined as Brief Health Literacy Screen ≤9. The primary outcome was all-cause mortality. Secondary outcomes were time to first rehospitalization and, separately, time to first emergency department visit within 90 days of discharge. Cox proportional hazards models determined their relationships with health literacy, adjusting for age, gender, race, insurance, education, comorbidity, and hospital length of stay. For the 1379 patients, average age was 63.1 years, 566 (41.0%) were female, and 324 (23.5%) had low health literacy. Median follow-up was 20.7 months (interquartile range 12.8 to 29.6 months), and 403 (29.2%) patients died. Adjusted hazard ratio for death among patients with low health literacy was 1.34 (95% CI 1.04, 1.73, P=0.02) compared to Brief Health Literacy Screen >9. Within 90 days of discharge, there were 415 (30.1%) rehospitalizations and 201 (14.6%) emergency department visits, with no evident association with health literacy. Conclusions Lower health literacy was associated with increased risk of death after hospitalization for acute heart failure. There was no evident relationship between health literacy and 90-day rehospitalization or emergency department visits. PMID:25926328

The perspective of allied health staff on the role of nurses in sub-acute care.

PubMed

Digby, Robin; Bolster, Danielle; Perta, Andrew; Bucknall, Tracey K

2018-06-12

To explore allied health staff perceptions on the role of nurses in sub-acute care wards. A consequence of earlier discharge from acute hospitals is higher acuity of patients in sub-acute care. The impact on nurses' roles and required skill mix remains unknown. Similarly, nurses' integration into the rehabilitation team is ambiguous. Descriptive qualitative inquiry. Semi-structured interviews conducted with 14 allied health staff from one sub-acute care facility in Melbourne, Australia. Interviews were audio-recorded and transcribed verbatim. Analysis using the framework approach. Three main themes were evident: 1) The changing context of care: patient acuity, rapid patient discharge and out-dated buildings influenced care, 2) Generalist as opposed to specialist rehabilitation nurses: a divide between traditional nursing roles of clinical and personal care and a specialist rehabilitation role, and 3) Interdisciplinary relations and communication demonstrated lack of respect for nurses and integrating holistic care into everyday routines. Allied health staff had limited understanding of nurses' role in sub-acute care, and expectations varied. Power relationships appeared to hamper teamwork. Failure to include nurses in team discussions and decision-making could hinder patient outcomes. Progressing patients to levels of independence involves both integrating rehabilitation into activities of daily living with nurses and therapy-based sessions. Promotion of the incorporation of nursing input into patient rehabilitation is needed with both nurses and allied health staff. Lack of understanding of the nurses' role contributes to lack of respect for the nursing contribution to rehabilitation. Nurses have a key role in rehabilitation sometimes impeded by poor teamwork with allied health staff. Processes in sub-acute care wards need examination to facilitate more effective team practices inclusive of nurses. Progressing patients' independence in rehabilitation units

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.

Health Impacts from Acute Radiation Exposure

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

Strom, Daniel J.

2003-09-30

Absorbed doses above1-2 Gy (100-200 rads) received over a period of a day or less lead to one or another of the acute radiation syndromes. These are the hematopoietic syndrome, the gastrointestinal (GI) syndrome, the cerebrovascular (CV) syndrome, the pulmonary syndrome, or the cutaneous syndrome. The dose that will kill about 50% of the exposed people within 60 days with minimal medical care, LD50-60, is around 4.5 Gy (450 rads) of low-LET radiation measured free in air. The GI syndrome may not be fatal with supportive medical care and growth factors below about 10 Gy (1000 rads), but above thismore » is likely to be fatal. Pulmonary and cutaneous syndromes may or may not be fatal, depending on many factors. The CV syndrome is invariably fatal. Lower acute doses, or protracted doses delivered over days or weeks, may lead to many other health outcomes than death. These include loss of pregnancy, cataract, impaired fertility or temporary or permanent sterility, hair loss, skin ulceration, local tissue necrosis, developmental abnormalities including mental and growth retardation in persons irradiated as children or fetuses, radiation dermatitis, and other symptoms listed in Table 2 on page 12. Children of parents irradiated prior to conception may experience heritable ill-health, that is, genetic changes from their parents. These effects are less strongly expressed than previously thought. Populations irradiated to high doses at high dose rates have increased risk of cancer incidence and mortality, taken as about 10-20% incidence and perhaps 5-10% mortality per sievert of effective dose of any radiation or per gray of whole-body absorbed dose low-LET radiation. Cancer risks for non-uniform irradiation will be less.« less

Intravenous iron vs blood for acute post-partum anaemia (IIBAPPA): a prospective randomised trial.

PubMed

Chua, Seng; Gupta, Sarika; Curnow, Jennifer; Gidaszewski, Beata; Khajehei, Marjan; Diplock, Hayley

2017-12-19

Acute post-partum anaemia can be associated with significant morbidity including a predisposition for postnatal depression. Lack of clear practice guidelines means a number of women are treated with multiple blood transfusions. Intravenous iron has the potential to limit the need for multiple blood transfusions but its role in the post-partum setting is unclear. IIBAPPA is a multi-centre randomised non-inferiority trial. Women with a primary post-partum haemorrhage (PPH) >1000 mL and resultant haemoglobin (Hb) 5.5-8.0 g/dL after resuscitation with ongoing symptomatic anaemia who are otherwise stable (no active bleeding) are eligible to participate. Patients with sepsis or conditions necessitating rapid Hb restoration are excluded. Eligible participants are randomised to receive a blood transfusion or a single dose of intravenous iron polymaltose calculated using the Ganzoni formula. Primary outcome measures include Hb, Ferritin and C-Reactive Protein levels on Day 7. Secondary outcomes evaluate (i) Hb, Ferritin and CRP levels on Day 14, 28, (ii) anaemia symptoms on Day 0, 7, 14 and 28 using structured health related quality of life questionnaires, (iii) treatment safety by assessing adverse reactions and infection endpoints and (iv) the quantitative impact of anaemia on breast feeding quality using a hospital designed questionnaire. If equivalence in Hb and ferritin levels, symptom scores and safety endpoints is demonstrated, intravenous iron may become the preferred treatment for women with acute post-partum anaemia to minimise transfusion reactions and costs. Australian and New Zealand Clinical Trials Registry: ACTRN12615001370594 on 16th December, 2015 (prospective approval).

Patients' preferences for selection of endpoints in cardiovascular clinical trials.

PubMed

Chow, Robert D; Wankhedkar, Kashmira P; Mete, Mihriye

2014-01-01

To reduce the duration and overall costs of cardiovascular trials, use of the combined endpoints in trial design has become commonplace. Though this methodology may serve the needs of investigators and trial sponsors, the preferences of patients or potential trial subjects in the trial design process has not been studied. To determine the preferences of patients in the design of cardiovascular trials. Participants were surveyed in a pilot study regarding preferences among various single endpoints commonly used in cardiovascular trials, preference for single vs. composite endpoints, and the likelihood of compliance with a heart medication if patients similar to them participated in the trial design process. One hundred adult English-speaking patients, 38% male, from a primary care ambulatory practice located in an urban setting. Among single endpoints, participants rated heart attack as significantly more important than death from other causes (4.53 vs. 3.69, p=0.004) on a scale of 1-6. Death from heart disease was rated as significantly more important than chest pain (4.73 vs. 2.47, p<0.001), angioplasty/PCI/CABG (4.73 vs. 2.43, p<0.001), and stroke (4.73 vs. 2.43, p<0.001). Participants also expressed a slight preference for combined endpoints over single endpoint (43% vs. 57%), incorporation of the opinions of the study patient population into the design of trials (48% vs. 41% for researchers), and a greater likelihood of medication compliance if patient preferences were considered during trial design (67% indicated a significant to major effect). Patients are able to make judgments and express preferences regarding trial design. They prefer that the opinions of the study population rather than the general population be incorporated into the design of the study. This novel approach to study design would not only incorporate patient preferences into medical decision making, but it also has the potential to improve compliance with cardiovascular medications.

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

Association of Cost Sharing With Mental Health Care Use, Involuntary Commitment, and Acute Care

PubMed Central

Schachar, Eli B.; Beekman, Aartjan T. F.; Janssen, Richard T. J. M.; Jeurissen, Patrick P. T.

2017-01-01

Importance A higher out-of-pocket price for mental health care may lead not only to cost savings but also to negative downstream consequences. Objective To examine the association of higher patient cost sharing with mental health care use and downstream effects, such as involuntary commitment and acute mental health care use. Design, Setting, and Participants This difference-in-differences study compared changes in mental health care use by adults, who experienced an increase in cost sharing, with changes in youths, who did not experience the increase and thus formed a control group. The study examined all 2 780 558 treatment records opened from January 1, 2010, through December 31, 2012, by 110 organizations that provide specialist mental health care in the Netherlands. Data analysis was performed from January 18, 2016, to May 9, 2017. Exposures On January 1, 2012, the Dutch national government increased the out-of-pocket price of mental health services for adults by up to €200 (US$226) per year for outpatient treatment and €150 (US$169) per month for inpatient treatment. Main Outcomes and Measures The number of treatment records opened each day in regular specialist mental health care, involuntary commitment, and acute mental health care, and annual specialist mental health care spending. Results This study included 1 448 541 treatment records opened from 2010 to 2012 (mean [SD] age, 41.4 [16.7] years; 712 999 men and 735 542 women). The number of regular mental health care records opened for adults decreased abruptly and persistently by 13.4% (95% CI, −16.0% to −10.8%; P < .001) per day when cost sharing was increased in 2012. The decrease was substantial and significant for severe and mild disorders and larger in low-income than in high-income neighborhoods. Simultaneously, in 2012, daily record openings increased for involuntary commitment by 96.8% (95% CI, 87.7%-105.9%; P < .001) and for acute mental health care by 25.1% (95% CI, 20

The Impact of Oral Health on Taste Ability in Acutely Hospitalized Elderly

PubMed Central

Solemdal, Kirsten; Sandvik, Leiv; Willumsen, Tiril; Mowe, Morten; Hummel, Thomas

2012-01-01

Objective To investigate to what extent various oral health variables are associated with taste ability in acutely hospitalized elderly. Background Impaired taste may contribute to weight loss in elderly. Many frail elderly have poor oral health characterized by caries, poor oral hygiene, and dry mouth. However, the possible influence of such factors on taste ability in acutely hospitalized elderly has not been investigated. Materials and Methods The study was cross-sectional. A total of 174 (55 men) acutely hospitalized elderly, coming from their own homes and with adequate cognitive function, were included. Dental status, decayed teeth, oral bacteria, oral hygiene, dry mouth and tongue changes were recorded. Growth of oral bacteria was assessed with CRT® Bacteria Kit. Taste ability was evaluated with 16 taste strips impregnated with sweet, sour, salty and bitter taste solutions in 4 concentrations each. Correct identification was given score 1, and maximum total taste score was 16. Results Mean age was 84 yrs. (range 70–103 yrs.). Total taste score was significantly and markedly reduced in patients with decayed teeth, poor oral hygiene, high growth of oral bacteria and dry mouth. Sweet and salty taste were particularly impaired in patients with dry mouth. Sour taste was impaired in patients with high growth of oral bacteria. Conclusion This study shows that taste ability was reduced in acutely hospitalized elderly with caries activity, high growth of oral bacteria, poor oral hygiene, and dry mouth. Our findings indicate that good oral health is important for adequate gustatory function. Maintaining proper oral hygiene in hospitalized elderly should therefore get high priority among hospital staff. PMID:22570725

Endovascular Management of Patients with Head and Neck Cancers Presenting with Acute Hemorrhage: A Single-Center Retrospective Study

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

Vilas Boas, P. P.; Castro-Afonso, L. H. de; Monsignore, L. M.

PurposeAcute hemorrhage associated with cancers of the head and neck is a life-threatening condition that requires immediate action. The aim of this study was to assess the safety and efficacy of endovascular embolization for acute hemorrhage in patients with head and neck cancers.Materials and MethodsData were retrospectively collected from patients with head and neck cancers who underwent endovascular embolization to treat acute hemorrhage. The primary endpoint was the rate of immediate control of hemorrhage during the first 24 h after embolization. The secondary endpoints were technical or clinical complications, rate of re-hemorrhage 24 h after the procedure, time from embolization to re-hemorrhage,more » hospitalization time, mortality rate, and time from embolization to death.ResultsFifty-one patients underwent endovascular embolization. The primary endpoint was achieved in 94% of patients. The rate of technical complications was 5.8%, and no clinical complication was observed. Twelve patients (23.5%) had hemorrhage recurrence after an average time of 127.5 days. The average hospitalization time was 7.4 days, the mortality rate during the follow-up period was 66.6%, and the average time from embolization to death was 132.5 days.ConclusionEndovascular embolization to treat acute hemorrhage in patients with head and neck cancers is a safe and effective method for the immediate control of hemorrhage and results in a high rate of hemorrhage control. Larger studies are necessary to determine which treatment strategy is best for improving patient outcomes.« less

Perfusion computed tomography-guided intravenous thrombolysis for acute ischemic stroke beyond 4.5 hours: a case-control study.

PubMed

García-Bermejo, Pablo; Calleja, Ana I; Pérez-Fernández, Santiago; Cortijo, Elisa; del Monte, José M; García-Porrero, Miguel; Fe Muñoz, M; Fernández-Herranz, Rosario; Arenillas, Juan F

2012-01-01

Extending the therapeutic window of intravenous thrombolysis for acute ischemic stroke beyond the established 4.5-hour limit is of critical importance in order to increase the proportion of thrombolysed stroke patients. In this setting, the capacity of MRI to select acute stroke patients for reperfusion therapies in delayed time windows has been and is being tested in clinical trials. However, whether the more available and cost-effective perfusion computed tomography (PCT) may be useful to select candidates for delayed intravenous thrombolysis remains largely unexplored. We aimed to evaluate the safety and efficacy of PCT-guided intravenous thrombolysis beyond 4.5 h after stroke onset. We prospectively studied all consecutive acute ischemic stroke patients treated with intravenous tissue plasminogen activator (tPA) in our stroke unit between January 2008 and December 2010. Patients treated within 0- 4.5 h were treated according to non-contrast CT (NCCT) criteria. Beyond 4.5 h, patients received intravenous tPA according to PCT criteria, i.e. an infarct core on cerebral blood volume (CBV) maps not exceeding one third of the middle cerebral artery (MCA) territory and tissue at risk as defined by mean transit time-CBV mismatch greater than 20%. Predetermined primary endpoints were symptomatic hemorrhagic transformation and favorable long-term outcome, while early neurological improvement and MCA recanalization were considered secondary endpoints. Statistical analysis included bivariate comparisons between the two groups for each endpoint and logistic regression models when significance was found in bivariate analyses. This study was approved by our local ethics committee. A total of 245 patients received intravenous thrombolysis. After the groups were matched by baseline National Institutes of Health Stroke Scale score, 172 patients treated at <4.5 h and 43 patients treated at >4.5 h were finally included. Early and late groups were comparable regarding baseline

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.

N-terminal pro-brain natriuretic peptide and high-sensitivity troponin in the evaluation of acute chest pain of uncertain etiology. A PITAGORAS substudy.

PubMed

Sanchis, Juan; Bardají, Alfredo; Bosch, Xavier; Loma-Osorio, Pablo; Marín, Francisco; Sánchez, Pedro L; Calvo, Francisco; Avanzas, Pablo; Hernández, Carolina; Serrano, Silvia; Carratalá, Arturo; Barrabés, José A

2013-07-01

High-sensitivity troponin assays have improved the diagnosis of acute coronary syndrome in patients presenting with chest pain and normal troponin levels as measured by conventional assays. Our aim was to investigate whether N-terminal pro-brain natriuretic peptide provides additional information to troponin determination in these patients. A total of 398 patients, included in the PITAGORAS study, presenting to the emergency department with chest pain and normal troponin levels as measured by conventional assay in 2 serial samples (on arrival and 6 h to 8h later) were studied. The samples were also analyzed in a central laboratory for high-sensitivity troponin T (both samples) and for N-terminal pro-brain natriuretic peptide (second sample). The endpoints were diagnosis of acute coronary syndrome and the composite endpoint of in-hospital revascularization or a 30-day cardiac event. Acute coronary syndrome was adjudicated to 79 patients (20%) and the composite endpoint to 59 (15%). When the N-terminal pro-brain natriuretic peptide quartile increased, the diagnosis of acute coronary syndrome also increased (12%, 16%, 23% and 29%; P=.01), as did the risk of the composite endpoint (6%, 13%, 16% and 24%; P=.004). N-terminal pro-brain natriuretic peptide elevation (>125ng/L) was associated with both endpoints (relative risk= 2.0; 95% confidence interval, 1.2-3.3; P=.02; relative risk=2.4; 95% confidence interval, 1.4-4.2; P=.004). However, in the multivariable models adjusted by clinical and electrocardiographic data, a predictive value was found for high-sensitivity T troponin but not for N-terminal pro-brain natriuretic peptide. In low-risk patients with chest pain of uncertain etiology evaluated using high-sensitivity T troponin, N-terminal pro-brain natriuretic peptide does not contribute additional predictive value to diagnosis or the prediction of short-term outcomes. Copyright © 2012 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights

Comparing Laboratory and Field Measured Bioaccumulation Endpoints

EPA Science Inventory

The report presents an approach that allows comparisons of all laboratory and field bioaccumulation endpoints measurements. The approach will enable the inclusion of large amounts of field data into evaluations of bioaccumulation potential for legacy chemicals. Currently, these...

Validation of surrogate endpoints in advanced solid tumors: systematic review of statistical methods, results, and implications for policy makers.

PubMed

Ciani, Oriana; Davis, Sarah; Tappenden, Paul; Garside, Ruth; Stein, Ken; Cantrell, Anna; Saad, Everardo D; Buyse, Marc; Taylor, Rod S

2014-07-01

Licensing of, and coverage decisions on, new therapies should rely on evidence from patient-relevant endpoints such as overall survival (OS). Nevertheless, evidence from surrogate endpoints may also be useful, as it may not only expedite the regulatory approval of new therapies but also inform coverage decisions. It is, therefore, essential that candidate surrogate endpoints be properly validated. However, there is no consensus on statistical methods for such validation and on how the evidence thus derived should be applied by policy makers. We review current statistical approaches to surrogate-endpoint validation based on meta-analysis in various advanced-tumor settings. We assessed the suitability of two surrogates (progression-free survival [PFS] and time-to-progression [TTP]) using three current validation frameworks: Elston and Taylor's framework, the German Institute of Quality and Efficiency in Health Care's (IQWiG) framework and the Biomarker-Surrogacy Evaluation Schema (BSES3). A wide variety of statistical methods have been used to assess surrogacy. The strength of the association between the two surrogates and OS was generally low. The level of evidence (observation-level versus treatment-level) available varied considerably by cancer type, by evaluation tools and was not always consistent even within one specific cancer type. Not in all solid tumors the treatment-level association between PFS or TTP and OS has been investigated. According to IQWiG's framework, only PFS achieved acceptable evidence of surrogacy in metastatic colorectal and ovarian cancer treated with cytotoxic agents. Our study emphasizes the challenges of surrogate-endpoint validation and the importance of building consensus on the development of evaluation frameworks.

An European inter-laboratory validation of alternative endpoints of the murine local lymph node assay: 2nd round.

PubMed

Ehling, G; Hecht, M; Heusener, A; Huesler, J; Gamer, A O; van Loveren, H; Maurer, Th; Riecke, K; Ullmann, L; Ulrich, P; Vandebriel, R; Vohr, H-W

2005-08-15

The original local lymph node assay (LLNA) is based on the use of radioactive labelling to measure cell proliferation. Other endpoints for the assessment of proliferation are also authorized by the OECD Guideline 429 provided there is appropriate scientific support, including full citations and description of the methodology (OECD, 2002. OECD Guideline for the Testing of Chemicals; Skin Sensitization: Local Lymph Node Assay, Guideline 429. Paris, adopted 24th April 2002.). Here, we describe the outcome of the second round of an inter-laboratory validation of alternative endpoints in the LLNA conducted in nine laboratories in Europe. The validation study was managed and supervised by the Swiss Agency for Therapeutic Products (Swissmedic) in Bern. Ear-draining lymph node (LN) weight and cell counts were used to assess LN cell proliferation instead of [3H]TdR incorporation. In addition, the acute inflammatory skin reaction was measured by ear weight determination of circular biopsies of the ears to identify skin irritation properties of the test items. The statistical analysis was performed in the department of statistics at the university of Bern. Similar to the EC(3) values defined for the radioactive method, threshold values were calculated for the endpoints measured in this modification of the LLNA. It was concluded that all parameters measured have to be taken into consideration for the categorisation of compounds due to their sensitising potencies. Therefore, an assessment scheme has been developed which turned out to be of great importance to consistently assess sensitisation versus irritancy based on the data of the different parameters. In contrast to the radioactive method, irritants have been picked up by all the laboratories applying this assessment scheme.

One universal common endpoint in mouse models of amyotrophic lateral sclerosis.

PubMed

Solomon, Jesse A; Tarnopolsky, Mark A; Hamadeh, Mazen J

2011-01-01

There is no consensus among research laboratories around the world on the criteria that define endpoint in studies involving rodent models of amyotrophic lateral sclerosis (ALS). Data from 4 nutrition intervention studies using 162 G93A mice, a model of ALS, were analyzed to determine if differences exist between the following endpoint criteria: CS 4 (functional paralysis of both hindlimbs), CS 4+ (CS 4 in addition to the earliest age of body weight loss, body condition deterioration or righting reflex), and CS 5 (CS 4 plus righting reflex >20 s). The age (d; mean ± SD) at which mice reached endpoint was recorded as the unit of measurement. Mice reached CS 4 at 123.9±10.3 d, CS 4+ at 126.6±9.8 d and CS 5 at 127.6±9.8 d, all significantly different from each other (P<0.001). There was a significant positive correlation between CS 4 and CS 5 (r = 0.95, P<0.001), CS 4 and CS 4+ (r = 0.96, P<0.001), and CS 4+ and CS 5 (r = 0.98, P<0.001), with the Bland-Altman plot showing an acceptable bias between all endpoints. Logrank tests showed that mice reached CS 4 24% and 34% faster than CS 4+ (P = 0.046) and CS 5 (P = 0.006), respectively. Adopting CS 4 as endpoint would spare a mouse an average of 4 days (P<0.001) from further neuromuscular disability and poor quality of life compared to CS 5. Alternatively, CS 5 provides information regarding proprioception and severe motor neuron death, both could be important parameters in establishing the efficacy of specific treatments. Converging ethics and discovery, would adopting CS 4 as endpoint compromise the acquisition of insight about the effects of interventions in animal models of ALS?

Misspecification of Cox regression models with composite endpoints

PubMed Central

Wu, Longyang; Cook, Richard J

2012-01-01

Researchers routinely adopt composite endpoints in multicenter randomized trials designed to evaluate the effect of experimental interventions in cardiovascular disease, diabetes, and cancer. Despite their widespread use, relatively little attention has been paid to the statistical properties of estimators of treatment effect based on composite endpoints. We consider this here in the context of multivariate models for time to event data in which copula functions link marginal distributions with a proportional hazards structure. We then examine the asymptotic and empirical properties of the estimator of treatment effect arising from a Cox regression model for the time to the first event. We point out that even when the treatment effect is the same for the component events, the limiting value of the estimator based on the composite endpoint is usually inconsistent for this common value. We find that in this context the limiting value is determined by the degree of association between the events, the stochastic ordering of events, and the censoring distribution. Within the framework adopted, marginal methods for the analysis of multivariate failure time data yield consistent estimators of treatment effect and are therefore preferred. We illustrate the methods by application to a recent asthma study. Copyright © 2012 John Wiley & Sons, Ltd. PMID:22736519

An European inter-laboratory validation of alternative endpoints of the murine local lymph node assay: first round.

PubMed

Ehling, G; Hecht, M; Heusener, A; Huesler, J; Gamer, A O; van Loveren, H; Maurer, Th; Riecke, K; Ullmann, L; Ulrich, P; Vandebriel, R; Vohr, H-W

2005-08-15

The new OECD guideline 429 (skin sensitization: local lymph node assay) is based upon a protocol, which utilises the incorporation of radioactivity into DNA as a measure for cell proliferation in vivo. The guideline also enables the use of alternative endpoints in order to assess draining lymph node (LN) cell proliferation. Here we describe the first round of an inter-laboratory validation of alternative endpoints in the LLNA conducted in seven laboratories. The validation study was managed and supervised by the Swiss Agency for Therapeutic Products, Swissmedic. Statistical analyses of all data were performed by an independent centre at the University of Bern, Department of Statistics. Ear-draining, LN weight and cell count were used to assess proliferation instead of radioactive labeling of lymph node cells. In addition, the acute inflammatory skin reaction was measured by ear swelling and weight of circular biopsies of the ears to identify skin irritating properties of the test items. Hexylcinnamaldehyde (HCA) and three blinded test items were applied to female, 8--10 weeks old NMRI and BALB/c mice. Results were sent via the independent study coordinator to the statistician. The results of this first round showed that the alternative endpoints of the LLNA are sensitive and robust parameters. The use of ear weights added an important parameter assessing the skin irritation potential, which supports the differentiation of pure irritative from contact allergenic potential. There were absolute no discrepancies between the categorisation of the three test substances A--C determined by each single participating laboratories. The results highlighted also that many parameters do have an impact on the strength of the responses. Therefore, such parameters have to be taken into consideration for the categorisation of compounds due to their relative sensitizing potencies.

PREDICTING CHRONIC TOXICITY OF CHEMICALS TO FISHES FROM ACUTE TOXICITY TEST DATA: CONCEPT AND LINEAR REGRESSION

EPA Science Inventory

A comprehensive approach to predicting chronic toxicity from acute.toxicity data was developed in which simultaneous consideration is given to concentration, degree of response, and time course of effect. onsistent endpoint (lethality) and degree of response (O%) were used to com...

EXTRAPOLATING ACUTE MORTALITY OF AMPELISCA ABDITA TO POPULATION RISK USING A POPULATION MODEL AND MONITORING DATA

EPA Science Inventory

Ten-day acute mortality of the benthic amphipod, Ampelisca abdita, is used in a number of regulatory, research, and monitoring programs to evaluate chemical contamination of marine sediments. Although this endpoint has proven to be valuable for characterizing the relative toxicit...

Multimedia based health information to parents in a pediatric acute ward: a randomized controlled trial.

PubMed

Botngård, Anja; Skranes, Lars P; Skranes, Jon; Døllner, Henrik

2013-12-01

To determine whether multimedia based health information presented to parents of children with breathing difficulties in a pediatric acute ward, is more effective than verbal information, to reduce parental anxiety and increase satisfaction. This randomized controlled trial was conducted in a pediatric acute ward in Norway, from January to March 2011. Parents were randomly assigned to a multimedia intervention (n=53), or verbal health information (n=48). Primary outcome measure was parental anxiety, and secondary outcome measures were parental satisfaction with nursing care and health information. Parental anxiety decreased from arrival to discharge within both groups. At discharge the anxiety levels in the intervention group were no lower than in the control group. There was no difference in satisfaction with nursing care between the groups, but parents in the intervention group reported higher satisfaction with the health information given in the acute ward (p=.005). Multimedia based health information did not reduce anxiety more than verbal information, among parents to children with breathing difficulties. However, after discharge the parents were more satisfied with the multimedia approach. More research is needed to recommend the use of multimedia based information as a routine to parents in pediatric emergency care. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Personality factors and depression as predictors of hospital-based health care utilization following acute myocardial infarction.

PubMed

Schlyter, Mona; Östman, Margareta; Engström, Gunnar; André-Petersson, Lena; Tydén, Patrik; Leosdottir, Margrét

2017-04-01

Whether personality factors and depressive traits affect patients' utilization of health care following an acute myocardial infarction is relatively unknown. The aim of this study was to examine whether hospital-based health care utilization after a myocardial infarction was correlated with patients' personality factors and depressive symptoms. We studied 366 myocardial infarction patients admitted to Malmö University Hospital between 2002 and 2005 who subsequently participated in a cardiac rehabilitation programme. The patients were followed for two years after their index event. We investigated whether personality factors and depressive traits were correlated with the participants' health care utilization, defined as a) out-patient Cardiology visits and phone calls to a physician, nurse or a social worker, and b) acute visits or admissions to the Emergency or Cardiology Departments, using negative binominal regression analysis. In unadjusted comparisons neuroticism predicted more out-patient contacts. This significance remained after adjusting for age, sex, smoking, alcohol consumption and size of the myocardial infarction (measured as max level on troponin-I and left ventricular ejection fraction). There were no significant correlations between other personality factors or depression and out-patient contacts. None of the personality factors or depression predicted acute admissions. Apart from neuroticism, personality factors did not explain utilization of health care in terms of Cardiology out-patient contacts or acute admissions in myocardial infarction patients participating in a cardiac rehabilitation programme. Neither did depressive symptoms predict more health care utilization. This might indicate a robust cardiac rehabilitation programme offered to the study subjects, minimizing the need for additional health care contacts.

Acute Bronchitis

MedlinePlus

... on unwashed hands). Being exposed to tobacco smoke, air pollution, dusts, vapors, and fumes can also cause acute bronchitis. Less often, bacteria can also cause acute bronchitis. To diagnose acute bronchitis, your health care provider will ask about your symptoms and ...

Resilience factors play an important role in the mental health of parents when children survive acute lymphoblastic leukaemia.

PubMed

Eilertsen, Mary-Elizabeth; Hjemdal, Odin; Le, Thien Thanh; Diseth, Trond H; Reinfjell, Trude

2016-01-01

Childhood cancer is a tremendous stressor that requires parents to adapt to new challenges, and research has mainly focused on psychopathology and rarely on a resource-oriented perspective, such as resilience. This study assessed resilience factors among parents of children surviving acute lymphoblastic leukaemia and parents of healthy children. We also explored the association between parental resilience and mental health. The study compared 57 parents of 40 children from eight to 15 years of age in remission from acute lymphoblastic leukaemia and 63 parents of 42 healthy children. The Resilience Scale for Adults and the General Health Questionnaire were used to assess parental resilience and mental health. Parents of children surviving acute lymphoblastic leukaemia showed significantly lower levels of resilience than parents of healthy children, but no significant difference was found for mental health. Certain resilience factors were positively associated with mental health, especially for mothers, such as family cohesion, good perception of self and being able to plan their future. Resilience factors may help to protect parents' mental health, especially mothers, when their child has survived acute lymphoblastic leukaemia and should be considered in a clinical setting. Further research on resilience factors for fathers is needed. ©2015 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

Health literacy and mortality: a cohort study of patients hospitalized for acute heart failure.

PubMed

McNaughton, Candace D; Cawthon, Courtney; Kripalani, Sunil; Liu, Dandan; Storrow, Alan B; Roumie, Christianne L

2015-04-29

More than 30% of patients hospitalized for heart failure are rehospitalized or die within 90 days of discharge. Lower health literacy is associated with mortality among outpatients with chronic heart failure; little is known about this relationship after hospitalization for acute heart failure. Patients hospitalized for acute heart failure and discharged home between November 2010 and June 2013 were followed through December 31, 2013. Nurses administered the Brief Health Literacy Screen at admission; low health literacy was defined as Brief Health Literacy Screen ≤9. The primary outcome was all-cause mortality. Secondary outcomes were time to first rehospitalization and, separately, time to first emergency department visit within 90 days of discharge. Cox proportional hazards models determined their relationships with health literacy, adjusting for age, gender, race, insurance, education, comorbidity, and hospital length of stay. For the 1379 patients, average age was 63.1 years, 566 (41.0%) were female, and 324 (23.5%) had low health literacy. Median follow-up was 20.7 months (interquartile range 12.8 to 29.6 months), and 403 (29.2%) patients died. Adjusted hazard ratio [aHR] for death among patients with LHL was 1.32 (95%confidence interval [CI] 1.05, 1.66, P=0.02) compared to BHLS>9 [corrected].Within 90 days of discharge, there were 415 (30.1%) rehospitalizations and 201 (14.6%) emergency department visits, with no evident association with health literacy. Lower health literacy was associated with increased risk of death after hospitalization for acute heart failure. There was no evident relationship between health literacy and 90-day rehospitalization or emergency department visits. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Quality of health information on acute myocardial infarction and stroke in the world wide web.

PubMed

Bastos, Ana; Paiva, Dagmara; Azevedo, Ana

2014-01-01

The quality of health information in the Internet may be low. This is a concerning issue in cardiovascular diseases which warrant patient self-management. We aimed to assess the quality of Portuguese websites as a source of health information on acute myocardial infarction and stroke. We used the search terms 'enfarte miocardio' and 'acidente vascular cerebral' (Portuguese terms for myocardial infarction and stroke) on Google(®), on April 5th and 7th 2011, respectively, using Internet Explorer(®). The first 200 URL retrieved in each search were independently visited and Portuguese websites in Portuguese language were selected. We analysed and classified 121 websites for structural characteristics, information coverage and accuracy of the web pages with items defined a priori, trustworthiness in general according to the Health on the Net Foundation and regarding treatments using the DISCERN instrument (48 websites). Websites were most frequently commercial (49.5%), not exclusively dedicated to acute myocardial infarction/ stroke (94.2%), and with information on medical facts (59.5%), using images, video or animation (60.3%). Websites' trustworthiness was low. None of the websites displayed the Health on the Net Foundation seal. Acute myocardial infarction/ stroke websites differed in information coverage but the accuracy of the information was acceptable, although often incomplete. The quality of information on acute myocardial infarction/ stroke in Portuguese websites was acceptable. Trustworthiness was low, impairing users' capability of identifying potentially more reliable content.

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...

Epidemiology of Recurrent Acute and Chronic Pancreatitis: Similarities and Differences.

PubMed

Machicado, Jorge D; Yadav, Dhiraj

2017-07-01

Emerging data in the past few years suggest that acute, recurrent acute (RAP), and chronic pancreatitis (CP) represent a disease continuum. This review discusses the similarities and differences in the epidemiology of RAP and CP. RAP is a high-risk group, comprised of individuals at varying risk of progression. The premise is that RAP is an intermediary stage in the pathogenesis of CP, and a subset of RAP patients during their natural course transition to CP. Although many clinical factors have been identified, accurately predicting the probability of disease course in individual patients remains difficult. Future studies should focus on providing more precise estimates of the risk of disease transition in a cohort of patients, quantification of clinical events during the natural course of disease, and discovery of biomarkers of the different stages of the disease continuum. Availability of clinically relevant endpoints and linked biomarkers will allow more accurate prediction of the natural course of disease over intermediate- or long-term-based characteristics of an individual patient. These endpoints will also provide objective measures for use in clinical trials of interventions that aim to alter the natural course of disease.

Mental and social health during and after acute emergencies: emerging consensus?

PubMed Central

van Ommeren, Mark; Saxena, Shekhar; Saraceno, Benedetto

2005-01-01

Mental health care programmes during and after acute emergencies in resource-poor countries have been considered controversial. There is no agreement on the public health value of the post-traumatic stress disorder concept and no agreement on the appropriateness of vertical (separate) trauma-focused services. A range of social and mental health intervention strategies and principles seem, however, to have the broad support of expert opinion. Despite continuing debate, there is emerging agreement on what entails good public health practice in respect of mental health. In terms of early interventions, this agreement is exemplified by the recent inclusion of a "mental and social aspects of health" standard in the Sphere handbook's revision on minimal standards in disaster response. This affirmation of emerging agreement is important and should give clear messages to health planners. PMID:15682252

Developing acute-to-chronic toxicity ratios for lead, cadmium, and zinc using rainbow trout, a mayfly, and a midge

USGS Publications Warehouse

Mebane, C.A.; Hennessy, D.P.; Dillon, F.S.

2008-01-01

In order to estimate acute-to-chronic toxicity ratios (ACRs) relevant to a coldwater stream community, we exposed rainbow trout (Oncorhynchus mykiss) to cadmium (Cd), lead (Pb), and zinc (Zn) in 96-h acute and 60+ day early-life stage (ELS) exposures. We also tested the acute and sublethal responses of a mayfly (Baetis tricaudatus) and a midge (Chironomus dilutus, formerly C. tentans) with Pb. We examine the statistical interpretation of test endpoints and the acute-to-chronic ratio concept. Increasing the number of control replicates by 2 to 3x decreased the minimum detectable differences by almost half. Pb ACR estimates mostly increased with increasing acute resistance of the organisms (rainbow trout ACRs endpoint and statistical analysis influenced ACR estimates by up to a factor of four. When calculated using the geometric means of the no- and lowest-observed effect concentrations, ACRs with rainbow trout and Cd were 0.6 and 0.95; Zn about 1.0; and for Pb 3.3 and 11. The comparable Pb ACRs for the mayfly and Chironomus were 5.2 and 51 respectively. Our rainbow trout ACRs with Pb were about 5-20x lower than earlier reports with salmonids. We suggest discounting previous ACR results that used larger and older fish in their acute tests. ?? 2007 GovernmentEmployee: U.S. Geological Survey.

Defining Surrogate Endpoints for Clinical Trials in Severe Falciparum Malaria

PubMed Central

Plewes, Katherine; Maude, Richard J.; Hanson, Josh; Herdman, M. Trent; Leopold, Stije J.; Ngernseng, Thatsanun; Charunwatthana, Prakaykaew; Phu, Nguyen Hoan; Ghose, Aniruddha; Hasan, M. Mahtab Uddin; Fanello, Caterina I.; Faiz, Md Abul; Hien, Tran Tinh; Day, Nicholas P. J.; White, Nicholas J.; Dondorp, Arjen M.

2017-01-01

Background Clinical trials in severe falciparum malaria require a large sample size to detect clinically meaningful differences in mortality. This means few interventions can be evaluated at any time. Using a validated surrogate endpoint for mortality would provide a useful alternative allowing a smaller sample size. Here we evaluate changes in coma score and plasma lactate as surrogate endpoints for mortality in severe falciparum malaria. Methods Three datasets of clinical studies in severe malaria were re-evaluated: studies from Chittagong, Bangladesh (adults), the African ‘AQUAMAT’ trial comparing artesunate and quinine (children), and the Vietnamese ‘AQ’ study (adults) comparing artemether with quinine. The absolute change, relative change, slope of the normalization over time, and time to normalization were derived from sequential measurements of plasma lactate and coma score, and validated for their use as surrogate endpoint, including the proportion of treatment effect on mortality explained (PTE) by these surrogate measures. Results Improvements in lactate concentration or coma scores over the first 24 hours of admission, were strongly prognostic for survival in all datasets. In hyperlactataemic patients in the AQ study (n = 173), lower mortality with artemether compared to quinine closely correlated with faster reduction in plasma lactate concentration, with a high PTE of the relative change in plasma lactate at 8 and 12 hours of 0.81 and 0.75, respectively. In paediatric patients enrolled in the ‘AQUAMAT’ study with cerebral malaria (n = 785), mortality was lower with artesunate compared to quinine, but this was not associated with faster coma recovery. Conclusions The relative changes in plasma lactate concentration assessed at 8 or 12 hours after admission are valid surrogate endpoints for severe malaria studies on antimalarial drugs or adjuvant treatments aiming at improving the microcirculation. Measures of coma recovery are not valid

Defining Surrogate Endpoints for Clinical Trials in Severe Falciparum Malaria.

PubMed

Jeeyapant, Atthanee; Kingston, Hugh W; Plewes, Katherine; Maude, Richard J; Hanson, Josh; Herdman, M Trent; Leopold, Stije J; Ngernseng, Thatsanun; Charunwatthana, Prakaykaew; Phu, Nguyen Hoan; Ghose, Aniruddha; Hasan, M Mahtab Uddin; Fanello, Caterina I; Faiz, Md Abul; Hien, Tran Tinh; Day, Nicholas P J; White, Nicholas J; Dondorp, Arjen M

2017-01-01

Clinical trials in severe falciparum malaria require a large sample size to detect clinically meaningful differences in mortality. This means few interventions can be evaluated at any time. Using a validated surrogate endpoint for mortality would provide a useful alternative allowing a smaller sample size. Here we evaluate changes in coma score and plasma lactate as surrogate endpoints for mortality in severe falciparum malaria. Three datasets of clinical studies in severe malaria were re-evaluated: studies from Chittagong, Bangladesh (adults), the African 'AQUAMAT' trial comparing artesunate and quinine (children), and the Vietnamese 'AQ' study (adults) comparing artemether with quinine. The absolute change, relative change, slope of the normalization over time, and time to normalization were derived from sequential measurements of plasma lactate and coma score, and validated for their use as surrogate endpoint, including the proportion of treatment effect on mortality explained (PTE) by these surrogate measures. Improvements in lactate concentration or coma scores over the first 24 hours of admission, were strongly prognostic for survival in all datasets. In hyperlactataemic patients in the AQ study (n = 173), lower mortality with artemether compared to quinine closely correlated with faster reduction in plasma lactate concentration, with a high PTE of the relative change in plasma lactate at 8 and 12 hours of 0.81 and 0.75, respectively. In paediatric patients enrolled in the 'AQUAMAT' study with cerebral malaria (n = 785), mortality was lower with artesunate compared to quinine, but this was not associated with faster coma recovery. The relative changes in plasma lactate concentration assessed at 8 or 12 hours after admission are valid surrogate endpoints for severe malaria studies on antimalarial drugs or adjuvant treatments aiming at improving the microcirculation. Measures of coma recovery are not valid surrogate endpoints for mortality.

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.

Pathways to catastrophic health expenditure for acute coronary syndrome in Kerala: ‘Good health at low cost’?

PubMed Central

2012-01-01

Background Universal health coverage through the removal of financial and other barriers to access, particularly for people who are poor, is a global priority. This viewpoint describes the many pathways to catastrophic health expenditure (CHE) for patients with Acute Coronary Syndrome (ACS) based on two case studies and the thematic analysis of field notes regarding 210 patients and their households from a study based in Kerala, India. Discussion There is evidence of the severe financial impact of non-communicable diseases (NCDs), which is in contradiction to the widely acclaimed Kerala model: Good health at low cost. However, it is important to look beyond the out-of-pocket expenditure (OOPE) and CHE to the possible pathways and identify the triggers that make families vulnerable to CHE. The identified pathways include a primary and secondary loop. The primary pathway describes the direct path by which families experience CHE. These include: 1) factors related to the pre-event period that increase the likelihood of experiencing CHE, such as being from the lower socio-economic strata (SES), past financial losses or loans that leave families with no financial shock absorber at the time of illness; 2) factors related to the acute event, diagnosis, treatment and hospitalization and expenditures incurred for the same and; 3) factors related to the post-event period such as loss of gainful employment and means of financing both the acute period and the long-term management particularly through distress financing. The secondary pathway arises from the primary and includes: 1) the impact of distress financing and; 2) the long- and short- term consequences of CHE. These factors ultimately result in a vicious cycle of debt and poverty through non-compliance and repeat acute events. Summary This paper outlines the direct and indirect pathways by which patients with ACS and their families are trapped in a vicious cycle of debt and poverty. It also contradicts the prevailing

Large Dataset of Acute Oral Toxicity Data Created for Testing in Silico Models (ASCCT meeting)

EPA Science Inventory

Acute toxicity data is a common requirement for substance registration in the US. Currently only data derived from animal tests are accepted by regulatory agencies, and the standard in vivo tests use lethality as the endpoint. Non-animal alternatives such as in silico models are ...

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

Trial endpoints for drug approval in oncology: Chemoprevention.

PubMed

Beitz, J

2001-04-01

As with other drugs, new drug applications for marketing approval of chemopreventive drugs must include data from adequate and well-controlled clinical trials that demonstrate effectiveness and safety for the intended use. This article summarizes the regulatory requirements for traditional marketing approval, as well as for approval under the accelerated approval regulations. Unlike traditional approval, accelerated approval is based on a surrogate endpoint that is reasonably likely to predict clinical benefit. Discussions with the Food and Drug Administration (FDA) regarding the validity of trial endpoints that may serve as surrogates for clinical benefit for accelerated approval should take place as early as possible in drug development. Meetings with the FDA to discuss these issues may be requested throughout the clinical development of a new drug.

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.

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

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.

A Review of Clinical Trial Endpoints of Patients with Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension and How They Relate to Patient Outcomes in the United States.

PubMed

Divers, Christine; Platt, David; Wang, Edward; Lin, Jay; Lingohr-Smith, Melissa; Mathai, Stephen C

2017-01-01

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are subgroups of pulmonary hypertension and are considered rare diseases. Understanding how endpoints of clinical trials (and patient registry studies) of patients with PAH and CTEPH are associated with patient outcomes is important in order to address the concerns of patients, health care providers, decision makers, and payers. The purpose of this review was to examine how endpoints used in clinical trials and patient registry studies are associated with outcomes of patients with PAH and CTEPH. A PubMed literature search was conducted to retrieve published studies, including randomized phase III clinical trials and observational studies, from years 2000 to May 2015 that evaluated the associations between change in 6-minute walking distance (6MWD), 6MWD thresholds, change in World Health Organization functional class (WHO-FC), and time to clinical worsening with outcomes of patients with PAH and CTEPH. Based on this review of published literature, a reduction in 6MWD as a criterion for PAH worsening, a deterioration in WHO-FC, and delay in the time to clinical worsening are clinically meaningful trial endpoints and are associated with outcomes of patients with PAH and CTEPH. Utilization and standardization of these endpoints will be useful for comparing interventions of clinical trials and therapies. Hospitalizations are frequent among patients with PAH and CTEPH, and total health care costs are high. From a U.S. payer perspective, clinical worsening is an important composite endpoint in that it includes hospitalization, which can be transformed into a preventative cost value associated with efficacious treatment of patients with PAH and CTEPH. In view of the greater number of medications available to treat PAH, the introduction of the first approved therapy to treat CTEPH, and the increasing use of combination pharmacotherapy, reliable prognostic markers of treatment

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.

Comparison of RNA-seq and microarray-based models for clinical endpoint prediction.

PubMed

Zhang, Wenqian; Yu, Ying; Hertwig, Falk; Thierry-Mieg, Jean; Zhang, Wenwei; Thierry-Mieg, Danielle; Wang, Jian; Furlanello, Cesare; Devanarayan, Viswanath; Cheng, Jie; Deng, Youping; Hero, Barbara; Hong, Huixiao; Jia, Meiwen; Li, Li; Lin, Simon M; Nikolsky, Yuri; Oberthuer, André; Qing, Tao; Su, Zhenqiang; Volland, Ruth; Wang, Charles; Wang, May D; Ai, Junmei; Albanese, Davide; Asgharzadeh, Shahab; Avigad, Smadar; Bao, Wenjun; Bessarabova, Marina; Brilliant, Murray H; Brors, Benedikt; Chierici, Marco; Chu, Tzu-Ming; Zhang, Jibin; Grundy, Richard G; He, Min Max; Hebbring, Scott; Kaufman, Howard L; Lababidi, Samir; Lancashire, Lee J; Li, Yan; Lu, Xin X; Luo, Heng; Ma, Xiwen; Ning, Baitang; Noguera, Rosa; Peifer, Martin; Phan, John H; Roels, Frederik; Rosswog, Carolina; Shao, Susan; Shen, Jie; Theissen, Jessica; Tonini, Gian Paolo; Vandesompele, Jo; Wu, Po-Yen; Xiao, Wenzhong; Xu, Joshua; Xu, Weihong; Xuan, Jiekun; Yang, Yong; Ye, Zhan; Dong, Zirui; Zhang, Ke K; Yin, Ye; Zhao, Chen; Zheng, Yuanting; Wolfinger, Russell D; Shi, Tieliu; Malkas, Linda H; Berthold, Frank; Wang, Jun; Tong, Weida; Shi, Leming; Peng, Zhiyu; Fischer, Matthias

2015-06-25

Gene expression profiling is being widely applied in cancer research to identify biomarkers for clinical endpoint prediction. Since RNA-seq provides a powerful tool for transcriptome-based applications beyond the limitations of microarrays, we sought to systematically evaluate the performance of RNA-seq-based and microarray-based classifiers in this MAQC-III/SEQC study for clinical endpoint prediction using neuroblastoma as a model. We generate gene expression profiles from 498 primary neuroblastomas using both RNA-seq and 44 k microarrays. Characterization of the neuroblastoma transcriptome by RNA-seq reveals that more than 48,000 genes and 200,000 transcripts are being expressed in this malignancy. We also find that RNA-seq provides much more detailed information on specific transcript expression patterns in clinico-genetic neuroblastoma subgroups than microarrays. To systematically compare the power of RNA-seq and microarray-based models in predicting clinical endpoints, we divide the cohort randomly into training and validation sets and develop 360 predictive models on six clinical endpoints of varying predictability. Evaluation of factors potentially affecting model performances reveals that prediction accuracies are most strongly influenced by the nature of the clinical endpoint, whereas technological platforms (RNA-seq vs. microarrays), RNA-seq data analysis pipelines, and feature levels (gene vs. transcript vs. exon-junction level) do not significantly affect performances of the models. We demonstrate that RNA-seq outperforms microarrays in determining the transcriptomic characteristics of cancer, while RNA-seq and microarray-based models perform similarly in clinical endpoint prediction. Our findings may be valuable to guide future studies on the development of gene expression-based predictive models and their implementation in clinical practice.

Endpoints in medical communication research, proposing a framework of functions and outcomes.

PubMed

de Haes, Hanneke; Bensing, Jozien

2009-03-01

The evidence base of medical communication has been underdeveloped and the field was felt to be in need for thorough empirical investigation. Studying medical communication can help to clarify what happens during medical encounters and, subsequently, whether the behavior displayed is effective. However, before effectiveness can be established, one should argue what functions or goals the communication has and what outcomes are relevant in medical communication research. In the present paper, we first suggest the six function model of medical communication based on the integration of earlier models. The model distinguishes (1) fostering the relationship, (2) gathering information, (3) information provision, (4) decision making, (5) enabling disease and treatment-related behavior, and (6) responding to emotions. Secondly, a framework for endpoints in such research is presented. Immediate, intermediate and long-term outcomes are distinguished on the one hand and patient-, provider- and process- or context-related outcomes on the other. Based on this framework priorities can be defined and a tentative hierarchy proposed. Health is suggested to be the primary goal of medical communication as are patient-related outcomes. Dilemmas are described. Finally, in medical communication research, theory is advocated to link health care provider behavior or skills to outcomes and to connect intermediate outcomes to long-term ones. By linking specific communication elements to concrete endpoints within the six function model of medical communication, communication will become better integrated within the process of medical care. This is helpful to medical teachers and motivational to medical students. This approach can provide the place to medical communication it deserves in the center of medical care.

Degree of target utilization influences the location of movement endpoint distributions.

PubMed

Slifkin, Andrew B; Eder, Jeffrey R

2017-03-01

According to dominant theories of motor control, speed and accuracy are optimized when, on the average, movement endpoints are located at the target center and when the variability of the movement endpoint distributions is matched to the width of the target (viz., Meyer, Abrams, Kornblum, Wright, & Smith, 1988). The current study tested those predictions. According to the speed-accuracy trade-off, expanding the range of variability to the amount permitted by the limits of the target boundaries allows for maximization of movement speed while centering the distribution on the target center prevents movement errors that would have occurred had the distribution been off center. Here, participants (N=20) were required to generate 100 consecutive targeted hand movements under each of 15 unique conditions: There were three movement amplitude requirements (80, 160, 320mm) and within each there were five target widths (5, 10, 20, 40, 80mm). According to the results, it was only at the smaller target widths (5, 10mm) that movement endpoint distributions were centered on the target center and the range of movement endpoint variability matched the range specified by the target boundaries. As target width increased (20, 40, 80mm), participants increasingly undershot the target center and the range of movement endpoint variability increasingly underestimated the variability permitted by the target region. The degree of target center undershooting was strongly predicted by the difference between the size of the target and the amount of movement endpoint variability, i.e., the amount of unused space in the target. The results suggest that participants have precise knowledge of their variability relative to that permitted by the target, and they use that knowledge to systematically reduce the travel distance to targets. The reduction in travel distance across the larger target widths might have resulted in greater cost savings than those associated with increases in speed

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.

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.

Review of meta-analyses evaluating surrogate endpoints for overall survival in oncology

PubMed Central

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. PMID:23109809

LIFE CYCLE IMPACT ASSESSMENT - MIDPOINTS VS. ENDPOINTS

EPA Science Inventory

The question of whether to use midpoints or endpoints or both in an LCIA framework is often dependent upon the goal and scope and the decision that is being supported by the LCIA. LCIAs for Enlightenment may not require an aggregation of impact categories and may be most useful ...

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...

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.

Solitaire™ with the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke (SWIFT PRIME) trial: protocol for a randomized, controlled, multicenter study comparing the Solitaire revascularization device with IV tPA with IV tPA alone in acute ischemic stroke.

PubMed

Saver, Jeffrey L; Goyal, Mayank; Bonafe, Alain; Diener, Hans-Christoph; Levy, Elad I; Pereira, Vitor M; Albers, Gregory W; Cognard, Christophe; Cohen, David J; Hacke, Werner; Jansen, Olav; Jovin, Tudor G; Mattle, Heinrich P; Nogueira, Raul G; Siddiqui, Adnan H; Yavagal, Dileep R; Devlin, Thomas G; Lopes, Demetrius K; Reddy, Vivek; du Mesnil de Rochemont, Richard; Jahan, Reza

2015-04-01

Early reperfusion in patients experiencing acute ischemic stroke is critical, especially for patients with large vessel occlusion who have poor prognosis without revascularization. Solitaire™ stent retriever devices have been shown to immediately restore vascular perfusion safely, rapidly, and effectively in acute ischemic stroke patients with large vessel occlusions. The aim of the study was to demonstrate that, among patients with large vessel, anterior circulation occlusion who have received intravenous tissue plasminogen activator, treatment with Solitaire revascularization devices reduces degree of disability 3 months post stroke. The study is a global multicenter, two-arm, prospective, randomized, open, blinded end-point trial comparing functional outcomes in acute ischemic stroke patients who are treated with either intravenous tissue plasminogen activator alone or intravenous tissue plasminogen activator in combination with the Solitaire device. Up to 833 patients will be enrolled. Patients who have received intravenous tissue plasminogen activator are randomized to either continue with intravenous tissue plasminogen activator alone or additionally proceed to neurothrombectomy using the Solitaire device within six-hours of symptom onset. The primary end-point is 90-day global disability, assessed with the modified Rankin Scale (mRS). Secondary outcomes include mortality at 90 days, functional independence (mRS ≤ 2) at 90 days, change in National Institutes of Health Stroke Scale at 27 h, reperfusion at 27 h, and thrombolysis in cerebral infarction 2b/3 flow at the end of the procedure. Statistical analysis will be conducted using simultaneous success criteria on the overall distribution of modified Rankin Scale (Rankin shift) and proportions of subjects achieving functional independence (mRS 0-2). © 2015 The Authors. International Journal of Stroke published by John Wiley & Sons Ltd on behalf of World Stroke Organization.

A systematic comparison of recurrent event models for application to composite endpoints.

PubMed

Ozga, Ann-Kathrin; Kieser, Meinhard; Rauch, Geraldine

2018-01-04

Many clinical trials focus on the comparison of the treatment effect between two or more groups concerning a rarely occurring event. In this situation, showing a relevant effect with an acceptable power requires the observation of a large number of patients over a long period of time. For feasibility issues, it is therefore often considered to include several event types of interest, non-fatal or fatal, and to combine them within a composite endpoint. Commonly, a composite endpoint is analyzed with standard survival analysis techniques by assessing the time to the first occurring event. This approach neglects that an individual may experience more than one event which leads to a loss of information. As an alternative, composite endpoints could be analyzed by models for recurrent events. There exists a number of such models, e.g. regression models based on count data or Cox-based models such as the approaches of Andersen and Gill, Prentice, Williams and Peterson or, Wei, Lin and Weissfeld. Although some of the methods were already compared within the literature there exists no systematic investigation for the special requirements regarding composite endpoints. Within this work a simulation-based comparison of recurrent event models applied to composite endpoints is provided for different realistic clinical trial scenarios. We demonstrate that the Andersen-Gill model and the Prentice- Williams-Petersen models show similar results under various data scenarios whereas the Wei-Lin-Weissfeld model delivers effect estimators which can considerably deviate under commonly met data scenarios. Based on the conducted simulation study, this paper helps to understand the pros and cons of the investigated methods in the context of composite endpoints and provides therefore recommendations for an adequate statistical analysis strategy and a meaningful interpretation of results.

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...

Experiences of mental health nursing staff working with voice hearers in an acute setting: An interpretive phenomenological approach.

PubMed

McMullan, E; Gupta, A; Collins, S C

2018-04-01

WHAT IS KNOWN ON THE SUBJECT?: Community mental health staff and their service users have reported mixed views on the importance of talking about the content of voices. Community staff have reported feeling that they do not have the skills to explore voice content and worry about making things worse. Voice hearers experiencing extreme distress due to the content of their voices can access support through acute inpatient mental health services. No previous studies have focused on the experiences of staff who nurse voice hearers at a time of acute distress. WHAT DOES THIS STUDY ADD TO EXISTING KNOWLEDGE?: MHNs and HSWs working with voice hearers in acute distress report feeling powerless and helpless, as they feel that they cannot lessen the distress experienced by the voice hearer. Despite these difficult feelings, staff report finding ways of coping, including using structured tools to help make sense of their service users' voice-hearing experiences and accessing reflective practice forums. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Due to the current context of increased acuity and limited resources in acute services, there may be a need to further protect time for staff to access reflective practice groups and supervision forums to help them manage the difficult feelings arising from their work with voice hearers. Introduction Mental health nursing (MHN) staff in acute settings work with voice hearers at times of crises when they experience high levels of distress. Previous research has focused on community mental health staff's experiences and their service users views on exploring the content of voices. No studies have explored this from an acute mental health service perspective. Aim This study therefore sought to explore the experiences of staff working with voice hearers in an acute mental health service. Method Due to the exploratory nature of the research, a qualitative design was chosen. Three MHNs and five healthcare support workers (HSWs) were

[Efficacy of racecadotril vs. smectite, probiotics or zinc as an integral part of treatment of acute diarrhea in children under five years: A meta-analysis of multiple treatments].

PubMed

Gutiérrez-Castrellón, Pedro; Ortíz-Hernández, Anna Alejandra; Llamosas-Gallardo, Beatriz; Acosta-Bastidas, Mario A; Jiménez-Gutiérrez, Carlos; Diaz-García, Luisa; Anzo-Osorio, Anahí; Estevez-Jiménez, Juliana; Jiménez-Escobar, Irma; Vidal-Vázquez, Rosa Patricia

2015-01-01

Despite major advances in treatment, acute diarrhea continues to be a public health problem in children under five years. There is no systematic approach to treatment and most evidence is assembled comparing active treatment vs. placebo. Systematic review of evidence on efficacy of adjuvants for treatment of acute diarrhea through a network meta-analysis. A systematic search of multiple databases searching clinical trials related to the use of racecadotril, smectite, Lactobacillus GG, Lactobacillus reuteri, Saccharomyces boulardii and zinc as adjuvants in acute diarrhea was done. The primary endpoint was duration of diarrhea. Information is displayed through network meta-analysis.The superiority of each coadjutant was analyzed by Sucra approach. Network meta-analysis showed race cadotril was better when compared with placebo and other adjuvants. Sucra analysis showed racecadotril as the first option followed by smectite and Lactobacillus reuteri. Considering a strategic decision making approach, network meta-analysis allows us to establish the therapeutic superiority of racecadotril as an adjunct for the comprehensive management of acute diarrhea in children aged less than five years.

Acute physiology and chronic health evaluation (APACHE II) and Medicare reimbursement

PubMed Central

Wagner, Douglas P.; Draper, Elizabeth A.

1984-01-01

This article describes the potential for the acute physiology score (APS) of acute physiology and chronic health evaluation (APACHE) II, to be used as a severity adjustment to diagnosis-related groups (DRG's) or other diagnostic classifications. The APS is defined by a relative value scale applied to 12 objective physiologic variables routinely measured on most hospitalized patients shortly after hospital admission. For intensive care patients, APS at admission is strongly related to subsequent resource costs of intensive care for 5,790 consecutive admissions to 13 large hospitals, across and within diagnoses. The APS could also be used to evaluate quality of care, medical technology, and the response to changing financial incentives. PMID:10311080

Development of acute and chronic sediment bioassays with the harpacticoid copepod Quinquelaophonte sp.

PubMed

Stringer, Tristan J; Glover, Chris N; Keesing, Vaughan; Northcott, Grant L; Gaw, Sally; Tremblay, Louis A

2014-01-01

Reliable environmentally realistic bioassay methodologies are increasingly needed to assess the effects of environmental pollution. This study describes two estuarine sediment bioassays, one acute (96 h) and one chronic (14 d), with the New Zealand harpacticoid copepod Quinquelaophonte sp. utilising behavioural and reproductive endpoints. Spiked sediments were used to expose Quinquelaophonte sp. to three reference compounds representing important categories of estuarine chemical stressors: zinc (a metal), atrazine (a pesticide), and phenanthrene (a polycyclic aromatic hydrocarbon). Acute-to-chronic ratios (ACR) were used to further characterise species responses. Acute sediment (sandy and low total organic content) 96 h EC50 values for the sublethal inhibition of mobility for zinc, atrazine and phenanthrene were 137, 5.4, and 2.6 µg/g, respectively. The chronic EC50 values for inhibition of reproduction (total offspring) were 54.5, 0.0083, and 0.067 µg/g for zinc, atrazine, and phenanthrene, respectively. For phenanthrene, a potentially novel mode of action was identified on reproduction. Quinquelaophonte sp. was found to be more sensitive than several other estuarine species indicating choice of test organism is important to characterising the effects of environmentally relevant levels of contamination. The bioassay sediment results demonstrate the sensitivity and suitability of Quinquelaophonte sp. as a tool for the assessment use of estuarine health. © 2013 Published by Elsevier Inc.

The Sleep Apnea cardioVascular Endpoints (SAVE) Trial: Rationale, Ethics, Design, and Progress

PubMed Central

Antic, Nick A.; Heeley, Emma; Anderson, Craig S.; Luo, Yuanming; Wang, Jiguang; Neal, Bruce; Grunstein, Ron; Barbe, Ferran; Lorenzi-Filho, Geraldo; Huang, Shaoguang; Redline, Susan; Zhong, Nanshan; McEvoy, R. Doug

2015-01-01

The Sleep Apnea cardioVascular Endpoints (SAVE) study is an ongoing investigator-initiated and conducted, international, multicenter, open, blinded endpoint, randomized controlled trial that was designed to determine whether treatment of obstructive sleep apnea (OSA) with continuous positive airways pressure (CPAP) can reduce the risk of serious cardiovascular (CV) events in patients with established CV disease (clinical trial registration NCT00738179). The results of this study will have important implications for the provision of health care to patients with sleep apnea around the world. The SAVE study has brought together respiratory, sleep, CV and stroke clinicians-scientists in an interdisciplinary collaboration with industry and government sponsorship to conduct an ambitious clinical trial. Following its launch in Australia and China in late 2008, the recruitment network expanded across 89 sites that included New Zealand, India, Spain, USA, and Brazil for a total of 2,717 patients randomized by December 2013. These patients are being followed until December 2015 so that the average length of follow-up of the cohort will be over 4 y. This article describes the rationale for the SAVE study, considerations given to the design including how various cultural and ethical challenges were addressed, and progress in establishing and maintaining the recruitment network, patient follow-up, and adherence to CPAP and procedures. The assumptions underlying the original trial sample size calculation and why this was revised downward in 2012 are also discussed. Clinical Trials Registration Number: NCT00738179. Australia New Zealand Clinical Trials Registry Number: ACTRN12608000409370. Citation: Antic NA, Heeley E, Anderson CS, Luo Y, Wang J, Neal B, Grunstein R, Barbe F, Lorenzi-Filho G, Huang S, Redline S, Zhong N, McEvoy RD. The sleep apnea cardiovascular endpoints (SAVE) trial: rationale, ethics, design, and progress. SLEEP 2015;38(8):1247–1257. PMID:25669180

Mobile integrated health to reduce post-discharge acute care visits: A pilot study.

PubMed

Siddle, Jennica; Pang, Peter S; Weaver, Christopher; Weinstein, Elizabeth; O'Donnell, Daniel; Arkins, Thomas P; Miramonti, Charles

2018-05-01

Mobile Integrated Health (MIH) leverages specially trained paramedics outside of emergency response to bridge gaps in local health care delivery. To evaluate the efficacy of a MIH led transitional care strategy to reduce acute care utilization. This was a retrospective cohort analysis of a quality improvement pilot of patients from an urban, single county EMS, MIH transitional care initiative. We utilized a paramedic/social worker (or social care coordinator) dyad to provide in home assessments, medication review, care coordination, and improve access to care. The primary outcome compared acute care utilization (ED visits, observation stays, inpatient visits) 90days before MIH intervention to 90days after. Of the 203 patients seen by MIH teams, inpatient utilization decreased significantly from 140 hospitalizations pre-MIH to 26 post-MIH (83% reduction, p=0.00). ED and observation stays, however, increased numerically, but neither was significant. (ED 18 to 19 stays, p=0.98; observation stays 95 to 106, p=0.30) Primary care visits increased 15% (p=0.11). In this pilot before/after study, MIH significantly reduces acute care hospitalizations. Copyright © 2017 Elsevier Inc. All rights reserved.

Combining SVM and flame radiation to forecast BOF end-point

NASA Astrophysics Data System (ADS)

Wen, Hongyuan; Zhao, Qi; Xu, Lingfei; Zhou, Munchun; Chen, Yanru

2009-05-01

Because of complex reactions in Basic Oxygen Furnace (BOF) for steelmaking, the main end-point control methods of steelmaking have insurmountable difficulties. Aiming at these problems, a support vector machine (SVM) method for forecasting the BOF steelmaking end-point is presented based on flame radiation information. The basis is that the furnace flame is the performance of the carbon oxygen reaction, because the carbon oxygen reaction is the major reaction in the steelmaking furnace. The system can acquire spectrum and image data quickly in the steelmaking adverse environment. The structure of SVM and the multilayer feed-ward neural network are similar, but SVM model could overcome the inherent defects of the latter. The model is trained and forecasted by using SVM and some appropriate variables of light and image characteristic information. The model training process follows the structure risk minimum (SRM) criterion and the design parameter can be adjusted automatically according to the sampled data in the training process. Experimental results indicate that the prediction precision of the SVM model and the executive time both meet the requirements of end-point judgment online.

Acute erythroid leukemia as defined in the World Health Organization classification is a rare and pathogenetically heterogeneous disease.

PubMed

Kasyan, Armen; Medeiros, L Jeffrey; Zuo, Zhuang; Santos, Favio P; Ravandi-Kashani, Farhad; Miranda, Roberto; Vadhan-Raj, Saroj; Koeppen, Hartmut; Bueso-Ramos, Carlos E

2010-08-01

The diagnostic criteria for acute erythroid leukemia have been controversial since this disease was initially described. Using the current World Health Organization classification criteria, we retrospectively reviewed cases of acute myeloid leukemia or myelodysplastic syndrome in which erythroid precursors were >or=50% of the bone marrow nucleated cell population and the diagnosis of erythroleukemia was considered using older classification schemes. We collected 90 cases and separated them into four diagnostic groups: acute erythroid leukemia, erythroleukemia or erythroid/myeloid type (n=20); acute myeloid leukemia with myelodysplasia-related changes (n=22); therapy-related acute myeloid leukemia (n=32); and refractory anemia with excess blasts and preceding or concurrent history of erythropoietin therapy for anemia (n=16). Patients with acute erythroid leukemia were the youngest patient group and had the best overall survival. There was a statistically significant difference in overall survival between patients with acute erythroid leukemia versus acute myeloid leukemia with myelodysplasia-related changes (P=0.003) and between patients with acute erythroid leukemia versus therapy-related acute myeloid leukemia (P<0.0001). The presence of complex cytogenetic abnormalities (>3) was the only statistically significant independent variable that adversely affected survival in the acute erythroid leukemia group. Monosomy 5/del(5q) and monosomy 7/del(7q) were overrepresented in the context of complex chromosomal abnormalities. Our data suggest that acute erythroid leukemia, as currently defined in the World Health Organization classification, has become a rare disease. A majority of the cases reported previously as erythroleukemia are now classified as other entities. In addition, our data suggest that the current definition of acute erythroid leukemia, erythroleukemia type remains heterogeneous. One subset of acute erythroid leukemia patients has relatively low blast

Analysis of risk factors for acute respiratory tract infections (ARI) of Toddlers in Ingin Jaya community health centre of Aceh Besar district

NASA Astrophysics Data System (ADS)

Safitri, Faradilla; Hayati, Risna; Marniati

2017-09-01

Acute Respiratory Infections (ARI) is a disease in developing countries 25% that caused the death of children under five. In Aceh province disease is always on the list of 10 biggest disease each year which amounted to 47.258 cases. In Ingin Jaya Community Health Centre cases of acute respiratory tract infections in infants in 2014 were 112 cases, while in 2015 an increase of as many as 123 cases. Objective: To analyze the risk factors of acute respiratory diseases in health centers of Toddlers Ingin Jaya, Aceh Besar district. Analytical research the design of case control, case-control comparison of 1: 1 ie the sample of 60 cases and 60 control, retrieval of data taken from the register space IMCI Health Center. The study was conducted in 2016. Results: Factor toddler age (OR=11.811), gender (OR=3.512), birth weight (OR=8.805), immunization status (OR=4.846), exclusive breastfeeding (OR=2.529). Conclusions and Recommendations: Toddlers aged>2 years has the opportunity 11.811 times of acute respiratory tract infections. Male Toddler has a chance 3.512 times of acute respiratory tract infections. Toddlers are born with a normal weight does not have a chance of 8.805 times of acute respiratory tract infections. Toddlers who do not get complete immunization has the opportunity 4.846 times of acute respiratory tract infections. Toddlers who did not receive exclusive breastfeeding has 2,529 times greater chance of respiratory tract infections. Health workers and the Aceh Provincial Health Office can provide information through health education each month for each work area of health centers, or create a billboard on the causes of the ispa in infants.

Comparing biomarkers as principal surrogate endpoints.

PubMed

Huang, Ying; Gilbert, Peter B

2011-12-01

Recently a new definition of surrogate endpoint, the "principal surrogate," was proposed based on causal associations between treatment effects on the biomarker and on the clinical endpoint. Despite its appealing interpretation, limited research has been conducted to evaluate principal surrogates, and existing methods focus on risk models that consider a single biomarker. How to compare principal surrogate value of biomarkers or general risk models that consider multiple biomarkers remains an open research question. We propose to characterize a marker or risk model's principal surrogate value based on the distribution of risk difference between interventions. In addition, we propose a novel summary measure (the standardized total gain) that can be used to compare markers and to assess the incremental value of a new marker. We develop a semiparametric estimated-likelihood method to estimate the joint surrogate value of multiple biomarkers. This method accommodates two-phase sampling of biomarkers and is more widely applicable than existing nonparametric methods by incorporating continuous baseline covariates to predict the biomarker(s), and is more robust than existing parametric methods by leaving the error distribution of markers unspecified. The methodology is illustrated using a simulated example set and a real data set in the context of HIV vaccine trials. © 2011, The International Biometric Society.

Fear of Severe Acute Respiratory Syndrome (SARS) among Health Care Workers

ERIC Educational Resources Information Center

Ho, Samuel M. Y.; Kwong-Lo, Rosalie S. Y.; Mak, Christine W. Y.; Wong, Joe S.

2005-01-01

In this study, the authors examined fear related to severe acute respiratory syndrome (SARS) among 2 samples of hospital staff in Hong Kong. Sample 1 included health care workers (n = 82) and was assessed during the peak of the SARS epidemic. Sample 2 included hospital staff who recovered from SARS (n = 97). The results show that participants in…

The Impact of Chemoembolization Endpoints on Survival in Hepatocellular Carcinoma Patients

PubMed Central

Jin, Brian; Wang, Dingxin; Lewandowski, Robert J.; Riaz, Ahsun; Ryu, Robert K.; Sato, Kent T.; Larson, Andrew C.; Salem, Riad; Omary, Reed A.

2010-01-01

OBJECTIVE To investigate the relationship between angiographic embolic endpoints of transarterial chemoembolization (TACE) and survival in patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS This study retrospectively assessed 105 patients with surgically unresectable HCC who underwent TACE. Patients were classified according to a previously established subjective angiographic chemoembolization endpoint (SACE) scale. Only one patient was classified as SACE level 1 and thus excluded from all subsequent analysis. Survival was evaluated with Kaplan-Meier analysis. Multivariate analysis with Cox’s proportional hazard regression model was used to determine independent prognostic risk factors of survival. RESULTS Overall median survival was 21.1 months (95% confidence interval [CI], 15.9–26.4). Patients embolized to SACE levels 2 and 3 were aggregated and had a significantly higher median survival (25.6 months; 95% CI, 16.2–35.0) than patients embolized to SACE level 4 (17.1 months; 95% CI, 13.3–20.9) (p = 0.035). Multivariate analysis indicated that SACE level 4 (Hazard ratio [HR], 2.49; 95% CI, 1.41–4.42; p = 0.002), European Cooperative Oncology Group performance status > 0 (HR, 1.97; 95% CI, 1.15–3.37; p = 0.013), American Joint Committee on Cancer stage 3 or 4 (HR, 2.42; 95% CI, 1.27–4.60; p = 0.007), and Child-Pugh class B (HR, 1.94; 95% CI, 1.09–3.46; p = 0.025) were all independent negative prognostic indicators of survival. CONCLUSION Embolization to an intermediate, sub-stasis endpoint (SACE levels 2 and 3) during TACE improves survival compared to embolization to a higher, stasis endpoint (SACE level 4). Interventional oncologists should consider targeting these intermediate, sub-stasis angiographic endpoints during TACE. PMID:21427346

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

Enhancing the fathead minnow fish embryo toxicity test: Optimizing embryo production and assessing the utility of additional test endpoints.

PubMed

Roush, Kyle S; Krzykwa, Julie C; Malmquist, Jacob A; Stephens, Dane A; Sellin Jeffries, Marlo K

2018-05-30

The fathead minnow fish embryo toxicity (FET) test has been identified as a potential alternative to toxicity test methods that utilize older fish. However, several challenges have been identified with the fathead minnow FET test, including: 1) difficulties in obtaining appropriately-staged embryos for FET test initiation, 2) a paucity of data comparing fathead minnow FET test performance to the fathead minnow larval growth and survival (LGS) test and 3) a lack of sublethal endpoints that could be used to estimate chronic toxicity and/or predict adverse effects. These challenges were addressed through three study objectives. The first objective was to optimize embryo production by assessing the effect of breeding group composition (number of males and females) on egg production. Results showed that groups containing one male and four females produced the largest clutches, enhancing the likelihood of procuring sufficient numbers of embryos for FET test initiation. The second study objective was to compare the performance of the FET test to that of the fathead minnow LGS test using three reference toxicants. The FET and LGS tests were similar in their ability to predict the acute toxicity of sodium chloride and ethanol, but the FET test was found to be more sensitive than the LGS test for sodium dodecyl sulfate. The last objective of the study was to evaluate the utility and practicality of several sublethal metrics (i.e., growth, developmental abnormalities and growth- and stress-related gene expression) as FET test endpoints. Developmental abnormalities, including pericardial edema and hatch success, were found to offer the most promise as additional FET test endpoints, given their responsiveness, potential for predicting adverse effects, ease of assessment and low cost of measurement. Copyright © 2018 Elsevier Inc. All rights reserved.

Weighted analysis of composite endpoints with simultaneous inference for flexible weight constraints.

PubMed

Duc, Anh Nguyen; Wolbers, Marcel

2017-02-10

Composite endpoints are widely used as primary endpoints of randomized controlled trials across clinical disciplines. A common critique of the conventional analysis of composite endpoints is that all disease events are weighted equally, whereas their clinical relevance may differ substantially. We address this by introducing a framework for the weighted analysis of composite endpoints and interpretable test statistics, which are applicable to both binary and time-to-event data. To cope with the difficulty of selecting an exact set of weights, we propose a method for constructing simultaneous confidence intervals and tests that asymptotically preserve the family-wise type I error in the strong sense across families of weights satisfying flexible inequality or order constraints based on the theory of χ¯2-distributions. We show that the method achieves the nominal simultaneous coverage rate with substantial efficiency gains over Scheffé's procedure in a simulation study and apply it to trials in cardiovascular disease and enteric fever. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

Bayesian meta-analytical methods to incorporate multiple surrogate endpoints in drug development process.

PubMed

Bujkiewicz, Sylwia; Thompson, John R; Riley, Richard D; Abrams, Keith R

2016-03-30

A number of meta-analytical methods have been proposed that aim to evaluate surrogate endpoints. Bivariate meta-analytical methods can be used to predict the treatment effect for the final outcome from the treatment effect estimate measured on the surrogate endpoint while taking into account the uncertainty around the effect estimate for the surrogate endpoint. In this paper, extensions to multivariate models are developed aiming to include multiple surrogate endpoints with the potential benefit of reducing the uncertainty when making predictions. In this Bayesian multivariate meta-analytic framework, the between-study variability is modelled in a formulation of a product of normal univariate distributions. This formulation is particularly convenient for including multiple surrogate endpoints and flexible for modelling the outcomes which can be surrogate endpoints to the final outcome and potentially to one another. Two models are proposed, first, using an unstructured between-study covariance matrix by assuming the treatment effects on all outcomes are correlated and second, using a structured between-study covariance matrix by assuming treatment effects on some of the outcomes are conditionally independent. While the two models are developed for the summary data on a study level, the individual-level association is taken into account by the use of the Prentice's criteria (obtained from individual patient data) to inform the within study correlations in the models. The modelling techniques are investigated using an example in relapsing remitting multiple sclerosis where the disability worsening is the final outcome, while relapse rate and MRI lesions are potential surrogates to the disability progression. © 2015 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

Health professionals' experience of teamwork education in acute hospital settings: a systematic review of qualitative literature.

PubMed

Eddy, Kylie; Jordan, Zoe; Stephenson, Matthew

2016-04-01

Teamwork is seen as an important element of patient care in acute hospital settings. The complexity of the journey of care for patients highlights the need for health professionals to collaborate and communicate clearly with each other. Health organizations in western countries are committed to improving patient safety through education of staff and teamwork education programs have been integral to this focus. There are no current systematic reviews of the experience of health professionals who participate in teamwork education in acute hospital settings. The objective of this systematic review was to search for the best available evidence on the experiences of health professionals who participate in teamwork education in acute hospital settings. This review considered studies reporting on experiences of registered health professionals who work in acute hospitals. This included medical, nursing and midwifery and allied health professionals. The focus of the meta-synthesis was the experiences and reflections of health professionals who were involved in teamwork education in acute hospital settings. The geographical context for this review was acute hospitals in rural or metropolitan settings in Australia and overseas countries. The review focused on the experiences of health professionals who work in acute hospitals and participated in teamwork education programs. This review considered studies that focused on qualitative data including, but not limited to, designs such as phenomenology, grounded theory, ethnography, action research and feminist research.In the absence of research studies, other text such as opinion papers, discussion papers and reports were considered. Studies published in English and from 1990 to 2013 were included in this review. The literature search for relevant papers occurred between 13 September and 26 October 2013. A three-step search strategy was utilized in this review. The databases searched were PubMed, CINAHL, Embase and Scopus. The

Principles and practical procedures for acute psychological first aid training for personnel without mental health experience.

PubMed

Everly, George S; Flynn, Brian W

2006-01-01

Most authorities agree that mass disasters leave in their wake a need for some form of acute mental health services. However, a review of current literature on crisis intervention and disaster mental health reveals differing points of view on the methods that should be employed (Raphael, 1986; NIMH, 2002). Nevertheless, there appears to be virtual universal endorsement, by relevant authorities, of the value of acute "psychological first aid" (American Psychiatric Association, 1954; USDHHS, 2004; Raphael, 1986; NIMH, 2002; Institute of Medicine, 2003; WHO, 2003; DoD/VAPTSD, 2004; Ritchie, et al., 2004; Friedman, Hamblin, Foa, & Charney, 2004). Psychological first aid (PFA), as an acute mental health intervention, seems uniquely applicable to public health settings, the workplace, the military, mass disaster venues, and even the demands of more well circumscribed critical incidents, e.g., dealing with the psychological aftermath of accidents, robberies, suicide, homicide, or community violence. In this document, we shall introduce the notion of psychological first aid (PFA) as one aspect of a psychological continuum of care, offer a rudimentary definition of PFA, and provide the reader with a practicalframework for its implementation utilizing the individual psychological first aid (iPFA)format. The goal of this paper is to better prepare public health, public safety, and other disaster response personnel who do not possess formal clinical mental health degrees or specialized training to provide iPFA services to primary and secondary disaster victims.

Does Insight Affect the Efficacy of Antipsychotics in Acute Mania?: An Individual Patient Data Regression Meta-Analysis.

PubMed

Welten, Carlijn C M; Koeter, Maarten W J; Wohlfarth, Tamar D; Storosum, Jitschak G; van den Brink, Wim; Gispen-de Wied, Christine C; Leufkens, Hubert G M; Denys, Damiaan A J P

2016-02-01

Patients having an acute manic episode of bipolar disorder often lack insight into their condition. Because little is known about the possible effect of insight on treatment efficacy, we examined whether insight at the start of treatment affects the efficacy of antipsychotic treatment in patients with acute mania. We used individual patient data from 7 randomized, double-blind, placebo-controlled registration studies of 4 antipsychotics in patients with acute mania (N = 1904). Insight was measured with item 11 of the Young Mania Rating Scale (YMRS) at baseline and study endpoint 3 weeks later. Treatment outcome was defined by (a) mean change score, (b) response defined as 50% or more improvement on YMRS, and (c) remission defined as YMRS score less than 8 at study endpoint. We used multilevel mixed effect linear (or logistic) regression analyses of individual patient data to assess the interaction between baseline insight and treatment outcomes. At treatment initiation, 1207 (63.5%) patients had impaired or no insight into their condition. Level of insight significantly modified the efficacy of treatment by mean change score (P = 0.039), response rate (P = 0.033), and remission rate (P = 0.043), with greater improvement in patients with more impaired insight. We therefore recommend that patients experiencing acute mania should be treated immediately and not be delayed until patients regain insight.

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.

A multicenter, randomized trial on neuroprotection with remote ischemic per-conditioning during acute ischemic stroke: the REmote iSchemic Conditioning in acUtE BRAin INfarction study protocol.

PubMed

Pico, Fernando; Rosso, Charlotte; Meseguer, Elena; Chadenat, Marie-Laure; Cattenoy, Amina; Aegerter, Philippe; Deltour, Sandrine; Yeung, Jennifer; Hosseini, Hassan; Lambert, Yves; Smadja, Didier; Samson, Yves; Amarenco, Pierre

2016-10-01

Rationale Remote ischemic per-conditioning-causing transient limb ischemia to induce ischemic tolerance in other organs-reduces final infarct size in animal stroke models. Aim To evaluate whether remote ischemic per-conditioning during acute ischemic stroke (<6 h) reduces brain infarct size at 24 h. Methods and design This study is being performed in five French hospitals using a prospective randomized open blinded end-point design. Adults with magnetic resonance imaging confirmed ischemic stroke within 6 h of symptom onset and clinical deficit of 5-25 according to National Institutes of Health Stroke Scale will be randomized 1:1 to remote ischemic per-conditioning or control (stratified by center and intravenous fibrinolysis use). Remote ischemic per-conditioning will consist of four cycles of electronic tourniquet inflation (5 min) and deflation (5 min) to a thigh within 6 h of symptom onset. Magnetic resonance imaging is repeated 24 h after stroke onset. Sample size estimates For a difference of 15 cm 3 in brain infarct growth between groups, 200 patients will be included for 5% significance and 80% power. Study outcomes The primary outcome will be the difference in brain infarct growth from baseline to 24 h in the intervention versus control groups (by diffusion-weighted image magnetic resonance imaging). Secondary outcomes include: National Institutes of Health Stroke Scale score absolute difference between baseline and 24 h, three-month modified Rankin score and daily living activities, mortality, and tolerance and side effects of remote ischemic per-conditioning. Discussion The only remote ischemic per-conditioning trial in humans with stroke did not show remote ischemic per-conditioning to be effective. REmote iSchemic Conditioning in acUtE BRAin INfarction, which has important design differences, should provide more information on the use of this intervention in patients with acute ischemic stroke.

A new proportion measure of the treatment effect captured by candidate surrogate endpoints.

PubMed

Kobayashi, Fumiaki; Kuroki, Manabu

2014-08-30

The use of surrogate endpoints is expected to play an important role in the development of new drugs, as they can be used to reduce the sample size and/or duration of randomized clinical trials. Biostatistical researchers and practitioners have proposed various surrogacy measures; however, (i) most of these surrogacy measures often fall outside the range [0,1] without any assumptions, (ii) these surrogacy measures do not provide a cut-off value for judging a surrogacy level of candidate surrogate endpoints, and (iii) most surrogacy measures are highly variable; thus, the confidence intervals are often unacceptably wide. In order to solve problems (i) and (ii), we propose a new surrogacy measure, a proportion of the treatment effect captured by candidate surrogate endpoints (PCS), on the basis of the decomposition of the treatment effect into parts captured and non-captured by the candidate surrogate endpoints. In order to solve problem (iii), we propose an estimation method based on the half-range mode method with the bootstrap distribution of the estimated surrogacy measures. Finally, through numerical experiments and two empirical examples, we show that the PCS with the proposed estimation method overcomes these difficulties. The results of this paper contribute to the reliable evaluation of how much of the treatment effect is captured by candidate surrogate endpoints. Copyright © 2014 John Wiley & Sons, Ltd.

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

Practice nurse and health visitor management of acute minor illness in a general practice.

PubMed

Pritchard, A; Kendrick, D

2001-11-01

To evaluate practice nurse (PN) and health visitor (HV) management of patients with acute minor illnesses, monitor the effect on general practitioner (GP) workload, and describe the range of conditions seen by nurses. Patients requesting 'urgent' appointments (within 24 hours) were offered consultations with a PN or HV trained in the management of acute minor illness. Comparative data were collected before and after the establishment of the acute minor illness service. A general practice in Nottingham, England. Patient satisfaction, consultation rate, prescriptions, investigations, referrals and urgent re-consultations for the same condition within 2 weeks. About 2056 urgent consultations were recorded in the study period, of which 332 (16.1%) were seen by PNs and 46 (2.2%) by a HV. High levels of patient satisfaction were reported for all health professionals. Patients seeing the HV reported higher levels of satisfaction than those consulting GPs (P=0.033) and PNs (P=0.010). There was no difference by health professional for prescription rates (P=0.76), re-consultations (P=0.14), or referrals to secondary care (P=0.07). General practitioners were more likely to initiate further investigations than the PNs or HV (P < 0.001). With suitable training, PNs and HVs can successfully manage patients with a range of conditions. General practitioner workload can be reduced while maintaining high patient satisfaction levels.

Evaluation of Gelatin Tannate Against Symptoms of Acute Diarrhea in Pediatric Patients.

PubMed

Çağan, Eren; Ceylan, Saime; Mengi, Şenay; Çağan, Havva Hasret

2017-04-27

BACKGROUND Acute diarrhea is the second most common cause of morbidity and mortality worldwide, especially in children aged ≤3 years. Some drugs (e.g., the mucoprotector gelatin tannate) plus a reduced osmolality oral rehydration solution (ORS) may effectively reduce symptom duration and severity. The current trial was therefore designed to assess the efficacy and safety of gelatin tannate in pediatric patients with acute diarrhea. MATERIAL AND METHODS This was a randomized, controlled, double-blind, parallel-group, single-center study comparing gelatin tannate plus ORS (103 patients) with ORS plus placebo (100 patients) in children aged 3 months to 12 years with infectious or noninfectious acute diarrhea. Details about stool consistency and total time to resolution of diarrhea comprised the primary study endpoints. Secondary study endpoints included symptoms of diarrhea at 12, 24, 36, 48, and 72 hours after the first dose of study medication. RESULTS From 12 hours onwards, the incidence of watery stools was significantly lower in the gelatin tannate group than in the ORS group (at 12 hours: 59.2% vs. 77.0%; p=0.01). The same was true for stool frequency (at 12 hours: mean 2 vs. 3 stool productions in the previous 12 hours; p<0.01). At all timepoints during the study, the proportion of patients with Stool Decrease Index improvement was significantly greater (p<0.01) in the gelatin tannate group than in the placebo group (at 12 hours: 66.6% vs. 33.3%; p<0.01). CONCLUSIONS Gelatin tannate plus ORS is an effective and safe option for the treatment of acute diarrhea in children. Significant symptom relief is evident 12 hours after starting treatment.

Evaluation of Gelatin Tannate Against Symptoms of Acute Diarrhea in Pediatric Patients

PubMed Central

Çağan, Eren; Ceylan, Saime; Mengi, Şenay; Çağan, Havva Hasret

2017-01-01

Background Acute diarrhea is the second most common cause of morbidity and mortality worldwide, especially in children aged ≤3 years. Some drugs (e.g., the mucoprotector gelatin tannate) plus a reduced osmolality oral rehydration solution (ORS) may effectively reduce symptom duration and severity. The current trial was therefore designed to assess the efficacy and safety of gelatin tannate in pediatric patients with acute diarrhea. Material/Methods This was a randomized, controlled, double-blind, parallel-group, single-center study comparing gelatin tannate plus ORS (103 patients) with ORS plus placebo (100 patients) in children aged 3 months to 12 years with infectious or noninfectious acute diarrhea. Details about stool consistency and total time to resolution of diarrhea comprised the primary study endpoints. Secondary study endpoints included symptoms of diarrhea at 12, 24, 36, 48, and 72 hours after the first dose of study medication. Results From 12 hours onwards, the incidence of watery stools was significantly lower in the gelatin tannate group than in the ORS group (at 12 hours: 59.2% vs. 77.0%; p=0.01). The same was true for stool frequency (at 12 hours: mean 2 vs. 3 stool productions in the previous 12 hours; p<0.01). At all timepoints during the study, the proportion of patients with Stool Decrease Index improvement was significantly greater (p<0.01) in the gelatin tannate group than in the placebo group (at 12 hours: 66.6% vs. 33.3%; p<0.01). Conclusions Gelatin tannate plus ORS is an effective and safe option for the treatment of acute diarrhea in children. Significant symptom relief is evident 12 hours after starting treatment. PMID:28448477

Depression screening: utility of the patient health questionnaire in patients with acute coronary syndrome.

PubMed

McGuire, Anthony W; Eastwood, Jo-Ann; Macabasco-O'Connell, Aurelia; Hays, Ron D; Doering, Lynn V

2013-01-01

Depression screening in cardiac patients has been recommended by the American Heart Association, but the best approach remains unclear. To evaluate nurse-administered versions of the Patient Health Questionnaire for depression screening in patients hospitalized for acute coronary syndrome. Staff nurses in an urban cardiac care unit administered versions 2, 9, and 10 of the questionnaire to 100 patients with acute coronary syndrome. The Depression Interview and Structured Hamilton was administered by advanced practice nurses blinded to the results of the Patient Health Questionnaire. With the results of the Depression Interview and Structured Hamilton as a criterion, receiver operating characteristic analyses were done for each version of the Patient Health Questionnaire. The Delong method was used for pairwise comparisons. Cutoff scores balancing false-negatives and false-positives were determined by using the Youden Index. Each version of the questionnaire had excellent area-under- the-curve statistics: 91.2%, 92.6%, and 93.4% for versions 2, 9, and 10, respectively. Differences among the 3 versions were not significant. Each version yielded higher symptom scores in depressed patients than in nondepressed patients: version 2 scores, 3.4 vs 0.6, P = .001; version 9 scores, 13 vs 3.4, P < .001; and version 10 scores, 14.5 vs 3.6, P < .001. For depression screening in hospitalized patients with acute coronary syndrome, the Patient Health Questionnaire 2 is as accurate as longer versions when administered by nurses. Further study is needed to determine if screening with this tool changes clinical decision making or improves outcomes in these patients.

Sperm count as a surrogate endpoint for male fertility control.

PubMed

Benda, Norbert; Gerlinger, Christoph

2007-11-30

When assessing the effectiveness of a hormonal method of fertility control in men, the classical approach used for the assessment of hormonal contraceptives in women, by estimating the pregnancy rate or using a life-table analysis for the time to pregnancy, is difficult to apply in a clinical development program. The main reasons are the dissociation of the treated unit, i.e. the man, and the observed unit, i.e. his female partner, the high variability in the frequency of male intercourse, the logistical cost and ethical concerns related to the monitoring of the trial. A reasonable surrogate endpoint of the definite endpoint time to pregnancy is sperm count. In addition to the avoidance of the mentioned problems, trials that compare different treatments are possible with reasonable sample sizes, and study duration can be shorter. However, current products do not suppress sperm production to 100 per cent in all men and the sperm count is only observed with measurement error. Complete azoospermia might not be necessary in order to achieve an acceptable failure rate compared with other forms of male fertility control. Therefore, the use of sperm count as a surrogate endpoint must rely on the results of a previous trial in which both the definitive- and surrogate-endpoint results were assessed. The paper discusses different estimation functions of the mean pregnancy rate (corresponding to the cumulative hazard) that are based on the results of sperm count trial and a previous trial in which both sperm count and time to pregnancy were assessed, as well as the underlying assumptions. Sample size estimations are given for pregnancy rate estimation with a given precision.

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

Comparison of methods for accurate end-point detection of potentiometric titrations

NASA Astrophysics Data System (ADS)

Villela, R. L. A.; Borges, P. P.; Vyskočil, L.

2015-01-01

Detection of the end point in potentiometric titrations has wide application on experiments that demand very low measurement uncertainties mainly for certifying reference materials. Simulations of experimental coulometric titration data and consequential error analysis of the end-point values were conducted using a programming code. These simulations revealed that the Levenberg-Marquardt method is in general more accurate than the traditional second derivative technique used currently as end-point detection for potentiometric titrations. Performance of the methods will be compared and presented in this paper.

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.

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.

Uncertainty in the Bayesian meta-analysis of normally distributed surrogate endpoints

PubMed Central

Thompson, John R; Spata, Enti; Abrams, Keith R

2015-01-01

We investigate the effect of the choice of parameterisation of meta-analytic models and related uncertainty on the validation of surrogate endpoints. Different meta-analytical approaches take into account different levels of uncertainty which may impact on the accuracy of the predictions of treatment effect on the target outcome from the treatment effect on a surrogate endpoint obtained from these models. A range of Bayesian as well as frequentist meta-analytical methods are implemented using illustrative examples in relapsing–remitting multiple sclerosis, where the treatment effect on disability worsening is the primary outcome of interest in healthcare evaluation, while the effect on relapse rate is considered as a potential surrogate to the effect on disability progression, and in gastric cancer, where the disease-free survival has been shown to be a good surrogate endpoint to the overall survival. Sensitivity analysis was carried out to assess the impact of distributional assumptions on the predictions. Also, sensitivity to modelling assumptions and performance of the models were investigated by simulation. Although different methods can predict mean true outcome almost equally well, inclusion of uncertainty around all relevant parameters of the model may lead to less certain and hence more conservative predictions. When investigating endpoints as candidate surrogate outcomes, a careful choice of the meta-analytical approach has to be made. Models underestimating the uncertainty of available evidence may lead to overoptimistic predictions which can then have an effect on decisions made based on such predictions. PMID:26271918

Uncertainty in the Bayesian meta-analysis of normally distributed surrogate endpoints.

PubMed

Bujkiewicz, Sylwia; Thompson, John R; Spata, Enti; Abrams, Keith R

2017-10-01

We investigate the effect of the choice of parameterisation of meta-analytic models and related uncertainty on the validation of surrogate endpoints. Different meta-analytical approaches take into account different levels of uncertainty which may impact on the accuracy of the predictions of treatment effect on the target outcome from the treatment effect on a surrogate endpoint obtained from these models. A range of Bayesian as well as frequentist meta-analytical methods are implemented using illustrative examples in relapsing-remitting multiple sclerosis, where the treatment effect on disability worsening is the primary outcome of interest in healthcare evaluation, while the effect on relapse rate is considered as a potential surrogate to the effect on disability progression, and in gastric cancer, where the disease-free survival has been shown to be a good surrogate endpoint to the overall survival. Sensitivity analysis was carried out to assess the impact of distributional assumptions on the predictions. Also, sensitivity to modelling assumptions and performance of the models were investigated by simulation. Although different methods can predict mean true outcome almost equally well, inclusion of uncertainty around all relevant parameters of the model may lead to less certain and hence more conservative predictions. When investigating endpoints as candidate surrogate outcomes, a careful choice of the meta-analytical approach has to be made. Models underestimating the uncertainty of available evidence may lead to overoptimistic predictions which can then have an effect on decisions made based on such predictions.

Validating the Manchester Acute Coronary Syndromes (MACS) and Troponin-only Manchester Acute Coronary Syndromes (T-MACS) rules for the prediction of acute myocardial infarction in patients presenting to the emergency department with chest pain.

PubMed

Greenslade, Jaimi H; Nayer, Robert; Parsonage, William; Doig, Shaela; Young, Joanna; Pickering, John W; Than, Martin; Hammett, Christopher; Cullen, Louise

2017-08-01

The Manchester Acute Coronary Syndromes (MACS) rule and the Troponin-only MACS (T-MACS) rule risk stratify patients with suspected acute coronary syndrome (ACS). This observational study sought to validate and compare the MACS and T-MACS rules for assessment of acute myocardial infarction (AMI). Prospectively collected data from twoEDs in Australia and New Zealand were analysed. Patients were assigned a probability of ACS based on the MACS and T-MACS rules, incorporating high-sensitivity troponin T, heart-type fatty acid-binding protein, ECG results and clinical symptoms. Patients were then deemed very low risk, low risk, intermediate or high risk if their MACS probability was less than 2%, between 2% and 5%, between 5% and 95% and greater than 95%, respectively. The primary endpoint was 30-day diagnosis of AMI. The secondary endpoint was 30-day major adverse cardiac event (MACE) including AMI, revascularisation or coronary stenosis (>70%). Sensitivity, specificity and predictive values were calculated to assess the accuracy of the MACS and T-MACS rules. Of the 1244 patients, 114 (9.2%) were diagnosed with AMI and 163 (13.1%) with MACE. The MACS and T-MACS rules categorised 133 (10.7%) and 246 (19.8%) patients, respectively, as very low risk and potentially suitable for early discharge from the ED. There was one false negative case for both rules making sensitivity 99.1% (95.2%-100%). MACS and T-MACS accurately risk stratify very low risk patients. The T-MACS rule would allow for more patients to be discharged early. The potential for missed MACE events means that further outpatient testing for coronary artery disease may be required for patients identified as very low risk. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Kidney function endpoints in kidney transplant trials: a struggle for power.

PubMed

Ibrahim, A; Garg, A X; Knoll, G A; Akbari, A; White, C A

2013-03-01

Kidney function endpoints are commonly used in randomized controlled trials (RCTs) in kidney transplantation (KTx). We conducted this study to estimate the proportion of ongoing RCTs with kidney function endpoints in KTx where the proposed sample size is large enough to detect meaningful differences in glomerular filtration rate (GFR) with adequate statistical power. RCTs were retrieved using the key word "kidney transplantation" from the National Institute of Health online clinical trial registry. Included trials had at least one measure of kidney function tracked for at least 1 month after transplant. We determined the proportion of two-arm parallel trials that had sufficient sample sizes to detect a minimum 5, 7.5 and 10 mL/min difference in GFR between arms. Fifty RCTs met inclusion criteria. Only 7% of the trials were above a sample size of 562, the number needed to detect a minimum 5 mL/min difference between the groups should one exist (assumptions: α = 0.05; power = 80%, 10% loss to follow-up, common standard deviation of 20 mL/min). The result increased modestly to 36% of trials when a minimum 10 mL/min difference was considered. Only a minority of ongoing trials have adequate statistical power to detect between-group differences in kidney function using conventional sample size estimating parameters. For this reason, some potentially effective interventions which ultimately could benefit patients may be abandoned from future assessment. © Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.

Ivabradine vs metoprolol in patients with acute inferior wall myocardial infarction-"Expanding arena for ivabradine".

PubMed

Priti, Kumari; Ranwa, Bhanwar L; Gokhroo, Rajendra K; Kishore, Kamal; Bisht, Devendra Singh; Gupta, Sajal

2017-08-01

Atrioventricular (AV) blocks are of concern with the use of beta blockers in inferior wall myocardial infarction (MI). Ivabradine lowers heart rate with a lesser risk of AV blocks. To compare ivabradine with metoprolol in acute inferior wall MI in terms of feasibility, tolerability, and efficacy. It was a prospective double-blind single-center randomized controlled study. Of 1032 patients with acute inferior wall MI, 468 eligible patients were randomized in 1:1 manner to ivabradine (group A) and metoprolol (group B). Intention to treat analysis of 426 patients (group A-232 and group B-232) was performed. The primary endpoint was 30-day incidence of major adverse cardiovascular events including death, reinfarction, complete heart block (CHB), and heart failure. Secondary endpoints included 30 days incidence of recurrent angina, readmission, first- or second-degree AV block, and tachyarrhythmias. Both the drugs decreased the mean heart rate to 62.22±2.95 (group A) vs 62.53±3.59 (group B) beats per minute (P=0.33). Ejection fraction improved in both the groups (5.15±1.93% in group A vs 5.52±2.18% in group B, P=0.065). The two groups did not differ significantly in their primary endpoints in terms of death (group A=1.72% vs group B=1.72%, OR=1.00, 95% CI=0.25-4.05, P=1.00), reinfarction (group A=0.86% vs group B=0.86%, OR=1.00, 95% CI=0.14-7.16, P=1.00), heart failure (group A=4.31% vs group B=2.59%, OR=1.70, 95% CI=0.61-4.75, P=0.31), or CHB (0% vs 2.59%, OR=0.07, 95% CI=0.00-1.34, P=0.08). There were no significant differences in the secondary endpoints of recurrent angina, readmission, and tachyarrhythmias except for more first- and second-degree AV blocks with metoprolol (12.93% vs 2.59%, OR=5.59, 95% CI=2.28-13.72, P=0.0002). Ivabradine is well tolerated and equally effective as metoprolol in acute inferior wall ST elevation myocardial infarction patients for lowering the heart rate with lesser risk of AV blocks. © 2017 John Wiley & Sons Ltd.

The endpoint detection technique for deep submicrometer plasma etching

NASA Astrophysics Data System (ADS)

Wang, Wei; Du, Zhi-yun; Zeng, Yong; Lan, Zhong-went

2009-07-01

The availability of reliable optical sensor technology provides opportunities to better characterize and control plasma etching processes in real time, they could play a important role in endpoint detection, fault diagnostics and processes feedback control and so on. The optical emission spectroscopy (OES) method becomes deficient in the case of deep submicrometer gate etching. In the newly developed high density inductively coupled plasma (HD-ICP) etching system, Interferometry endpoint (IEP) is introduced to get the EPD. The IEP fringe count algorithm is investigated to predict the end point, and then its signal is used to control etching rate and to call end point with OES signal in over etching (OE) processes step. The experiment results show that IEP together with OES provide extra process control margin for advanced device with thinner gate oxide.

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

Helicopter EMS: Research Endpoints and Potential Benefits

PubMed Central

Thomas, Stephen H.; Arthur, Annette O.

2012-01-01

Patients, EMS systems, and healthcare regions benefit from Helicopter EMS (HEMS) utilization. This article discusses these benefits in terms of specific endpoints utilized in research projects. The endpoint of interest, be it primary, secondary, or surrogate, is important to understand in the deployment of HEMS resources or in planning further HEMS outcomes research. The most important outcomes are those which show potential benefits to the patients, such as functional survival, pain relief, and earlier ALS care. Case reports are also important “outcomes” publications. The benefits of HEMS in the rural setting is the ability to provide timely access to Level I or Level II trauma centers and in nontrauma, interfacility transport of cardiac, stroke, and even sepsis patients. Many HEMS crews have pharmacologic and procedural capabilities that bring a different level of care to a trauma scene or small referring hospital, especially in the rural setting. Regional healthcare and EMS system's benefit from HEMS by their capability to extend the advanced level of care throughout a region, provide a “backup” for areas with limited ALS coverage, minimize transport times, make available direct transport to specialized centers, and offer flexibility of transport in overloaded hospital systems. PMID:22203905

Empowerment in the interpersonal field: discourses of acute mental health nurses.

PubMed

Lloyd, M

2007-08-01

Social policy greatly influences the working environment of mental health nurses but in practice can be difficult to translate. Empowerment of service users is one area that is constantly significant in policy, locally and nationally, yet quite difficult to define in practice. This ethnomethodological study explored the practice of 10 mental health nurses working in an acute admissions unit. Through semi-structured interviews, the nurses were asked to discuss the taken-for-granted methods of empowerment with individual service users, their families and with work colleagues. The results were thematically analysed and compared with international findings, which reflected an awareness among mental health nurses of empowering practice in four areas. These were: Working with mental illness, Making connections, Responsibility and Teamworking.

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.

Improving the home health acute-care hospitalization quality measure.

PubMed

Schade, Charles P; Brehm, John G

2010-06-01

(1) To demonstrate average length of service (ALOS) bias in the currently used acute-care hospitalization (ACH) home health quality measure, limiting comparability across agencies, and (2) to propose alternative ACH measures. Secondary analysis of Medicare home health service data 2004-2007; convenience sample of Medicare fee-for-service hospital discharges. Cross-sectional analysis and patient-level simulation. We aggregated outcome and ALOS data from 2,347 larger Medicare-certified home health agencies (HHAs) in the United States between 2004 and 2007, and calculated risk-adjusted monthly ACH rates. We used multiple regression to identify agency characteristics associated with ACH. We simulated ACH during and immediately after home health care using patient and agency characteristics similar to those in the actual data, comparing the existing measure with alternative fixed-interval measures. Of agency characteristics studied, ALOS had by far the highest partial correlation with the current ACH measure (r(2)=0.218, p<.0001). We replicated the correlation between ACH and ALOS in the patient-level simulation. We found no correlation between ALOS and the alternative measures. Alternative measures do not exhibit ALOS bias and would be appropriate for comparing HHA ACH rates with one another or over time.

Post-fall reporting in aged acute inpatient mental health units: an 18-month observational cohort study.

PubMed

Furness, Trentham; Mnatzaganian, George; Garlick, Robyn; Ireland, Susan; McKenna, Brian; Hill, Keith D

2017-12-01

Despite the high risk of falling for people with severe mental illness, there is limited falls research in mental health settings. Therefore, the objective of this observational cohort study was to conduct a focused post-fall review of fall episodes within aged acute inpatient mental health units at one of Australia's largest publicly funded mental health organizations. A post-fall reporting tool was developed to collect intrinsic and extrinsic fall risk factors among three aged acute mental health inpatient units over an 18-month period. Descriptive and inferential analyses were conducted to describe fall risk factors and predictors of fall risk. There were a total of 115 falls, of which the tool was used for 93 (80.9%) episodes. Falls occurred most often in consumer's bedroom/bathroom and were unwitnessed. Intrinsic risk factors were most often attributed to postural drop and losing balance during walking. However, that was in contrast to consumer's who self-reported feeling dizzy as the reason of the fall. Based on the cohort, future falls could be reduced by targeting those aged above 82 years, or with a diagnosis of dementia. Recurrent falls during admission could be reduced by targeting those with psychotic illness and males with a diagnosis of dementia. A clearer dialogue among consumers and clinical staff reporting about fall episodes may support future remedial interventions and inform programs to reduce fall risk and assist the challenge of describing unwitnessed falls in aged acute inpatient mental health settings.

COMPARISON OF ILLNESS ENDPOINTS IN SWIMMERS' HEALTH STUDIES

EPA Science Inventory

Prospective epidemiological studies on swimmers¿ health that were conducted by the U.S. Environmental Protection Agency (U.S. EPA) between 1973 and 1980 defined highly credible gastrointestinal illness (HCGI) as the occurrence of one or more of the following set of symptoms: (1) ...

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.

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.

Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level meta-analysis.

PubMed

Schuetz, Philipp; Wirz, Yannick; Sager, Ramon; Christ-Crain, Mirjam; Stolz, Daiana; Tamm, Michael; Bouadma, Lila; Luyt, Charles E; Wolff, Michel; Chastre, Jean; Tubach, Florence; Kristoffersen, Kristina B; Burkhardt, Olaf; Welte, Tobias; Schroeder, Stefan; Nobre, Vandack; Wei, Long; Bucher, Heiner C; Annane, Djillali; Reinhart, Konrad; Falsey, Ann R; Branche, Angela; Damas, Pierre; Nijsten, Maarten; de Lange, Dylan W; Deliberato, Rodrigo O; Oliveira, Carolina F; Maravić-Stojković, Vera; Verduri, Alessia; Beghé, Bianca; Cao, Bin; Shehabi, Yahya; Jensen, Jens-Ulrik S; Corti, Caspar; van Oers, Jos A H; Beishuizen, Albertus; Girbes, Armand R J; de Jong, Evelien; Briel, Matthias; Mueller, Beat

2018-01-01

In February, 2017, the US Food and Drug Administration approved the blood infection marker procalcitonin for guiding antibiotic therapy in patients with acute respiratory infections. This meta-analysis of patient data from 26 randomised controlled trials was designed to assess safety of procalcitonin-guided treatment in patients with acute respiratory infections from different clinical settings. Based on a prespecified Cochrane protocol, we did a systematic literature search on the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase, and pooled individual patient data from trials in which patients with respiratory infections were randomly assigned to receive antibiotics based on procalcitonin concentrations (procalcitonin-guided group) or control. The coprimary endpoints were 30-day mortality and setting-specific treatment failure. Secondary endpoints were antibiotic use, length of stay, and antibiotic side-effects. We identified 990 records from the literature search, of which 71 articles were assessed for eligibility after exclusion of 919 records. We collected data on 6708 patients from 26 eligible trials in 12 countries. Mortality at 30 days was significantly lower in procalcitonin-guided patients than in control patients (286 [9%] deaths in 3336 procalcitonin-guided patients vs 336 [10%] in 3372 controls; adjusted odds ratio [OR] 0·83 [95% CI 0·70 to 0·99], p=0·037). This mortality benefit was similar across subgroups by setting and type of infection (p interactions >0·05), although mortality was very low in primary care and in patients with acute bronchitis. Procalcitonin guidance was also associated with a 2·4-day reduction in antibiotic exposure (5·7 vs 8·1 days [95% CI -2·71 to -2·15], p<0·0001) and a reduction in antibiotic-related side-effects (16% vs 22%, adjusted OR 0·68 [95% CI 0·57 to 0·82], p<0·0001). Use of procalcitonin to guide antibiotic treatment in patients with acute respiratory infections reduces antibiotic

Troponin elevation in acute ischemic stroke (TRELAS) - protocol of a prospective observational trial

PubMed Central

2011-01-01

Background Levels of the cardiac muscle regulatory protein troponin T (cTnT) are frequently elevated in patients with acute ischemic stroke and elevated cTnT predicts poor outcome and mortality. The pathomechanism of troponin release may relate to co-morbid coronary artery disease and myocardial ischemia or, alternatively, to neurogenic cardiac damage due to autonomic activation after acute ischemic stroke. Therefore, there is uncertainty about how acute ischemic stroke patients with increased cTnT levels should be managed regarding diagnostic and therapeutic workup. Methods/Design The primary objective of the prospective observational trial TRELAS (TRoponin ELevation in Acute ischemic Stroke) is to investigate the frequency and underlying pathomechanism of cTnT elevation in acute ischemic stroke patients in order to give guidance for clinical practice. All consecutive patients with acute ischemic stroke admitted within 72 hours after symptom onset to the Department of Neurology at the Campus Benjamin Franklin of the University Hospital Charité will be screened for cTnT elevations (i.e. >= 0.05 μg/l) on admission and again on the following day. Patients with increased cTnT will undergo coronary angiography within 72 hours. Diagnostic findings of coronary angiograms will be compared with age- and gender-matched patients presenting with Non-ST-Elevation myocardial infarction to the Department of Cardiology. The primary endpoint of the study will be the occurrence of culprit lesions in the coronary angiogram indicating underlying co-morbid obstructive coronary artery disease. Secondary endpoints will be the localization of stroke in the cerebral imaging and left ventriculographic findings of wall motion abnormalities suggestive of stroke-induced global cardiac dysfunction. Discussion TRELAS will prospectively determine the frequency and possible etiology of troponin elevation in a large cohort of ischemic stroke patients. The findings are expected to contribute to

Surrogate Endpoints and Risk Adaptive Strategies in Previously Untreated Follicular Lymphoma.

PubMed

Narkhede, Mayur S; Cheson, Bruce D

2018-05-05

Follicular lymphoma is the second most common subtype of non-Hodgkin lymphoma with an estimated 3.18 cases per 100,000 people. Despite the prolongation of survival with chemoimmunotherapy, variability in response to initial treatment and outcome still exists. Whereas prolonging overall survival is important, it is generally an unreasonable primary endpoint in the front-line setting. The long follow-up needed and the influence of subsequent therapies creates a potential bias. Thus, clinical trials require approximately 5 to 8 years from activation to completion and analysis of outcomes. This duration results in enormous cost and a delay in developing newer therapies. Thus, there is a need to identify markers or surrogate endpoints that can be used in clinical trials to expedite the development of new treatments. This review will discuss various clinical, radiologic, and laboratory measures used to assess outcomes and overall survival in patients with untreated follicular lymphoma, and gauge their utility in clinical trials as surrogate endpoints. Copyright © 2018 Elsevier Inc. All rights reserved.

Sample size determination in group-sequential clinical trials with two co-primary endpoints

PubMed Central

Asakura, Koko; Hamasaki, Toshimitsu; Sugimoto, Tomoyuki; Hayashi, Kenichi; Evans, Scott R; Sozu, Takashi

2014-01-01

We discuss sample size determination in group-sequential designs with two endpoints as co-primary. We derive the power and sample size within two decision-making frameworks. One is to claim the test intervention’s benefit relative to control when superiority is achieved for the two endpoints at the same interim timepoint of the trial. The other is when the superiority is achieved for the two endpoints at any interim timepoint, not necessarily simultaneously. We evaluate the behaviors of sample size and power with varying design elements and provide a real example to illustrate the proposed sample size methods. In addition, we discuss sample size recalculation based on observed data and evaluate the impact on the power and Type I error rate. PMID:24676799

Noninvasive ventilation for acute exacerbations of asthma: A systematic review of the literature.

PubMed

Green, Elyce; Jain, Paras; Bernoth, Maree

2017-11-01

Asthma is a chronic disease characterised by reversible airway obstruction caused by bronchospasm, mucous and oedema. People with asthma commonly experience acute exacerbations of their disease requiring hospitalisation and subsequent utilisation of economic and healthcare resources. Noninvasive ventilation has been suggested as a treatment for acute exacerbations of asthma due to its ability to provide airway stenting, optimal oxygen delivery and decreased work of breathing. This paper is a systematic review of the available published research focused on the use of noninvasive ventilation for the treatment of acute exacerbations of asthma to determine if this treatment provides better outcomes for patients compared to standard medical therapy. Database searches were conducted using EBSCOhost, MEDLINE and PubMed. Search terms used were combinations of 'noninvasive ventilation', 'BiPAP', 'CPAP', 'wheez*' and 'asthma'. Articles were included if they were research papers focused on adult patients with asthma and a treatment of noninvasive ventilation, and were published in full text in English. Included articles were reviewed using the National Health and Medical Research Council (Australia) evidence hierarchy and quality appraisal tools. There were 492 articles identified from the database searches. After application of inclusion/exclusion criteria 13 articles were included in the systematic review. Studies varied significantly in design, endpoints and outcomes. There was a trend in better outcomes for patients with acute asthma who were treated with noninvasive ventilation compared to standard medical therapy, however, the variability of the studies meant that no conclusive recommendations could be made. More research is required before noninvasive ventilation can be conclusively recommended for the treatment of acute exacerbations of asthma. Copyright © 2017 Australian College of Critical Care Nurses Ltd. Published by Elsevier Ltd. All rights reserved.

Clinical features and prognosis of patients with acute non-specific chest pain in emergency and cardiology departments after the introduction of high-sensitivity troponins: a prospective cohort study.

PubMed

Ilangkovan, Nivethitha; Mickley, Hans; Diederichsen, Axel; Lassen, Annmarie; Sørensen, Thomas L; Sheta, Hussam Mahmoud; Stæhr, Peter B; Mogensen, Christian Backer

2017-12-22

To determine the incidence of clinical, cardiac-related endpoints and mortality among patients presenting to an emergency or cardiology department with non-specific chest pain (NSCP), and who receive testing with a high-sensitivity troponin. A second objective was to identify risk factors for the above-noted endpoints during 12 months of follow-up. A prospective multicentre study. Emergency and cardiology departments in Southern Denmark. The study enrolled 1027 patients who were assessed for acute chest pain in an emergency or cardiology department, and in whom a myocardial infarction or another obvious reason for chest pain had been ruled out. Patients were enrolled from September 2014 to June 2015 and followed for 1 year. Clinical, cardiac-related endpoints (cardiac-related death, acute myocardial infarction, unstable angina and coronary revascularisation) and all-cause mortality. Over a period of 1 year, cardiac-related endpoints were found in 19 patients (1.9%): 0 patients experienced cardiac-related death, 2 (0.2%) had myocardial infarction, 4 (0.4%) had unstable angina pectoris and 17 (1.7%) underwent coronary revascularisation. All-cause mortality was observed in seven patients (0.7%). When compared with the general population, the standardised mortality ratio did not differ. The risk factors associated with the study endpoints included male gender, body mass index >25 kg/m 2 , previous known coronary artery disease, hypertension, hypercholesterolaemia, diabetes mellitus and the use of statins. A total of 73% of the endpoints occurred in males. The prognosis for patients with NSCP is favourable, with a 1-year mortality after discharge that is comparable with the background population. Few clinical endpoints took place during follow-up, and those that did were predominantly in males. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise

Disentangling the effect of illness perceptions on health status in people with type 2 diabetes after an acute coronary event.

PubMed

Vos, Rimke Cathelijne; Kasteleyn, Marise Jeannine; Heijmans, Monique Johanna; de Leeuw, Elke; Schellevis, François Georges; Rijken, Mieke; Rutten, Guy Emile

2018-03-02

Chronically ill patients such as people with type 2 diabetes develop perceptions of their illness, which will influence their coping behaviour. Perceptions are formed once a health threat has been recognised. Many people with type 2 diabetes suffer from multimorbidity, for example the combination with cardiovascular disease. Perceptions of one illness may influence perceptions of the other condition. The aim of the current study was to evaluate the effect of an intervention in type 2 diabetes patients with a first acute coronary event on change in illness perceptions and whether this mediates the intervention effect on health status. The current study is a secondary data analysis of a RCT. Two hundred one participants were randomised (1:1 ratio) to the intervention (n = 101, three home visits) or control group (n = 100). Outcome variables were diabetes and acute coronary event perceptions, assessed with the two separate Brief Illness Perceptions Questionnaires (BIPQs); and health status (Euroqol Visual Analog Scale (EQ-VAS)). The intervention effect was analysed using ANCOVA. Linear regression analyses were used to assess whether illness perceptions mediated the intervention effect on health status. A positive intervention effect was found on the BIPQ diabetes items coherence and treatment control (F = 8.19, p = 0.005; F = 14.01, p < 0.001). No intervention effect was found on the other BIPQ diabetes items consequence, personal control, identity, illness concern and emotional representation. Regarding the acute coronary event, a positive intervention effect on treatment control was found (F = 7.81, p = 0.006). No intervention effect was found on the other items of the acute coronary event BIPQ. Better diabetes coherence was associated with improved health status, whereas perceiving more treatment control was not. The mediating effect of the diabetes perception 'coherence' on health status was not significant. Targeting illness

Understanding factors that influence the integration of acute malnutrition interventions into the national health system in Niger.

PubMed

Deconinck, Hedwig; Hallarou, Mahaman Elh; Pesonen, Anais; Gérard, Jean Christophe; Criel, Bart; Donnen, Philippe; Macq, Jean

2016-12-01

Since 2007 to address a high burden, integration of acute malnutrition has been promoted in Niger. This paper studies factors that influenced the integration process of acute malnutrition into the Niger national health system.We used qualitative methods of observation, key informant interviews and focus group discussions at national level, two districts and nine communities selected through convenience sampling, as well as document review. A framework approach constructed around the problem, intervention, adoption system, health system characteristics and broad context guided the analysis. Data were recorded on paper, transcribed in a descriptive record, coded by themes deduced by building on the framework and triangulated for comprehensiveness.Key facilitating factors identified were knowledge and recognition of the problem helped by accurate information; effectiveness of decentralized continuity of care; compatibility with goals, support and involvement of health actors; and leadership for aligning policies and partnerships and mobilizing resources within a favourable political context driven by multisectoral development goals. Key hindering factors identified were not fully understanding severity, causes and consequences of the problem; limited utilization and trust in health interventions; high workload, and health worker turnover and attrition; and high dependence on financial and technical support based on short-term emergency funding within a context of high demographic pressure.The study uncovered influencing factors of integrating acute malnutrition into the national health system and their complex dynamics and relationships. It elicited the need for goal-oriented strategies and alignment of health actors to achieve sustainability, and systems thinking to understand pathways that foster integration. We recommend that context-specific learning of integrating acute malnutrition may expand to include causal modelling and scenario testing to inform strategy

Access to primary health care for acute vascular events in rural low income settings: a mixed methods study.

PubMed

Ahmed, Shyfuddin; Chowdhury, Muhammad Ashique Haider; Khan, Md Alfazal; Huq, Nafisa Lira; Naheed, Aliya

2017-01-18

Cardiovascular diseases (CVDs) are the leading cause of global mortality. Among the CVDs, acute vascular events (AVE) mainly ischemic heart diseases and stroke are the largest contributors. To achieve 25% reduction in preventable deaths from CVDs by 2025, health systems need to be equipped with extended service coverage in order to provide person-centered care. The overall goal of this proposed study is to assess access to health care in-terms of service availability, care seeking patterns and barriers to access care after AVE in rural Bangladesh. We will consider myocardial infarction (MI) and stroke as acute vascular events. We will conduct a mixed methods study in rural Matlab, Bangladesh. This study will comprise of a) health facility survey, b) structured questionnaire interview and c) qualitative study. We will assess service availabilities by creating an inventory of public and private health facilities. Readiness of the facilities to deliver services for AVE will be assessed through a health facility survey using 'service availability and readiness assessment' (SARA) tools of the World Health Organization (WHO). We will interview survivors of AVE and caregivers (present and accompanied the person during the event) of person who died from AVE for exploring patterns of care seeking during an AVE. For exploring barriers to access care for AVE, we will conduct in-depth interview with survivors of AVE and caregivers of the person who died from AVE. We will also conduct key informant interviews with the service providers at primary health care (PHC) facilities and government high level officials at central health administration of Bangladesh. This study will provide a comprehensive picture of access to primary health care services during acute cardiovascular events as stroke & MI in rural context of Bangladesh. It will explore available service facilities in rural area for management, utilization of services and barriers to access care during an acute emergency

Art, music, story: The evaluation of a person-centred arts in health programme in an acute care older persons' unit.

PubMed

Ford, Karen; Tesch, Leigh; Dawborn, Jacqueline; Courtney-Pratt, Helen

2018-06-01

To evaluate the impact of an arts in health programme delivered by a specialised artist within an acute older person's unit. Acute hospitals must meet the increasingly complex needs of older people who experience multiple comorbidities, often including cognitive impairment, either directly related to their admission or longer term conditions, including dementia. A focus on physical illness, efficiency and tasks within an acute care environment can all divert attention from the psychosocial well-being of patients. This focus also decreases capacity for person-centred approaches that acknowledge and value the older person, their life story, relationships and the care context. The importance of arts for health and wellness, including responsiveness to individual need, is well established: however, there is little evidence about its effectiveness for older people in acute hospital settings. We report on a collaborative arts in health programme on an acute medical ward for older people. The qualitative study used collaborative enquiry underpinned by a constructivist approach to evaluate an arts programme that involved participatory art-making activities, customised music, song and illustration work, and enlivening the unit environment. Data sources included observation of art activities, semi-structured interviews with patients and family members, and focus groups with staff. Data were transcribed and thematically analysed using a line by line approach. The programme had positive impacts for the environment, patients, families and staff. The environment exhibited changes as a result of programme outputs; patients and families were engaged and enjoyed activities that aided recovery from illness; and staff also enjoyed activities and importantly learnt new ways of working with patients. An acute care arts in health programme is a carefully nuanced programme where the skills of the arts health worker are critical to success. Utilising such skill, continued focus on person

Weighting Composite Endpoints in Clinical Trials: Essential Evidence for the Heart Team

PubMed Central

Tong, Betty C.; Huber, Joel C.; Ascheim, Deborah D.; Puskas, John D.; Ferguson, T. Bruce; Blackstone, Eugene H.; Smith, Peter K.

2013-01-01

Background Coronary revascularization trials often use a composite endpoint of major adverse cardiac and cerebrovascular events (MACCE). The usual practice in analyzing data with a composite endpoint is to assign equal weights to each of the individual MACCE elements. Non-inferiority margins are used to offset effects of presumably less important components, but their magnitudes are subject to bias. This study describes the relative importance of MACCE elements from a patient perspective. Methods A discrete choice experiment was conducted. Survey respondents were presented with a scenario that would make them eligible for the SYNTAX 3-Vessel Disease cohort. Respondents chose among pairs of procedures that differed on the 3-year probability of MACCE, potential for increased longevity, and procedure/recovery time. Conjoint analysis derived relative weights for these attributes. Results In all, 224 respondents completed the survey. The attributes did not have equal weight. Risk of death was most important (relative weight 0.23), followed by stroke (.18), potential increased longevity and recovery time (each 0.17), MI (0.14) and risk of repeat revascularization (0.11). Applying these weights to the SYNTAX 3-year endpoints resulted in a persistent, but decreased margin of difference in MACCE favoring CABG compared to PCI. When labeled only as “Procedure A” and “B,” 87% of respondents chose CABG over PCI. When procedures were labeled as “Coronary Stent” and “Coronary Bypass Surgery,” only 73% chose CABG. Procedural preference varied with demographics, gender and familiarity with the procedures. Conclusions MACCE elements do not carry equal weight in a composite endpoint, from a patient perspective. Using a weighted composite endpoint increases the validity of statistical analyses and trial conclusions. Patients are subject to bias by labels when considering coronary revascularization. PMID:22795064

Evaluating the impact of depression, anxiety & autonomic function on health related quality of life, vocational functioning and health care utilisation in acute coronary syndrome patients: the ADVENT study protocol

PubMed Central

2013-01-01

Background Depression and anxiety are highly prevalent and co-morbid in acute coronary syndrome patients. Somatic and cognitive subtypes of depression and anxiety in acute coronary syndrome have been shown to be associated with mortality although their association with patient outcomes is unknown, as are the mechanisms that underpin these associations. We are conducting a prospective cohort study which aims to examine in acute coronary syndrome patients: (1) the role of somatic subtypes of depression and anxiety as predictors of health related quality of life outcomes; (2) how somatic subtypes of depression and anxiety relate to long term vocational functioning and healthcare utilisation; and (3) the role of the autonomic nervous system assessed by heart rate variability as a moderator of these associations. Methods Patients are being screened after index admission for acute coronary syndrome at a single, high volume centre, MonashHeart, Monash Health, Victoria, Australia. The inclusion criterion is all patients aged > 21 years old and fluent in English admitted to MonashHeart, Monash Health with a diagnosis of acute coronary syndrome. The primary outcome is mean health related quality of life (Short Form-36) Physical and Mental Health Summary scores at 12 and 24 months in subtypes with somatic symptoms of depression and anxiety. Depressive domains are assessed by the Beck Depression Inventory II and the Cardiac Depression Scale. Anxiety is measured using the Speilberger State-Trait Anxiety Inventory and the Crown Crisp Phobic Anxiety questionnaire. Secondary outcomes include clinical variables, healthcare service utilisation and vocational functioning. Discussion This manuscript presents the protocol for a prospective cohort study which will investigate the role of somatic subtypes of depression and anxiety as predictors of health related quality of life, long-term vocational functioning and health service use, and the role of the autonomic nervous system in

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.

The matron's role in acute National Health Service trusts.

PubMed

Gould, Dinah

2008-10-01

The aim of this study was to describe how matrons in an acute National Health Service trust perceive and undertake their role since its reconfiguration in 2005 and to investigate their needs for continuing professional development. Matrons returned to acute National Health Service trusts in 2002 to provide a senior, authoritative nursing presence throughout clinical areas. Their function is to promote high standards of clinical care and leadership; ensure that administrative and support services are in place to deliver high standards of care; and provide a visible, accessible and authoritative presence in ward settings. Data were obtained by interview. A qualitative approach using a semi-structured interview schedule was used to obtain data from 22 matrons and the data were subjected to thematic analysis. There were differences in the way that matrons performed their role. They promoted clinical leadership effectively and maintained a high clinical profile. Attempts to promote high standards of cleanliness and infection control were less effective because of the shortcomings of the domestic service. Overall the matron role is proving effective. However, matrons' ability to promote adequate levels of environmental cleanliness and control infection is a cause for concern. IMPLICATIONS FOR NURSING MANAGERS: The study findings suggest that where an existing service is performing poorly, expecting another occupational group to oversee it will not contribute to improvement unless resources can be improved. WHAT THIS PAPER ADDS TO CURRENT KNOWLEDGE: This study has provided an in-depth evaluation of the matron role at a local level. It is to date the most comprehensive study of its kind.

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.

[Attaching importance to study on acute health risk assessment and adaptation of air pollution and climate change].

PubMed

Shi, X M

2017-03-10

Air pollution and climate change have become key environmental and public health problems around the world, which poses serious threat to human health. How to assess and mitigate the health risks and increase the adaptation of the public have become an urgent topic of research in this area. The six papers in this issue will provide important and rich information on design, analysis method, indicator selection and setting about acute health risk assessment and adaptation study of air pollution and climate change in China, reflecting the advanced conceptions of multi-center and area-specific study and multi-pollutant causing acute effect study. However, the number and type of the cities included in these studies were still limited. In future, researchers should further expand detailed multi-center and multi-area study coverage, conduct area specific predicting and early warning study and strengthen adaptation study.

Biomarkers of Host Response Predict Primary End-Point Radiological Pneumonia in Tanzanian Children with Clinical Pneumonia: A Prospective Cohort Study

PubMed Central

Erdman, Laura K.; D’Acremont, Valérie; Hayford, Kyla; Kilowoko, Mary; Kyungu, Esther; Hongoa, Philipina; Alamo, Leonor; Streiner, David L.; Genton, Blaise; Kain, Kevin C.

2015-01-01

Background Diagnosing pediatric pneumonia is challenging in low-resource settings. The World Health Organization (WHO) has defined primary end-point radiological pneumonia for use in epidemiological and vaccine studies. However, radiography requires expertise and is often inaccessible. We hypothesized that plasma biomarkers of inflammation and endothelial activation may be useful surrogates for end-point pneumonia, and may provide insight into its biological significance. Methods We studied children with WHO-defined clinical pneumonia (n = 155) within a prospective cohort of 1,005 consecutive febrile children presenting to Tanzanian outpatient clinics. Based on x-ray findings, participants were categorized as primary end-point pneumonia (n = 30), other infiltrates (n = 31), or normal chest x-ray (n = 94). Plasma levels of 7 host response biomarkers at presentation were measured by ELISA. Associations between biomarker levels and radiological findings were assessed by Kruskal-Wallis test and multivariable logistic regression. Biomarker ability to predict radiological findings was evaluated using receiver operating characteristic curve analysis and Classification and Regression Tree analysis. Results Compared to children with normal x-ray, children with end-point pneumonia had significantly higher C-reactive protein, procalcitonin and Chitinase 3-like-1, while those with other infiltrates had elevated procalcitonin and von Willebrand Factor and decreased soluble Tie-2 and endoglin. Clinical variables were not predictive of radiological findings. Classification and Regression Tree analysis generated multi-marker models with improved performance over single markers for discriminating between groups. A model based on C-reactive protein and Chitinase 3-like-1 discriminated between end-point pneumonia and non-end-point pneumonia with 93.3% sensitivity (95% confidence interval 76.5–98.8), 80.8% specificity (72.6–87.1), positive likelihood ratio 4.9 (3.4–7

Identifying patient-level health and social care costs for older adults discharged from acute medical units in England.

PubMed

Franklin, Matthew; Berdunov, Vladislav; Edmans, Judi; Conroy, Simon; Gladman, John; Tanajewski, Lukasz; Gkountouras, Georgios; Elliott, Rachel A

2014-09-01

acute medical units allow for those who need admission to be correctly identified, and for those who could be managed in ambulatory settings to be discharged. However, re-admission rates for older people following discharge from acute medical units are high and may be associated with substantial health and social care costs. identifying patient-level health and social care costs for older people discharged from acute medical units in England. a prospective cohort study of health and social care resource use. an acute medical unit in Nottingham, England. four hundred and fifty-six people aged over 70 who were discharged from an acute medical unit within 72 h of admission. hospitalisation and social care data were collected for 3 months post-recruitment. In Nottingham, further approvals were gained to obtain data from general practices, ambulance services, intermediate care and mental healthcare. Resource use was combined with national unit costs. costs from all sectors were available for 250 participants. The mean (95% CI, median, range) total cost was £1926 (1579-2383, 659, 0-23,612). Contribution was: secondary care (76.1%), primary care (10.9%), ambulance service (0.7%), intermediate care (0.2%), mental healthcare (2.1%) and social care (10.0%). The costliest 10% of participants accounted for 50% of the cost. this study highlights the costs accrued by older people discharged from acute medical units (AMUs): they are mainly (76%) in secondary care and half of all costs were incurred by a minority of participants (10%). © The Author 2014. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Evaluation of an acute oral gavage method for assessment of pesticide toxicity in terrestrial amphibians.

PubMed

Fort, Douglas J; Mathis, Michael B; Kee, Faith; Whatling, Paul; Clerkin, David; Staveley, Jane; Habig, Clifford

2018-02-01

Development of an acute oral toxicity test with a terrestrial-phase amphibian was considered necessary to remove the uncertainty within the field of agrochemical risk assessments. The bullfrog (Lithobates catesbeianus) was selected for use as it is a representative of the family Ranidae and historically this species has been used as an amphibian test model species. Prior to definitive study, oral gavage methods were developed with fenthion and tetraethyl pyrophosphate. Dimethoate and malathion were subsequently tested with both male and female juvenile bullfrogs in comprehensive acute oral median lethal dose (LD50) studies. Juvenile bullfrogs were administered a single dose of the test article via oral gavage of a single gelatin capsule of dimethoate technical (dimethoate) or neat liquid Fyfanon ® Technical (synonym malathion), returned to their respective aquaria, and monitored for survival for 14 d. The primary endpoint was mortality, whereas behavioral responses, food consumption, body weight, and snout-vent length (SVL) were used to evaluate indications of sublethal toxicity (secondary endpoints). Acute oral LD50 values (95% fiducial interval) for dimethoate were 1459 (1176-1810, males) and 1528 (1275-1831, females), and for malathion they were 1829 (1480-2259, males) and 1672 (1280-2183, females) mg active substance/kg body weight, respectively. Based on the results of these studies, the methodology for the acute oral gavage administration of test items to terrestrial-phase amphibians was demonstrated as being a practical method of providing data for risk assessments. Environ Toxicol Chem 2018;37:436-450. © 2017 SETAC. © 2017 SETAC.

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

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.

Arsenate (As V) in water: quantitative sensitivity relationships among biomarker, ecotoxicity and genotoxicity endpoints.

PubMed

Silva, Valéria C; Almeida, Sônia M; Resgalla, Charrid; Masfaraud, Jean-François; Cotelle, Sylvie; Radetski, Claudemir M

2013-06-01

It is useful to test ecotoxicity and genotoxicity endpoints in the environmental impact assessment. Here, we compare and discuss ecotoxicity and genotoxicity effects in organisms in response to exposure to arsenate (As V) in solution. Eco(geno)toxicity responses in Aliivibrio fischeri, Lytechinus variegatus, Daphnia magna, Skeletonema costatum and Vicia faba were analyzed by assessing different endpoints: biomass growth, peroxidase activity, mitotic index, micronucleus frequency, and lethality in accordance with the international protocols. Quantitative sensitivity relationships (QSR) between these endpoints were established in order to rank endpoint sensitivity. The results for the QSR values based on the lowest observed effect concentration (LOEC) ratios varied from 2 (for ratio of root peroxidase activity to leaf peroxidase activity) to 2286 (for ratio of higher plant biomass growth to root peroxidase activity). The QSR values allowed the following sensitivity ranking to be established: higher plant enzymatic activity>daphnids≈echinoderms>bacteria≈algae>higher plant biomass growth. The LOEC values for the mitotic index and micronucleus frequency (LOEC=0.25mgAsL(-1)) were similar to the lowest LOEC values observed in aquatic organisms. This approach to the QSR of different endpoints could form the basis for monitoring and predicting early effects of pollutants before they give rise to significant changes in natural community structures. Copyright © 2013 Elsevier Inc. All rights reserved.

Module modified acute physiology and chronic health evaluation II: predicting the mortality of neuro-critical disease.

PubMed

Su, Yingying; Wang, Miao; Liu, Yifei; Ye, Hong; Gao, Daiquan; Chen, Weibi; Zhang, Yunzhou; Zhang, Yan

2014-12-01

This study aimed to conduct and assess a module modified acute physiology and chronic health evaluation (MM-APACHE) II model, based on disease categories modified-acute physiology and chronic health evaluation (DCM-APACHE) II model, in predicting mortality more accurately in neuro-intensive care units (N-ICUs). In total, 1686 patients entered into this prospective study. Acute physiology and chronic health evaluation (APACHE) II scores of all patients on admission and worst 24-, 48-, 72-hour scores were obtained. Neurological diagnosis on admission was classified into five categories: cerebral infarction, intracranial hemorrhage, neurological infection, spinal neuromuscular (SNM) disease, and other neurological diseases. The APACHE II scores of cerebral infarction, intracranial hemorrhage, and neurological infection patients were used for building the MM-APACHE II model. There were 1386 cases for cerebral infarction disease, intracranial hemorrhage disease, and neurological infection disease. The logistic linear regression showed that 72-hour APACHE II score (Wals  =  173.04, P < 0.001) and disease classification (Wals  =  12.51, P  =  0.02) were of importance in forecasting hospital mortality. Module modified acute physiology and chronic health evaluation II model, built on the variables of the 72-hour APACHE II score and disease category, had good discrimination (area under the receiver operating characteristic curve (AU-ROC  =  0.830)) and calibration (χ2  =  12.518, P  =  0.20), and was better than the Knaus APACHE II model (AU-ROC  =  0.778). The APACHE II severity of disease classification system cannot provide accurate prognosis for all kinds of the diseases. A MM-APACHE II model can accurately predict hospital mortality for cerebral infarction, intracranial hemorrhage, and neurologic infection patients in N-ICU.

Physiological Ischemic Training Promotes Brain Collateral Formation and Improves Functions in Patients with Acute Cerebral Infarction.

PubMed

Zhen, Xiaoyue; Zheng, Yu; Hong, Xunning; Chen, Yan; Gu, Ping; Tang, Jinrong; Cheng, Hong; Yuan, Ti-Fei; Lu, Xiao

2016-01-01

To observe the effectiveness and mechanisms of physiological ischemic training (PIT) on brain cerebral collateral formation and functional recovery in patients with acute cerebral infarction. 20 eligible patients with acute cerebral infarction were randomly assigned to either PIT group ( n  = 10) or Control group ( n  = 10). Both groups received 4 weeks of routine rehabilitation therapy, while an additional session of PIT, which consisted of 10 times of maximal voluntary isometric handgrip for 1 min followed by 1 min rest, was prescribed for patients in the PIT groups. Each patient was trained with four sections a day and 5 days a week for 4 weeks. The Fugl-Meyer Assessment (FMA), the Modified Barthel Index (MBI), and the short-form 36-item health survey questionnaire (SF-36) were applied for the evaluation of motor impairment, activity of daily living, and quality of life at the baseline and endpoint. MRI was applied to detect the collateral formation in the brain. The concentration of vascular endothelial growth factor (VEGF) and endothelial progenitor cells (EPCs) number in plasma were also tested at the endpoint. Demographic data were consistent between experimental groups. At the endpoint, the scores of the FMA, MBI, and SF-36 were significantly higher than that at baseline. As compared to the Control group, the score of FMA and SF-36 in PIT group was significantly higher, while no significant difference was detected between groups in terms of MBI. Both groups had significantly higher cerebral blood flow (CBF) level at endpoint as compared to that at baseline. Moreover, the CBF level was even higher in the PIT group as compared to that in the Control group after 4 weeks of training. The same situations were also found in the plasma VEGF and EPCs assessment. In addition, positive correlations were found between FMA score and CBF level ( r  = 0.686, p  < 0.01), CBF level and VEGF concentration ( r  = 0.675, p  < 0.01), and

Health-related quality of life, sense of coherence and leisure-time physical activity in women after an acute myocardial infarction.

PubMed

Løvlien, Mona; Mundal, Liv; Hall-Lord, Marie-Louise

2017-04-01

To examine the relationship between leisure-time physical activity, health-related quality of life and sense of coherence in women after an acute myocardial infarction, and further to investigate whether these aspects were associated with age. Physical activity and health-related quality of life are vital aspects for patients after an acute myocardial infarction. Cross-sectional. All eligible women diagnosed with acute myocardial infarction received a postal questionnaire two to three months after hospital discharge, and 142 women were included. To measure health-related quality of life and sense of coherence, The MacNew Heart disease questionnaire and the Sense of coherence-13 scale was used. Respondents reporting at least one type of physical activity had significantly higher health-related quality of life as compared to respondents reporting no kind of physical activity. Respondents reporting physical activity for at least 30 minutes twice a week had significantly higher health-related quality of life scores than respondents being active less than twice a week. A weak association was found between physical activity level and sense of coherence. Reduction in physical activity after the acute myocardial infarction was associated with reduced health-related quality of life and sense of coherence. Sense of coherence was significantly associated with age, as respondents 75 years and older had significantly higher scores than respondents younger than 75 years. Physical activity, even at a low level, is significantly associated with increased health-related quality of life and to some extent to sense of coherence. Tailoring women after an acute myocardial infarction about lifestyle changes must include knowledge about the benefits of leisure-time physical activity, and that even a small amount of activity is associated with a better health-related quality of life. The utmost important assignment is to motivate the women for regular physical activity in their leisure

Acute and early life stage toxicity of industrial effluent on Japanese medaka (Oryzias latipes).

PubMed

Zha, Jinmiao; Wang, Zijian

2006-03-15

To develop the whole effluent toxicity testing methods (WET), embryo larval stage toxicity test using Japanese medaka (Oryzias latipes) was conducted to evaluate an effluent from a banknote printing plant (BPP). The method is based on acute toxicity using endpoint of 96-h larval morality and on chronic toxicity using endpoints such as the time to hatch, hatching success, deformity, growth rate, swim-up failure, accumulative mortality and sexual ratio. In test for 96-h larval mortality, LC50 (the concentration was lethal to 50% of newly hatching medaka larvae) was 72.9%. In chronic toxicity test, newly fertilized embryos (<5-h old) were exposed to 1%, 6.25%, 12.5%, 25%, 50% effluent concentrations and to 200 mug/l BPA in a 24-h static renewal system at 25+/-1 degrees C until 15 day post-hatch. The results showed that all chronic endpoints were significantly different from the control at 50% dilution (p < 0.01). Embryos began to show lesions on 4th day at higher concentrations (12.5%, 25%, 50% BPP effluent concentrations). Treatment group of 25% dilution showed delayed time to hatch. A reduction in body weight was observed at 25% dilutions for males and females, respectively. Deformities were observed in newly hatched larvae at 25% and 50% BPP effluent concentrations. At 25% dilution, sex ratio of larvae was alternated and there was feminization phenomenon. We conclude that embryo larval stage test using medaka is feasible to evaluate both acute and chronic toxicities and potential endocrine disrupting activity of industrial effluents.

Individuals versus organisms versus populations in the definition of ecological assessment endpoints.

PubMed

Suter, Glenn W; Norton, Susan B; Fairbrother, Anne

2005-11-01

Discussions and applications of the policies and practices of the U.S. Environmental Protection Agency (USEPA) in ecological risk assessment will benefit from continued clarification of the concepts of assessment endpoints and of levels of biological organization. First, assessment endpoint entities and attributes can be defined at different levels of organization. Hence, an organism-level attribute, such as growth or survival, can be applied collectively to a population-level entity such as the brook trout in a stream. Second, assessment endpoints for ecological risk assessment are often mistakenly described as "individual level," which leads to the idea that such assessments are intended to protect individuals. Finally, populations play a more important role in risk assessments than is generally recognized. Organism-level attributes are used primarily for population-level assessments. In addition, the USEPA and other agencies already are basing management decisions on population or community entities and attributes such as production of fisheries, abundance of migratory bird populations, and aquatic community composition.

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.

Meta-Analysis of Early Nutrition: The Benefits of Enteral Feeding Compared to a Nil Per Os Diet Not Only in Severe, but Also in Mild and Moderate Acute Pancreatitis.

PubMed

Márta, Katalin; Farkas, Nelli; Szabó, Imre; Illés, Anita; Vincze, Áron; Pár, Gabriella; Sarlós, Patrícia; Bajor, Judit; Szűcs, Ákos; Czimmer, József; Mosztbacher, Dóra; Párniczky, Andrea; Szemes, Kata; Pécsi, Dániel; Hegyi, Péter

2016-10-20

The recently published guidelines for acute pancreatitis (AP) suggest that enteral nutrition (EN) should be the primary therapy in patients suffering from severe acute pancreatitis (SAP); however, none of the guidelines have recommendations on mild and moderate AP (MAP). A meta-analysis was performed using the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P). The following PICO (problem, intervention, comparison, outcome) was applied: P: nutrition in AP; I: enteral nutrition (EN); C: nil per os diet (NPO); and O: outcome. There were 717 articles found in Embase, 831 in PubMed, and 10 in the Cochrane database. Altogether, seven SAP and six MAP articles were suitable for analyses. In SAP, forest plots were used to illustrate three primary endpoints (mortality, multiorgan failure, and intervention). In MAP, 14 additional secondary endpoints were analyzed (such as CRP (C-reactive protein), WCC (white cell count), complications, etc.). After pooling the data, the Mann-Whitney U test was used to detect significant differences. Funnel plots were created for testing heterogeneity. All of the primary endpoints investigated showed that EN is beneficial vs. NPO in SAP. In MAP, all of the six articles found merit in EN. Analyses of the primary endpoints did not show significant differences between the groups; however, analyzing the 17 endpoints together showed a significant difference in favor of EN vs. NPO. EN is beneficial compared to a nil per os diet not only in severe, but also in mild and moderate AP.

Potential surrogate endpoints for prostate cancer survival: analysis of a phase III randomized trial.

PubMed

Ray, Michael E; Bae, Kyounghwa; Hussain, Maha H A; Hanks, Gerald E; Shipley, William U; Sandler, Howard M

2009-02-18

The identification of surrogate endpoints for prostate cancer-specific survival may shorten the length of clinical trials for prostate cancer. We evaluated distant metastasis and general clinical treatment failure as potential surrogates for prostate cancer-specific survival by use of data from the Radiation Therapy and Oncology Group 92-02 randomized trial. Patients (n = 1554 randomly assigned and 1521 evaluable for this analysis) with locally advanced prostate cancer had been treated with 4 months of neoadjuvant and concurrent androgen deprivation therapy with external beam radiation therapy and then randomly assigned to no additional therapy (control arm) or 24 additional months of androgen deprivation therapy (experimental arm). Data from landmark analyses at 3 and 5 years for general clinical treatment failure (defined as documented local disease progression, regional or distant metastasis, initiation of androgen deprivation therapy, or a prostate-specific antigen level of 25 ng/mL or higher after radiation therapy) and/or distant metastasis were tested as surrogate endpoints for prostate cancer-specific survival at 10 years by use of Prentice's four criteria. All statistical tests were two-sided. At 3 years, 1364 patients were alive and contributed data for analysis. Both distant metastasis and general clinical treatment failure at 3 years were consistent with all four of Prentice's criteria for being surrogate endpoints for prostate cancer-specific survival at 10 years. At 5 years, 1178 patients were alive and contributed data for analysis. Although prostate cancer-specific survival was not statistically significantly different between treatment arms at 5 years (P = .08), both endpoints were consistent with Prentice's remaining criteria. Distant metastasis and general clinical treatment failure at 3 years may be candidate surrogate endpoints for prostate cancer-specific survival at 10 years. These endpoints, however, must be validated in other datasets.

Exposing the cancer genome atlas as a SPARQL endpoint.

PubMed

Deus, Helena F; Veiga, Diogo F; Freire, Pablo R; Weinstein, John N; Mills, Gordon B; Almeida, Jonas S

2010-12-01

The Cancer Genome Atlas (TCGA) is a multidisciplinary, multi-institutional effort to characterize several types of cancer. Datasets from biomedical domains such as TCGA present a particularly challenging task for those interested in dynamically aggregating its results because the data sources are typically both heterogeneous and distributed. The Linked Data best practices offer a solution to integrate and discover data with those characteristics, namely through exposure of data as Web services supporting SPARQL, the Resource Description Framework query language. Most SPARQL endpoints, however, cannot easily be queried by data experts. Furthermore, exposing experimental data as SPARQL endpoints remains a challenging task because, in most cases, data must first be converted to Resource Description Framework triples. In line with those requirements, we have developed an infrastructure to expose clinical, demographic and molecular data elements generated by TCGA as a SPARQL endpoint by assigning elements to entities of the Simple Sloppy Semantic Database (S3DB) management model. All components of the infrastructure are available as independent Representational State Transfer (REST) Web services to encourage reusability, and a simple interface was developed to automatically assemble SPARQL queries by navigating a representation of the TCGA domain. A key feature of the proposed solution that greatly facilitates assembly of SPARQL queries is the distinction between the TCGA domain descriptors and data elements. Furthermore, the use of the S3DB management model as a mediator enables queries to both public and protected data without the need for prior submission to a single data source. Copyright © 2010 Elsevier Inc. All rights reserved.

Exposing the cancer genome atlas as a SPARQL endpoint

PubMed Central

Deus, Helena F.; Veiga, Diogo F.; Freire, Pablo R.; Weinstein, John N.; Mills, Gordon B.; Almeida, Jonas S.

2011-01-01

The Cancer Genome Atlas (TCGA) is a multidisciplinary, multi-institutional effort to characterize several types of cancer. Datasets from biomedical domains such as TCGA present a particularly challenging task for those interested in dynamically aggregating its results because the data sources are typically both heterogeneous and distributed. The Linked Data best practices offer a solution to integrate and discover data with those characteristics, namely through exposure of data as Web services supporting SPARQL, the Resource Description Framework query language. Most SPARQL endpoints, however, cannot easily be queried by data experts. Furthermore, exposing experimental data as SPARQL endpoints remains a challenging task because, in most cases, data must first be converted to Resource Description Framework triples. In line with those requirements, we have developed an infrastructure to expose clinical, demographic and molecular data elements generated by TCGA as a SPARQL endpoint by assigning elements to entities of the Simple Sloppy Semantic Database (S3DB) management model. All components of the infrastructure are available as independent Representational State Transfer (REST) Web services to encourage reusability, and a simple interface was developed to automatically assemble SPARQL queries by navigating a representation of the TCGA domain. A key feature of the proposed solution that greatly facilitates assembly of SPARQL queries is the distinction between the TCGA domain descriptors and data elements. Furthermore, the use of the S3DB management model as a mediator enables queries to both public and protected data without the need for prior submission to a single data source. PMID:20851208

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.

The effects of repeated nitroglycerin administrations in rats; modeling migraine-related endpoints and chronification.

PubMed

Harris, Hannah M; Carpenter, Jessica M; Black, Jonathan R; Smitherman, Todd A; Sufka, Kenneth J

2017-06-01

Rodent models typically use a single nitroglycerin injection to induce migraine, yet migraine in clinical populations presents as recurrent episodes. Further, these models quantify behavioral endpoints that do not align with the clinical features of episodic migraine or migraine chronification and therefore may limit translational relevance. Rats received 5 nitroglycerin (10mg/kg/2ml), propylene glycol/ethanol vehicle, or saline injections every third day over 15days. Behavioral endpoints were assessed 110min post nitroglycerin administration and included time spent light/dark chambers for photophobia as well as activity, facial pain expressions, and tactile allodynia. Animals administered nitroglycerin displayed photophobia, decreased activity, and increased facial pain expression. Similar alterations in photophobia and activity were seen in the vehicle treated animals, but these tended to diminish by the 4th or 5th injection. The presentation of spontaneous tactile allodynia was observed in the nitroglycerin group by the 5th episode. Most NTG migraine models entail a single NTG administration and quantification of evoked allodynia. This paradigm employs recurring NTG episodes and clinically-relevant measures of photophobia, hypoactivity and facial grimace endpoints as well as introduces a novel arena apparatus to quantify spontaneous allodynia. This repeated NTG procedure and endpoint measures aligns with the frequency and clinical presentation of episodic migraine and its chronification, respectively. Further, propylene glycol ethanol vehicle contributes to migraine endpoints. Copyright © 2017 Elsevier B.V. All rights reserved.

Natriuretic Peptides, 6-Min Walk Test, and Quality-of-Life Questionnaires as Clinically Meaningful Endpoints in HF Trials.

PubMed

Ferreira, João Pedro; Duarte, Kevin; Graves, Todd L; Zile, Michael R; Abraham, William T; Weaver, Fred A; Lindenfeld, JoAnn; Zannad, Faiez

2016-12-20

The Expedited Access for Premarket Approval and De Novo Medical Devices Intended for Unmet Medical Need for Life Threatening or Irreversibly Debilitating Diseases or Conditions document was issued as a guidance for industry and for the Food and Drug Administration. The Expedited Access Pathway was designed as a new program for medical devices that demonstrated the potential to address unmet medical needs for life threatening or irreversibly debilitating conditions. The Food and Drug Administration would consider assessments of a device's effect on intermediate endpoints that, when improving in a congruent fashion, are reasonably likely to predict clinical benefit. The purpose of this review is to provide evidence to support the use of 3 such intermediate endpoints: natriuretic peptides, such as N-terminal pro-B-type natriuretic peptide/B-type natriuretic peptide, the 6-min walk test distance, and health-related quality of life in heart failure. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

RTOG 0529: A Phase 2 Evaluation of Dose-Painted Intensity Modulated Radiation Therapy in Combination With 5-Fluorouracil and Mitomycin-C for the Reduction of Acute Morbidity in Carcinoma of the Anal Canal

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

Kachnic, Lisa A., E-mail: lisa.kachnic@bmc.org; Winter, Kathryn; Myerson, Robert J.

2013-05-01

Purpose: A multi-institutional phase 2 trial assessed the utility of dose-painted intensity modulated radiation therapy (DP-IMRT) in reducing grade 2+ combined acute gastrointestinal and genitourinary adverse events (AEs) of 5-fluorouracil (5FU) and mitomycin-C (MMC) chemoradiation for anal cancer by at least 15% compared with the conventional radiation/5FU/MMC arm from RTOG 9811. Methods and Materials: T2-4N0-3M0 anal cancer patients received 5FU and MMC on days 1 and 29 of DP-IMRT, prescribed per stage: T2N0, 42 Gy elective nodal and 50.4 Gy anal tumor planning target volumes (PTVs) in 28 fractions; T3-4N0-3, 45 Gy elective nodal, 50.4 Gy ≤3 cm or 54more » Gy >3 cm metastatic nodal and 54 Gy anal tumor PTVs in 30 fractions. The primary endpoint is described above. Planned secondary endpoints assessed all AEs and the investigator’s ability to perform DP-IMRT. Results: Of 63 accrued patients, 52 were evaluable. Tumor stage included 54% II, 25% IIIA, and 21% IIIB. In primary endpoint analysis, 77% experienced grade 2+ gastrointestinal/genitourinary acute AEs (9811 77%). There was, however, a significant reduction in acute grade 2+ hematologic, 73% (9811 85%, P=.032), grade 3+ gastrointestinal, 21% (9811 36%, P=.0082), and grade 3+ dermatologic AEs 23% (9811 49%, P<.0001) with DP-IMRT. On initial pretreatment review, 81% required DP-IMRT replanning, and final review revealed only 3 cases with normal tissue major deviations. Conclusions: Although the primary endpoint was not met, DP-IMRT was associated with significant sparing of acute grade 2+ hematologic and grade 3+ dermatologic and gastrointestinal toxicity. Although DP-IMRT proved feasible, the high pretreatment planning revision rate emphasizes the importance of real-time radiation quality assurance for IMRT trials.« less

The Sleep Apnea cardioVascular Endpoints (SAVE) Trial: Rationale, Ethics, Design, and Progress.

PubMed

Antic, Nick A; Heeley, Emma; Anderson, Craig S; Luo, Yuanming; Wang, Jiguang; Neal, Bruce; Grunstein, Ron; Barbe, Ferran; Lorenzi-Filho, Geraldo; Huang, Shaoguang; Redline, Susan; Zhong, Nanshan; McEvoy, R Doug

2015-08-01

The Sleep Apnea cardioVascular Endpoints (SAVE) study is an ongoing investigator-initiated and conducted, international, multicenter, open, blinded endpoint, randomized controlled trial that was designed to determine whether treatment of obstructive sleep apnea (OSA) with continuous positive airways pressure (CPAP) can reduce the risk of serious cardiovascular (CV) events in patients with established CV disease (clinical trial registration NCT00738179). The results of this study will have important implications for the provision of health care to patients with sleep apnea around the world. The SAVE study has brought together respiratory, sleep, CV and stroke clinicians-scientists in an interdisciplinary collaboration with industry and government sponsorship to conduct an ambitious clinical trial. Following its launch in Australia and China in late 2008, the recruitment network expanded across 89 sites that included New Zealand, India, Spain, USA, and Brazil for a total of 2,717 patients randomized by December 2013. These patients are being followed until December 2015 so that the average length of follow-up of the cohort will be over 4 y. This article describes the rationale for the SAVE study, considerations given to the design including how various cultural and ethical challenges were addressed, and progress in establishing and maintaining the recruitment network, patient follow-up, and adherence to CPAP and procedures. The assumptions underlying the original trial sample size calculation and why this was revised downward in 2012 are also discussed. NCT00738179. ACTRN12608000409370. © 2015 Associated Professional Sleep Societies, LLC.

ECOLOGICAL ENDPOINT MODELING: EFFECTS OF SEDIMENT ON FISH POPULATIONS

EPA Science Inventory

Sediment is one of the main stressors of concern for TMDLs (Total Maximum Daily Loads) for streams, and often it is a concern because of its impact on biological endpoints. The National Research Council (NRC) has recommended that the EPA promote the development of models that ca...

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.

Contextual factors associated with health care service utilization for children with acute childhood illnesses in Nigeria.

PubMed

Adedokun, Sulaimon T; Adekanmbi, Victor T; Uthman, Olalekan A; Lilford, Richard J

2017-01-01

To examine the independent contribution of individual, community and state-level factors to health care service utilization for children with acute childhood illnesses in Nigeria. The study was based on secondary analyses of cross-sectional population-based data from the 2013 Nigeria Demographic and Health Survey (DHS). Multilevel logistic regression models were applied to the data on 6,427 under-five children who used or did not use health care service when they were sick (level 1), nested within 896 communities (level 2) from 37 states (level 3). About one-quarter of the mothers were between 15 and 24 years old and almost half of them did not have formal education (47%). While only 30% of the children utilized health service when they were sick, close to 67% lived in the rural area. In the fully adjusted model, mothers with higher education attainment (Adjusted odds ratio [aOR] = 1.63; 95% credible interval [CrI] = 1.31-2.03), from rich households (aOR = 1.76; 95% CrI = 1.35-2.25), with access to media (radio, television or magazine) (aOR = 1.18; 95% CrI = 1.08-1.29), and engaging in employment (aOR = 1.18; 95% CrI = 1.02-1.37) were significantly more likely to have used healthcare services for acute childhood illnesses. On the other hand, women who experienced difficulty getting to health facilities (aOR = 0.87; 95% CrI = 0.75-0.99) were less likely to have used health service for their children. Our findings highlight that utilization of healthcare service for acute childhood illnesses was influenced by not only maternal factors but also community-level factors, suggesting that public health strategies should recognise this complex web of individual composition and contextual composition factors to guide provision of healthcare services. Such interventions could include: increase in female school enrolment, provision of interest-free loans for small and medium scale enterprises, introduction of mobile clinics and establishment of more primary health care

[Factors influencing antibiotics prescribing of primary health physicians in acute upper respiratory infections].

PubMed

Kim, Nam-Soon; Jang, Soong Nang; Jang, Sun-Mee

2005-02-01

To explore the factors influencing antibiotics prescription by primary health physicians for acute upper respiratory infections (URI). We performed a survey of 370 primary health physicians randomly sampled in April, 2003. The questionnaire consisted of a prescription on the scenario of acute bronchitis case, along with opinions and reasons for prescribing antibiotics on URI. We found that 54.7% of the physicians prescribed antibiotics on the example case of acute bronchitis which is known as not needing antibiotics. Female physicians and ENT physicians had a greater tendency to prescribe antibiotics. The factors influencing antibiotics prescription on URI were the belief about the effectiveness of antibiotics, preference for their own experiences rather than clinical guidelines, perception of patients' expectations, and perception of competitive environment. The prescription of antibiotics in the example case was affected by how much they usually prescribe antibiotics (OR = 2.400, 95% CI = 1.470-3.917) and the physicians who thought that antibiotics were helpful for their income prescribed antibiotics more than others (OR = 6.773, 95% CI = 1.816-25.254). These findings demonstrated that the false belief on the effectiveness of antibiotics, patient's expectation of medication and fast relief of symptoms, and perception of competitive environment all affected the physicians' prescription of antibiotics on URI. It may help to find barriers to accommodate scientific evidence and clinical guidelines among physicians and to specify subgroups for education about appropriate prescription behaviors.

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

Comparison of the Mortality Probability Admission Model III, National Quality Forum, and Acute Physiology and Chronic Health Evaluation IV hospital mortality models: implications for national benchmarking*.

PubMed

Kramer, Andrew A; Higgins, Thomas L; Zimmerman, Jack E

2014-03-01

To examine the accuracy of the original Mortality Probability Admission Model III, ICU Outcomes Model/National Quality Forum modification of Mortality Probability Admission Model III, and Acute Physiology and Chronic Health Evaluation IVa models for comparing observed and risk-adjusted hospital mortality predictions. Retrospective paired analyses of day 1 hospital mortality predictions using three prognostic models. Fifty-five ICUs at 38 U.S. hospitals from January 2008 to December 2012. Among 174,001 intensive care admissions, 109,926 met model inclusion criteria and 55,304 had data for mortality prediction using all three models. None. We compared patient exclusions and the discrimination, calibration, and accuracy for each model. Acute Physiology and Chronic Health Evaluation IVa excluded 10.7% of all patients, ICU Outcomes Model/National Quality Forum 20.1%, and Mortality Probability Admission Model III 24.1%. Discrimination of Acute Physiology and Chronic Health Evaluation IVa was superior with area under receiver operating curve (0.88) compared with Mortality Probability Admission Model III (0.81) and ICU Outcomes Model/National Quality Forum (0.80). Acute Physiology and Chronic Health Evaluation IVa was better calibrated (lowest Hosmer-Lemeshow statistic). The accuracy of Acute Physiology and Chronic Health Evaluation IVa was superior (adjusted Brier score = 31.0%) to that for Mortality Probability Admission Model III (16.1%) and ICU Outcomes Model/National Quality Forum (17.8%). Compared with observed mortality, Acute Physiology and Chronic Health Evaluation IVa overpredicted mortality by 1.5% and Mortality Probability Admission Model III by 3.1%; ICU Outcomes Model/National Quality Forum underpredicted mortality by 1.2%. Calibration curves showed that Acute Physiology and Chronic Health Evaluation performed well over the entire risk range, unlike the Mortality Probability Admission Model and ICU Outcomes Model/National Quality Forum models. Acute

The Effect of Acute Exercise on Affect and Arousal in Inpatient Mental Health Consumers.

PubMed

Stanton, Robert; Reaburn, Peter; Happell, Brenda

2016-09-01

Acute exercise performed at a self-selected intensity improves affect and may improve long-term adherence. Similarly, in people with severe depression, acute aerobic exercise performed at self-selected intensity improves affect and arousal. However, the relationship between changes in affect and arousal and perceived exercise intensity in people with mental illness has not been evaluated. Affect and arousal were assessed immediately prior to, and immediately following, a group exercise program performed at a self-selected intensity in 40 inpatient mental health consumers who received a diagnosis of anxiety or bipolar or depressive disorders. Exercise intensity was assessed immediately after exercise. Postexercise affect was significantly improved for people with bipolar and depressive disorders but not for people with anxiety disorders. For the group as a whole, results showed a significant curvilinear relationship between ratings of perceived exertion and postexercise affect. These data will inform the development and delivery of future exercise interventions for inpatient mental health consumers.

Detecting acute neurotoxicity during platinum chemotherapy by neurophysiological assessment of motor nerve hyperexcitability

PubMed Central

2010-01-01

Background Platinum-based drugs, such as cisplatin and oxaliplatin, are well-known for inducing chronic sensory neuropathies but their acute and motor neurotoxicities are less well characterised. Use was made of nerve conduction studies and needle electromyography (EMG) to assess motor nerve excitability in cancer patients during their first treatment cycle with platinum-based chemotherapy in this study. Methods Twenty-nine adult cancer patients had a neurophysiological assessment either before oxaliplatin plus capecitabine, on days 2 to 4 or 14 to 20 after oxaliplatin plus capecitabine, or on days 2 to 4 after carboplatin plus paclitaxel or cisplatin, undertaken by a neurophysiologist who was blinded to patient and treatment details. Patients completed a symptom questionnaire at the end of the treatment cycle. Results Abnormal spontaneous high frequency motor fibre action potentials were detected in 100% of patients (n = 6) and 72% of muscles (n = 22) on days 2 to 4 post-oxaliplatin, and in 25% of patients (n = 8) and 13% of muscles (n = 32) on days 14 to 20 post-oxaliplatin, but in none of the patients (n = 14) or muscles (n = 56) tested prior to oxaliplatin or on days 2 to 4 after carboplatin plus paclitaxel or cisplatin. Repetitive compound motor action potentials were less sensitive and less specific than spontaneous high frequency motor fibre action potentials for detection of acute oxaliplatin-induced motor nerve hyperexcitability but were present in 71% of patients (n = 7) and 32% of muscles (n = 32) on days 2 to 4 after oxaliplatin treatment. Acute neurotoxicity symptoms, most commonly cold-induced paraesthesiae and jaw or throat tightness, were reported by all patients treated with oxaliplatin (n = 22) and none of those treated with carboplatin plus paclitaxel or cisplatin (n = 6). Conclusions Abnormal spontaneous high frequency motor fibre activity is a sensitive and specific endpoint of acute oxaliplatin-induced motor nerve hyperexcitability, detectable

Efficacy and safety of parecoxib in the treatment of acute renal colic: a randomized clinical trial.

PubMed

Glina, Sidney; Damiao, Ronaldo; Afif-Abdo, Joao; Santa Maria, Carlos Francisco; Novoa, Raúl; Cairoli, Carlos Eurico Dornelles; Wajsbrot, Dalia; Araya, Gaston

2011-01-01

Although non-selective non-steroidal anti-inflammatory drugs (nsNSAIDs) and opioids are effective treatments for acute renal colic, they are associated with adverse events (AEs). As cyclooxygenase-2 selective NSAIDs may provide a safer alternative, we compared the efficacy and safety of parecoxib versus an nsNSAID in subjects with acute renal colic. Phase IV., multicenter, double-blind, noninferiority, active-controlled study: 338 subjects with acute renal colic were randomized to parecoxib 40 mg i.v. plus placebo (n = 174) or ketoprofen 100 mg IV plus placebo (n = 164). 338 subjects with acute renal colic were randomized to parecoxib 40 mg IV (n = 174) or ketoprofen 100 mg IV(n = 164) plus placebo. Subjects were evaluated 15, 30, 45, 60, 90 and 120 minutes after treatment start and 24 hours after discharge. Primary endpoint was the mean pain intensity difference (PID) at 30 minutes by visual analog scale (VAS) (per-protocol population). An ANCOVA model was used with treatment group, country, and baseline score as covariates. Non-inferiority of parecoxib to ketoprofen was declared if the lower bound of the 95% confidence interval (CI) for the difference between the two groups excluded the pre-established margin of 10 mm for the primary endpoint. Baseline demographics were similar. The mean (SD) mPID30 min was 33.84 (24.61) and 35.16 (26.01) for parecoxib and ketoprofen, respectively. For treatment difference (parecoxib-ketoprofen) the lower bound of the 95% CI was 6.53. The mean change from baseline in VAS 30 minutes after study medication was ~43 mm; AEs were comparable between treatments. Parecoxib is as effective as ketoprofen in the treatment of pain due to acute renal colic, is well tolerated, and has a comparable safety profile.

Effect of multiple honey doses on non-specific acute cough in children. An open randomised study and literature review.

PubMed

Miceli Sopo, S; Greco, M; Monaco, S; Varrasi, G; Di Lorenzo, G; Simeone, G

2015-01-01

Honey is recommended for non-specific acute paediatric cough by the Australian guidelines. Current available randomised clinical trials evaluated the effects of a single evening dose of honey, but multiple doses outcomes have never been studied. To evaluate the effects of wildflower honey, given for three subsequent evenings, on non-specific acute paediatric cough, compared to dextromethorphan (DM) and levodropropizine (LDP), which are the most prescribed over-the-counter (OTC) antitussives in Italy. 134 children suffering from non-specific acute cough were randomised to receive for three subsequent evenings a mixture of milk (90ml) and wildflower honey (10ml) or a dose of DM or LDP adjusted for the specific age. The effectiveness was evaluated by a cough questionnaire answered by parents. Primary end-point efficacy was therapeutic success. The latter was defined as a decrease in cough questionnaire score greater than 50% after treatment compared with baseline values. Three children were excluded from the study, as their parents did not complete the questionnaire. Therapeutic success was achieved by 80% in the honey and milk group and 87% in OTC medication group (p=0.25). Milk and honey mixture seems to be at least as effective as DM or LDP in non-specific acute cough in children. These results are in line with previous studies, which reported the health effects of honey on paediatric cough, even if placebo effect cannot be totally excluded. Copyright © 2014 SEICAP. Published by Elsevier Espana. All rights reserved.

Muscle short-range stiffness can be used to estimate the endpoint stiffness of the human arm

PubMed Central

Hu, Xiao; Murray, Wendy M.

2011-01-01

The mechanical properties of the human arm are regulated to maintain stability across many tasks. The static mechanics of the arm can be characterized by estimates of endpoint stiffness, considered especially relevant for the maintenance of posture. At a fixed posture, endpoint stiffness can be regulated by changes in muscle activation, but which activation-dependent muscle properties contribute to this global measure of limb mechanics remains unclear. We evaluated the role of muscle properties in the regulation of endpoint stiffness by incorporating scalable models of muscle stiffness into a three-dimensional musculoskeletal model of the human arm. Two classes of muscle models were tested: one characterizing short-range stiffness and two estimating stiffness from the slope of the force-length curve. All models were compared with previously collected experimental data describing how endpoint stiffness varies with changes in voluntary force. Importantly, muscle properties were not fit to the experimental data but scaled only by the geometry of individual muscles in the model. We found that force-dependent variations in endpoint stiffness were accurately described by the short-range stiffness of active arm muscles. Over the wide range of evaluated arm postures and voluntary forces, the musculoskeletal model incorporating short-range stiffness accounted for 98 ± 2, 91 ± 4, and 82 ± 12% of the variance in stiffness orientation, shape, and area, respectively, across all simulated subjects. In contrast, estimates based on muscle force-length curves were less accurate in all measures, especially stiffness area. These results suggest that muscle short-range stiffness is a major contributor to endpoint stiffness of the human arm. Furthermore, the developed model provides an important tool for assessing how the nervous system may regulate endpoint stiffness via changes in muscle activation. PMID:21289133

Safety of air travel following acute myocardial infarction.

PubMed

Roby, Howard; Lee, Anna; Hopkins, Andrew

2002-02-01

A randomized, single-blind, controlled trial was carried out to: 1) examine the safety of patients flying on commercial airlines 2 wk after a myocardial infarction; 2) determine whether or not the use of supplemental oxygen was associated with a reduced risk of in-flight adverse events; and 3) determine the need for a medical escort. There were 38 patients who were prospectively and randomly assigned supplemental continuous oxygen therapy (2 L x min(-1) via nasal prongs; n = 19) or no oxygen (n = 19) during the flight. Prior to flying, an escorting doctor completed a medical questionnaire for each patient. Both groups underwent Holter monitoring throughout the flight. The major end-point was the development of inflight myocardial ischemia, as detected by Holter monitoring. Minor end-points included patients complaining of chest pain or dyspnea; the detection of bigeminy or trigeminy by Holter monitoring; or oxygen desaturation to less than 90%, as measured by pulse oximetry. Of the 38 patients enrolled, there was only 1 major end-point. This patient had a brief, self-limiting, asymptomatic episode of myocardial ischemia diagnosed by Holter monitoring. Minor end-points occurred in 13 (34%) patients. One patient had asymptomatic evidence of S-T depression on a transport monitor, but not on the Holter. Five patients had transient low (<90%) oxygen saturations, two complained of chest pain, and five had complex ventricular ectopic beats or periods of transient ventricular tachycardia. None of the minor end-points were associated with Holter evidence of myocardial ischemia. Of the 30 patients with completed questionnaires and Holter results, there was no difference in the incidence of minor end-points between the oxygen (5/13) and no oxygen groups (6/15) (p = 0.93). Intervention by the medical escort consisted of commencing oxygen therapy on those patients with low oxygen saturations and those with chest pain. Use of an already dispensed glyceryl trinitrate spray was

Impact of intravenous nitroglycerin in the management of acute decompensated heart failure.

PubMed

den Uil, Corstiaan A; Brugts, Jasper J

2015-02-01

Intravenous nitroglycerin is a well-known, but underused, treatment for acute decompensated heart failure. Nitroglycerin has a rapid onset of action and short half-life and there is a clear dose-response curve on both global hemodynamics and peripheral circulation. IV nitroglycerin reduces LV and RV filling pressures and afterload. In the case of acute decompensated heart failure, there is a typical decreased bioavailability of nitric oxide (NO), which needs to be supplemented by exogenous nitrates. Additionally, there is benefit on clinical endpoints, such as fast optimization of arterial oxygenation, lower rates of mechanical ventilation, and improved survival. Drawbacks of therapy include not only side effects such as headache, resistance, and development of tolerability to nitrates but also free radical production. However, nitrates in combination with diuretics remain the cornerstone of acute decompensated heart failure treatment. We propose a more aggressive use of nitrates and a more limited use of inotropes (due to ischemic demand and pro-arrhythmogenic characteristics) in normo- or hypertensive patients with acute heart failure.

Management of acute respiratory infections by community health volunteers: experience of Bangladesh Rural Advancement Committee (BRAC).

PubMed Central

Hadi, Abdullahel

2003-01-01

OBJECTIVE: To assess the role of management practices for acute respiratory infections (ARIs) in improving the competency of community health volunteers in diagnosing and treating acute respiratory infections among children. METHODS: Data were collected by a group of research physicians who observed the performance of a sample of 120 health volunteers in 10 sub-districts in Bangladesh in which Bangladesh Rural Advancement Committee (BRAC) had run a community-based ARI control programme since mid-1992. Standardized tests were conducted until the 95% interphysician reliability on the observation of clinical examination was achieved. FINDINGS:The sensitivity, specificity, and overall agreement rates in diagnosing and treating ARIs were significantly higher among the health volunteers who had basic training and were supervised routinely than among those who had not. CONCLUSION: Diagnosis and treatment of ARIs at the household level in developing countries are possible if intensive basic training and the close supervision of service providers are ensured. PMID:12764514

Endpoint in plasma etch process using new modified w-multivariate charts and windowed regression

NASA Astrophysics Data System (ADS)

Zakour, Sihem Ben; Taleb, Hassen

2017-09-01

Endpoint detection is very important undertaking on the side of getting a good understanding and figuring out if a plasma etching process is done in the right way, especially if the etched area is very small (0.1%). It truly is a crucial part of supplying repeatable effects in every single wafer. When the film being etched has been completely cleared, the endpoint is reached. To ensure the desired device performance on the produced integrated circuit, the high optical emission spectroscopy (OES) sensor is employed. The huge number of gathered wavelengths (profiles) is then analyzed and pre-processed using a new proposed simple algorithm named Spectra peak selection (SPS) to select the important wavelengths, then we employ wavelet analysis (WA) to enhance the performance of detection by suppressing noise and redundant information. The selected and treated OES wavelengths are then used in modified multivariate control charts (MEWMA and Hotelling) for three statistics (mean, SD and CV) and windowed polynomial regression for mean. The employ of three aforementioned statistics is motivated by controlling mean shift, variance shift and their ratio (CV) if both mean and SD are not stable. The control charts show their performance in detecting endpoint especially W-mean Hotelling chart and the worst result is given by CV statistic. As the best detection of endpoint is given by the W-Hotelling mean statistic, this statistic will be used to construct a windowed wavelet Hotelling polynomial regression. This latter can only identify the window containing endpoint phenomenon.

Mixed response and time-to-event endpoints for multistage single-arm phase II design.

PubMed

Lai, Xin; Zee, Benny Chung-Ying

2015-06-04

The objective of phase II cancer clinical trials is to determine if a treatment has sufficient activity to warrant further study. The efficiency of a conventional phase II trial design has been the object of considerable debate, particularly when the study regimen is characteristically cytostatic. At the time of development of a phase II cancer trial, we accumulated clinical experience regarding the time to progression (TTP) for similar classes of drugs and for standard therapy. By considering the time to event (TTE) in addition to the tumor response endpoint, a mixed-endpoint phase II design may increase the efficiency and ability of selecting promising cytotoxic and cytostatic agents for further development. We proposed a single-arm phase II trial design by extending the Zee multinomial method to fully use mixed endpoints with tumor response and the TTE. In this design, the dependence between the probability of response and the TTE outcome is modeled through a Gaussian copula. Given the type I and type II errors and the hypothesis as defined by the response rate (RR) and median TTE, such as median TTP, the decision rules for a two-stage phase II trial design can be generated. We demonstrated through simulation that the proposed design has a smaller expected sample size and higher early stopping probability under the null hypothesis than designs based on a single-response endpoint or a single TTE endpoint. The proposed design is more efficient for screening new cytotoxic or cytostatic agents and less likely to miss an effective agent than the alternative single-arm design.

Proof of concept demonstration of optimal composite MRI endpoints for clinical trials.

PubMed

Edland, Steven D; Ard, M Colin; Sridhar, Jaiashre; Cobia, Derin; Martersteck, Adam; Mesulam, M Marsel; Rogalski, Emily J

2016-09-01

Atrophy measures derived from structural MRI are promising outcome measures for early phase clinical trials, especially for rare diseases such as primary progressive aphasia (PPA), where the small available subject pool limits our ability to perform meaningfully powered trials with traditional cognitive and functional outcome measures. We investigated a composite atrophy index in 26 PPA participants with longitudinal MRIs separated by two years. Rogalski et al . [ Neurology 2014;83:1184-1191] previously demonstrated that atrophy of the left perisylvian temporal cortex (PSTC) is a highly sensitive measure of disease progression in this population and a promising endpoint for clinical trials. Using methods described by Ard et al . [ Pharmaceutical Statistics 2015;14:418-426], we constructed a composite atrophy index composed of a weighted sum of volumetric measures of 10 regions of interest within the left perisylvian cortex using weights that maximize signal-to-noise and minimize sample size required of trials using the resulting score. Sample size required to detect a fixed percentage slowing in atrophy in a two-year clinical trial with equal allocation of subjects across arms and 90% power was calculated for the PSTC and optimal composite surrogate biomarker endpoints. The optimal composite endpoint required 38% fewer subjects to detect the same percent slowing in atrophy than required by the left PSTC endpoint. Optimal composites can increase the power of clinical trials and increase the probability that smaller trials are informative, an observation especially relevant for PPA, but also for related neurodegenerative disorders including Alzheimer's disease.

Testing for qualitative heterogeneity: An application to composite endpoints in survival analysis.

PubMed

Oulhaj, Abderrahim; El Ghouch, Anouar; Holman, Rury R

2017-01-01

Composite endpoints are frequently used in clinical outcome trials to provide more endpoints, thereby increasing statistical power. A key requirement for a composite endpoint to be meaningful is the absence of the so-called qualitative heterogeneity to ensure a valid overall interpretation of any treatment effect identified. Qualitative heterogeneity occurs when individual components of a composite endpoint exhibit differences in the direction of a treatment effect. In this paper, we develop a general statistical method to test for qualitative heterogeneity, that is to test whether a given set of parameters share the same sign. This method is based on the intersection-union principle and, provided that the sample size is large, is valid whatever the model used for parameters estimation. We propose two versions of our testing procedure, one based on a random sampling from a Gaussian distribution and another version based on bootstrapping. Our work covers both the case of completely observed data and the case where some observations are censored which is an important issue in many clinical trials. We evaluated the size and power of our proposed tests by carrying out some extensive Monte Carlo simulations in the case of multivariate time to event data. The simulations were designed under a variety of conditions on dimensionality, censoring rate, sample size and correlation structure. Our testing procedure showed very good performances in terms of statistical power and type I error. The proposed test was applied to a data set from a single-center, randomized, double-blind controlled trial in the area of Alzheimer's disease.

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.

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.

Acute health effects associated with exposure to volcanic air pollution (vog) from increased activity at Kilauea Volcano in 2008.

PubMed

Longo, Bernadette M; Yang, Wei; Green, Joshua B; Crosby, Frederick L; Crosby, Vickie L

2010-01-01

In 2008, the Kilauea Volcano on the island of Hawai'i increased eruption activity and emissions of sulfurous volcanic air pollution called vog. The purpose of this study was to promptly assess for a relative increase in cases of medically diagnosed acute illnesses in an exposed Hawaiian community. Using a within-clinic retrospective cohort design, comparisons were made for visits of acute illnesses during the 14 wk prior to the increased volcanic emissions (low exposure) to 14 wk of high vog exposure when ambient sulfur dioxide was threefold higher and averaged 75 parts per billion volume per day. Logistic regression analysis estimated effect measures between the low- and high-exposure cohorts for age, gender, race, and smoking status. There were statistically significant positive associations between high vog exposure and visits for medically diagnosed cough, headache, acute pharyngitis, and acute airway problems. More than a sixfold increase in odds was estimated for visits with acute airway problems, primarily experienced by young Pacific Islanders. These findings suggest that the elevated volcanic emissions in 2008 were associated with increased morbidity of acute illnesses in age and racial subgroups of the general Hawaiian population. Continued investigation is crucial to fully assess the health impact of this natural source of sulfurous air pollution. Culturally appropriate primary- and secondary-level health prevention initiatives are recommended for populations in Hawai'i and volcanically active areas worldwide.

[Online endpoint detection algorithm for blending process of Chinese materia medica].

PubMed

Lin, Zhao-Zhou; Yang, Chan; Xu, Bing; Shi, Xin-Yuan; Zhang, Zhi-Qiang; Fu, Jing; Qiao, Yan-Jiang

2017-03-01

Blending process, which is an essential part of the pharmaceutical preparation, has a direct influence on the homogeneity and stability of solid dosage forms. With the official release of Guidance for Industry PAT, online process analysis techniques have been more and more reported in the applications in blending process, but the research on endpoint detection algorithm is still in the initial stage. By progressively increasing the window size of moving block standard deviation (MBSD), a novel endpoint detection algorithm was proposed to extend the plain MBSD from off-line scenario to online scenario and used to determine the endpoint in the blending process of Chinese medicine dispensing granules. By online learning of window size tuning, the status changes of the materials in blending process were reflected in the calculation of standard deviation in a real-time manner. The proposed method was separately tested in the blending processes of dextrin and three other extracts of traditional Chinese medicine. All of the results have shown that as compared with traditional MBSD method, the window size changes according to the proposed MBSD method (progressively increasing the window size) could more clearly reflect the status changes of the materials in blending process, so it is suitable for online application. Copyright© by the Chinese Pharmaceutical Association.

Marital quality and health: A meta-analytic review

PubMed Central

Robles, Theodore F.; Slatcher, Richard B.; Trombello, Joseph M.; McGinn, Meghan M.

2013-01-01

This meta-analysis reviewed 126 published empirical articles over the past 50 years describing associations between marital relationship quality and physical health in over 72,000 individuals. Health outcomes included clinical endpoints (objective assessments of function, disease severity, and mortality; subjective health assessments) and surrogate endpoints (biological markers that substitute for clinical endpoints, such as blood pressure). Biological mediators included cardiovascular reactivity and hypothalamic-pituitary-adrenal axis activity. Greater marital quality was related to better health, with mean effect sizes from r = .07 to .21, including lower risk of mortality, r = .11, and lower cardiovascular reactivity during marital conflict, r = −.13, but not daily cortisol slopes or cortisol reactivity during conflict. The small effect sizes were similar in magnitude to previously found associations between health behaviors (e.g., diet) and health outcomes. Effect sizes for a small subset of clinical outcomes were susceptible to publication bias. In some studies, effect sizes remained significant after accounting for confounds such as age and socioeconomic status. Studies with a higher proportion of women in the sample demonstrated larger effect sizes, but we found little evidence for gender differences in studies that explicitly tested gender moderation, with the exception of surrogate endpoint studies. Our conclusions are limited by small numbers of studies for specific health outcomes, unexplained heterogeneity, and designs that limit causal inferences. These findings highlight the need to explicitly test affective, health behavior, and biological mechanisms in future research, and focus on moderating factors that may alter the relationship between marital quality and health. PMID:23527470

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...

Acute health impacts of airborne particles estimated from satellite remote sensing.

PubMed

Wang, Zhaoxi; Liu, Yang; Hu, Mu; Pan, Xiaochuan; Shi, Jing; Chen, Feng; He, Kebin; Koutrakis, Petros; Christiani, David C

2013-01-01

Satellite-based remote sensing provides a unique opportunity to monitor air quality from space at global, continental, national and regional scales. Most current research focused on developing empirical models using ground measurements of the ambient particulate. However, the application of satellite-based exposure assessment in environmental health is still limited, especially for acute effects, because the development of satellite PM(2.5) model depends on the availability of ground measurements. We tested the hypothesis that MODIS AOD (aerosol optical depth) exposure estimates, obtained from NASA satellites, are directly associated with daily health outcomes. Three independent healthcare databases were used: unscheduled outpatient visits, hospital admissions, and mortality collected in Beijing metropolitan area, China during 2006. We use generalized linear models to compare the short-term effects of air pollution assessed by ground monitoring (PM(10)) with adjustment of absolute humidity (AH) and AH-calibrated AOD. Across all databases we found that both AH-calibrated AOD and PM(10) (adjusted by AH) were consistently associated with elevated daily events on the current day and/or lag days for cardiovascular diseases, ischemic heart diseases, and COPD. The relative risks estimated by AH-calibrated AOD and PM(10) (adjusted by AH) were similar. Additionally, compared to ground PM(10), we found that AH-calibrated AOD had narrower confidence intervals for all models and was more robust in estimating the current day and lag day effects. Our preliminary findings suggested that, with proper adjustment of meteorological factors, satellite AOD can be used directly to estimate the acute health impacts of ambient particles without prior calibrating to the sparse ground monitoring networks. Copyright © 2012 Elsevier Ltd. All rights reserved.

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...

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

Meta-Analysis of Early Nutrition: The Benefits of Enteral Feeding Compared to a Nil Per Os Diet Not Only in Severe, but Also in Mild and Moderate Acute Pancreatitis

PubMed Central

Márta, Katalin; Farkas, Nelli; Szabó, Imre; Illés, Anita; Vincze, Áron; Pár, Gabriella; Sarlós, Patrícia; Bajor, Judit; Szűcs, Ákos; Czimmer, József; Mosztbacher, Dóra; Párniczky, Andrea; Szemes, Kata; Pécsi, Dániel; Hegyi, Péter

2016-01-01

The recently published guidelines for acute pancreatitis (AP) suggest that enteral nutrition (EN) should be the primary therapy in patients suffering from severe acute pancreatitis (SAP); however, none of the guidelines have recommendations on mild and moderate AP (MAP). A meta-analysis was performed using the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P). The following PICO (problem, intervention, comparison, outcome) was applied: P: nutrition in AP; I: enteral nutrition (EN); C: nil per os diet (NPO); and O: outcome. There were 717 articles found in Embase, 831 in PubMed, and 10 in the Cochrane database. Altogether, seven SAP and six MAP articles were suitable for analyses. In SAP, forest plots were used to illustrate three primary endpoints (mortality, multiorgan failure, and intervention). In MAP, 14 additional secondary endpoints were analyzed (such as CRP (C-reactive protein), WCC (white cell count), complications, etc.). After pooling the data, the Mann–Whitney U test was used to detect significant differences. Funnel plots were created for testing heterogeneity. All of the primary endpoints investigated showed that EN is beneficial vs. NPO in SAP. In MAP, all of the six articles found merit in EN. Analyses of the primary endpoints did not show significant differences between the groups; however, analyzing the 17 endpoints together showed a significant difference in favor of EN vs. NPO. EN is beneficial compared to a nil per os diet not only in severe, but also in mild and moderate AP. PMID:27775609

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.

The role of imperfect surrogate endpoint information in drug approval and reimbursement decisions.

PubMed

Bognar, Katalin; Romley, John A; Bae, Jay P; Murray, James; Chou, Jacquelyn W; Lakdawalla, Darius N

2017-01-01

Approval of new drugs is increasingly reliant on "surrogate endpoints," which correlate with but imperfectly predict clinical benefits. Proponents argue surrogate endpoints allow for faster approval, but critics charge they provide inadequate evidence. We develop an economic framework that addresses the value of improvement in the predictive power, or "quality," of surrogate endpoints, and clarifies how quality can influence decisions by regulators, payers, and manufacturers. For example, the framework shows how lower-quality surrogates lead to greater misalignment of incentives between payers and regulators, resulting in more drugs that are approved for use but not covered by payers. Efficient price-negotiation in the marketplace can help align payer incentives for granting access based on surrogates. Higher-quality surrogates increase manufacturer profits and social surplus from early access to new drugs. Since the return on better quality is shared between manufacturers and payers, private incentives to invest in higher-quality surrogates are inefficiently low. Copyright © 2016 The Author(s). Published by Elsevier B.V. All rights reserved.

Dexketoprofen/tramadol 25 mg/75 mg: randomised double-blind trial in moderate-to-severe acute pain after abdominal hysterectomy.

PubMed

Moore, R A; McQuay, H J; Tomaszewski, J; Raba, G; Tutunaru, D; Lietuviete, N; Galad, J; Hagymasy, L; Melka, D; Kotarski, J; Rechberger, T; Fülesdi, B; Nizzardo, A; Guerrero-Bayón, C; Cuadripani, S; Pizà-Vallespir, B; Bertolotti, M

2016-01-22

Dexketoprofen trometamol plus tramadol hydrochloride is a new oral combination of two analgesics, which have different mechanisms of action for the treatment of moderate to severe acute pain. Randomised, double-blind, parallel, placebo and active-controlled, single and multiple-dose study to evaluate the analgesic efficacy and safety of dexketoprofen/tramadol 25 mg/75 mg in comparison with the single agents (dexketoprofen 25 mg and tramadol 100 mg) in moderate to severe acute pain after abdominal hysterectomy. Patients received seven consecutive doses of study drug within a 3-day period, each dose separated by an 8-hour interval. A placebo arm was included during the single-dose phase to validate the pain model. Efficacy assessments included pain intensity, pain relief, patient global evaluation and use of rescue medication. The primary endpoint was the mean sum of pain intensity differences over the first 8 h (SPID8). The efficacy analysis included 606 patients, with a mean age of 48 years (range 25-73). The study results confirmed the superiority of the combination over the single agents in terms of the primary endpoint (p <0.001). Secondary endpoints were generally supportive of the superiority of the combination for both single and multiple doses. Most common adverse drug reactions (ADRs) were nausea (4.6%) and vomiting (2.3%). All other ADRs were experienced by less than 2% of patients. The study results provided robust evidence of the superiority of dexketoprofen/tramadol 25 mg/75 mg over the single components in the management of moderate to severe acute pain, as confirmed by the single-dose efficacy, repeated-dose sustained effect and good safety profile observed. EU Clinical Trials Register (EudraCT number 2012-004545-32, registered 04 October 2012); Clinicaltrials.gov ( NCT01904149, registered 17 July 2013).

Is Suicide Ideation a Surrogate Endpoint for Geriatric Suicide?

ERIC Educational Resources Information Center

Links, Paul S.; Heisel, Marnin J.; Quastel, Adam

2005-01-01

The present study explored the validity of treating suicide ideation as a surrogate endpoint that can serve as a proxy for suicide in clinical intervention research with suicidal seniors. Two criteria; that suicide ideation is modulated by the proposed intervention and that modulation of suicide ideation leads to a quantitative reduction in…

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.

EXPOSURE DOMAINS: ROLE OF TIMING, PATTERN AND MAGNITUDE OF EXPOSURE ON HEALTH RISKS

EPA Science Inventory

Environmental health risk assessment may be broadly separated into assessment of risks from exposures to agents affecting health endpoints for which it may be presumed there is no dose threshold, and to agents affecting endpoints that more likely have a dose threshold. For hea...

Development and Validation of a High-Quality Composite Real-World Mortality Endpoint.

PubMed

Curtis, Melissa D; Griffith, Sandra D; Tucker, Melisa; Taylor, Michael D; Capra, William B; Carrigan, Gillis; Holzman, Ben; Torres, Aracelis Z; You, Paul; Arnieri, Brandon; Abernethy, Amy P

2018-05-14

To create a high-quality electronic health record (EHR)-derived mortality dataset for retrospective and prospective real-world evidence generation. Oncology EHR data, supplemented with external commercial and US Social Security Death Index data, benchmarked to the National Death Index (NDI). We developed a recent, linkable, high-quality mortality variable amalgamated from multiple data sources to supplement EHR data, benchmarked against the highest completeness U.S. mortality data, the NDI. Data quality of the mortality variable version 2.0 is reported here. For advanced non-small-cell lung cancer, sensitivity of mortality information improved from 66 percent in EHR structured data to 91 percent in the composite dataset, with high date agreement compared to the NDI. For advanced melanoma, metastatic colorectal cancer, and metastatic breast cancer, sensitivity of the final variable was 85 to 88 percent. Kaplan-Meier survival analyses showed that improving mortality data completeness minimized overestimation of survival relative to NDI-based estimates. For EHR-derived data to yield reliable real-world evidence, it needs to be of known and sufficiently high quality. Considering the impact of mortality data completeness on survival endpoints, we highlight the importance of data quality assessment and advocate benchmarking to the NDI. © 2018 The Authors. Health Services Research published by Wiley Periodicals, Inc. on behalf of Health Research and Educational Trust.

Directional constraint of endpoint force emerges from hindlimb anatomy.

PubMed

Bunderson, Nathan E; McKay, J Lucas; Ting, Lena H; Burkholder, Thomas J

2010-06-15

Postural control requires the coordination of force production at the limb endpoints to apply an appropriate force to the body. Subjected to horizontal plane perturbations, quadruped limbs stereotypically produce force constrained along a line that passes near the center of mass. This phenomenon, referred to as the force constraint strategy, may reflect mechanical constraints on the limb or body, a specific neural control strategy or an interaction among neural controls and mechanical constraints. We used a neuromuscular model of the cat hindlimb to test the hypothesis that the anatomical constraints restrict the mechanical action of individual muscles during stance and constrain the response to perturbations to a line independent of perturbation direction. In a linearized neuromuscular model of the cat hindlimb, muscle lengthening directions were highly conserved across 10,000 different muscle activation patterns, each of which produced an identical, stance-like endpoint force. These lengthening directions were closely aligned with the sagittal plane and reveal an anatomical structure for directionally constrained force responses. Each of the 10,000 activation patterns was predicted to produce stable stance based on Lyapunov stability analysis. In forward simulations of the nonlinear, seven degree of freedom model under the action of 200 random muscle activation patterns, displacement of the endpoint from its equilibrium position produced restoring forces, which were also biased toward the sagittal plane. The single exception was an activation pattern based on minimum muscle stress optimization, which produced destabilizing force responses in some perturbation directions. The sagittal force constraint increased during simulations as the system shifted from an inertial response during the acceleration phase to a viscoelastic response as peak velocity was obtained. These results qualitatively match similar experimental observations and suggest that the force

Directional constraint of endpoint force emerges from hindlimb anatomy

PubMed Central

Bunderson, Nathan E.; McKay, J. Lucas; Ting, Lena H.; Burkholder, Thomas J.

2010-01-01

Postural control requires the coordination of force production at the limb endpoints to apply an appropriate force to the body. Subjected to horizontal plane perturbations, quadruped limbs stereotypically produce force constrained along a line that passes near the center of mass. This phenomenon, referred to as the force constraint strategy, may reflect mechanical constraints on the limb or body, a specific neural control strategy or an interaction among neural controls and mechanical constraints. We used a neuromuscular model of the cat hindlimb to test the hypothesis that the anatomical constraints restrict the mechanical action of individual muscles during stance and constrain the response to perturbations to a line independent of perturbation direction. In a linearized neuromuscular model of the cat hindlimb, muscle lengthening directions were highly conserved across 10,000 different muscle activation patterns, each of which produced an identical, stance-like endpoint force. These lengthening directions were closely aligned with the sagittal plane and reveal an anatomical structure for directionally constrained force responses. Each of the 10,000 activation patterns was predicted to produce stable stance based on Lyapunov stability analysis. In forward simulations of the nonlinear, seven degree of freedom model under the action of 200 random muscle activation patterns, displacement of the endpoint from its equilibrium position produced restoring forces, which were also biased toward the sagittal plane. The single exception was an activation pattern based on minimum muscle stress optimization, which produced destabilizing force responses in some perturbation directions. The sagittal force constraint increased during simulations as the system shifted from an inertial response during the acceleration phase to a viscoelastic response as peak velocity was obtained. These results qualitatively match similar experimental observations and suggest that the force

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

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

Ideal discrimination of discrete clinical endpoints using multilocus genotypes.

PubMed

Hahn, Lance W; Moore, Jason H

2004-01-01

Multifactor Dimensionality Reduction (MDR) is a method for the classification and prediction of discrete clinical endpoints using attributes constructed from multilocus genotype data. Empirical studies with both real and simulated data suggest that MDR has good power for detecting gene-gene interactions in the absence of independent main effects. The purpose of this study is to develop an objective, theory-driven approach to evaluate the strengths and limitations of MDR. To accomplish this goal, we borrow concepts from ideal observer analysis used in visual perception to evaluate the theoretical limits of classifying and predicting discrete clinical endpoints using multilocus genotype data. We conclude that MDR ideally discriminates between low risk and high risk subjects using attributes constructed from multilocus genotype data. We also how that the classification approach used once a multilocus attribute is constructed is similar to that of a naive Bayes classifier. This study provides a theoretical foundation for the continued development, evaluation, and application of the MDR as a data mining tool in the domain of statistical genetics and genetic epidemiology.

Time-dependent efficacy of longitudinal biomarker for clinical endpoint.

PubMed

Kolamunnage-Dona, Ruwanthi; Williamson, Paula R

2018-06-01

Joint modelling of longitudinal biomarker and event-time processes has gained its popularity in recent years as they yield more accurate and precise estimates. Considering this modelling framework, a new methodology for evaluating the time-dependent efficacy of a longitudinal biomarker for clinical endpoint is proposed in this article. In particular, the proposed model assesses how well longitudinally repeated measurements of a biomarker over various time periods (0,t) distinguish between individuals who developed the disease by time t and individuals who remain disease-free beyond time t. The receiver operating characteristic curve is used to provide the corresponding efficacy summaries at various t based on the association between longitudinal biomarker trajectory and risk of clinical endpoint prior to each time point. The model also allows detecting the time period over which a biomarker should be monitored for its best discriminatory value. The proposed approach is evaluated through simulation and illustrated on the motivating dataset from a prospective observational study of biomarkers to diagnose the onset of sepsis.

Comparison and Evaluation of Laboratory and Field Measured Bioaccumulation Endpoints

EPA Science Inventory

Evaluation of bioaccumulation endpoints on a fugacity basis allows provides a framework to assess the biomagnification potential of a chemical and assess data deficiencies, i.e., uncertainties and lack of data. In addition, it is suggested that additional guidance is needed in o...

Educating Mental Health Clinicians About Sensory Modulation to Enhance Clinical Practice in a Youth Acute Inpatient Mental Health Unit: A Feasibility Study.

PubMed

Blackburn, Julie; McKenna, Brian; Jackson, Brian; Hitch, Danielle; Benitez, Jessica; McLennan, Cathy; Furness, Trentham

2016-07-01

There is an emergence of literature describing effective sensory modulation (SM) interventions to de-escalate violence and aggression among mental health inpatients. However, the evidence is limited to adult settings, with the effect of SM in youth acute settings unknown. Yet, before SM may be used as a de-escalation intervention in youth acute settings, multidisciplinary staff need to be educated about and supported in the clinical application of SM. In the current study, an online SM education package was developed to assist mental health staff understand SM. This was blended with action learning sets (ALS), small group experiential opportunities consisting staff and consumers to learn about SM resources, and the support of SM trained nurses. The aims of the study were to evaluate the effectiveness of this SM education intervention in (a) transferring knowledge of SM to staff, and (b) translating this knowledge into practice in a youth acute inpatient mental health unit. A mixed methods research design with an 11-item pre- and post-education questionnaire was used along with three-month follow-up focus groups. The SM education improved understanding about SM (all 11-items p ≤ 0.004, r ≥ 0.47). Three-months after SM education, four themes evident in the focus group data emerged about the practice and process of SM; (1) translating of learning into practice, (2) SM in practice, (3) perceptions of SM benefits, and (4) limitations of SM. A blended SM education process enhanced clinical practice in the unit, yet participants were mindful of limitations of SM in situations of distress or escalating agitation.

Clinically relevant behavioral endpoints in a recurrent nitroglycerin migraine model in rats.

PubMed

Sufka, Kenneth J; Staszko, Stephanie M; Johnson, Ainslee P; Davis, Morgan E; Davis, Rachel E; Smitherman, Todd A

2016-01-01

This research sought to further validate the rat nitroglycerin (NTG) migraine model by comparing the effects of single versus recurrent NTG episodes on behavioral endpoints that mirror ICHD-3 diagnostic criteria for migraine, and to determine if the altered behavioral endpoints are reduced after administration of sumatriptan. Separate cohorts of rats were administered NTG (10 mg/kg/2 ml) or saline (Experiment 1: single injection; Experiment 2: repeated injections; Experiment 3: repeated injections with sumatriptan [0.0, 0.3 and 1.0 mg/kg/ml] rescue. Behavioral endpoints were assessed 2 h after final NTG administration and included time in light/dark chambers for photophobia and activity, pain facial ratings, and cool (5 °C) and warm (46 °C) tail dip. The first two experiments demonstrated that repeated (n = 5) but not single NTG injections produced photophobia, decreased activity, and yielded less weight gain than saline injections. Experiment 3 showed that sumatriptan attenuated hypoactivity, reduced facial expressions of pain, and reversed weight alterations in a dose-dependent manner. These findings identify numerous clinical homologies of a recurrent NTG rat migraine model that may be useful for screening novel pharmacotherapies.

Facilitators and barriers to doing workplace mental health research: Case study of acute psychological trauma in a public transit system.

PubMed

Links, Paul S; Bender, Ash; Eynan, Rahel; O'Grady, John; Shah, Ravi

2016-03-10

The Acute Psychological Trauma (APT) Study was a collaboration between an acute care hospital, a specialized multidisciplinary program designed to meet the mental health needs of injured workers, and a large urban public transit system. The overall purpose was to evaluate a Best Practices Intervention (BPI) for employees affected by acute psychological trauma compared to a Treatment as Usual (TAU) group. The specific purpose is to discuss facilitators and barriers that were recognized in implementing and carrying out mental health research in a workplace setting. Over the course of the APT study, a joint implementation committee was responsible for day-to-day study operations and made regular observations on the facilitators and barriers that arose throughout the study. The facilitators to this study included the longstanding relationships among the partners, increased recognition for the need of mental health research in the workplace, and the existence of a community advisory committee. The significant barriers to doing this study of mental health research in the workplace included differences in organizational culture, inconsistent union support, co-interventions, and stigma. Researchers and funding agencies need to be flexible and provide additional resources in order to overcome the barriers that can exist doing workplace mental health research.

Sustaining a culture of practice development in an acute adolescent inpatient mental health unit.

PubMed

Vella, Natalie; Page, Laura; Edwards, Clair; Wand, Timothy

2014-08-01

It is recognized that facilitating change in workplace culture is a significant challenge in healthcare service delivery. Practice development strategies and principles provide a framework for initiating and sustaining programs focused on enhancing patient-centered care by concentrating on the therapeutic attributes of nursing. However, little literature exists on explicating "what worked" in practice development programs. This paper details the processes, people, resources, and relationships that enabled the successful implementation, and led to the sustainability, of a practice development program employed in an acute adolescent mental health unit in Sydney, Australia. Following an external review of the unit, a meeting of key stakeholders was convened and subsequently an advisory panel formed to address specific issues facing nursing staff. This process resulted in the development of an educational package and adoption of the tidal model as the framework for mental health nursing practice in the unit. Clinical reasoning sessions and journal article presentations were incorporated to consolidate and maintain the change in nursing care. A planned, structured, and inclusive practice development program has transformed the nursing culture and vastly improved the care provided to adolescents presenting in acute states of distress to this mental health unit. © 2014 Wiley Periodicals, Inc.

Review of the health effects of wildland fire smoke on wildland firefighters and the public.

PubMed

Adetona, Olorunfemi; Reinhardt, Timothy E; Domitrovich, Joe; Broyles, George; Adetona, Anna M; Kleinman, Michael T; Ottmar, Roger D; Naeher, Luke P

2016-01-01

Each year, the general public and wildland firefighters in the US are exposed to smoke from wildland fires. As part of an effort to characterize health risks of breathing this smoke, a review of the literature was conducted using five major databases, including PubMed and MEDLINE Web of Knowledge, to identify smoke components that present the highest hazard potential, the mechanisms of toxicity, review epidemiological studies for health effects and identify the current gap in knowledge on the health impacts of wildland fire smoke exposure. Respiratory events measured in time series studies as incidences of disease-caused mortality, hospital admissions, emergency room visits and symptoms in asthma and chronic obstructive pulmonary disease patients are the health effects that are most commonly associated with community level exposure to wildland fire smoke. A few recent studies have also determined associations between acute wildland fire smoke exposure and cardiovascular health end-points. These cardiopulmonary effects were mostly observed in association with ambient air concentrations of fine particulate matter (PM2.5). However, research on the health effects of this mixture is currently limited. The health effects of acute exposures beyond susceptible populations and the effects of chronic exposures experienced by the wildland firefighter are largely unknown. Longitudinal studies of wildland firefighters during and/or after the firefighting career could help elucidate some of the unknown health impacts of cumulative exposure to wildland fire smoke, establish occupational exposure limits and help determine the types of exposure controls that may be applicable to the occupation.

[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.

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

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

A recovery room-based acute pain service.

PubMed

Leykin, Y; Pellis, T; Ambrosio, C; Zanette, G; Malisano, A; Rapotec, A; Casati, A

2007-04-01

Despite routine postoperative pain management improves recovery and reduces postoperative morbidity and overall costs, and the availability of a large armamentarium of analgesic techniques and drugs, a significant portion of patients do not receive adequate postoperative pain control. We describe a recovery room (RR) based acute pain service model. Guidelines on postoperative pain and therapeutic protocols were instituted in January 1999. The analgesic endpoint was a visual analogic scale (VAS) below 4 for all surgical patients for the first 48-72 h. The RR, run by one anesthesiologist and 2 nurses and one assistant, acted as a coordination centre. Discharge from the RR was subject to achieving effective analgesia. Nurses of each ward monitored VAS along with vital signs, administered rescue doses if necessary, and reported to the RR nurse when needed. RR nurses monitored the patient at least twice daily and reported to the anesthesiologist. We have distributed an anonymous questionnaire, within surgical wards, to both surgeons and nurses to evaluate their perception of pain management and of this acute pain service (APS) model. VAS was maintained significantly <4. Analgesic drug consumption increased between 1997, 2000 (first year of APS) and 2004. The auditing process confirmed the desire of all professional figures to be informed and involved in acute pain management as part of a coordinated and systematic approach to the surgical patient. A RR-based APS can effectively act as coordinating centre for acute pain treatment without adjunctive personnel.

A multicenter randomized clinical trial investigating the cost-effectiveness of treatment strategies with or without antibiotics for uncomplicated acute diverticulitis (DIABOLO trial).

PubMed

Unlü, Cağdaş; de Korte, Niels; Daniels, Lidewine; Consten, Esther C J; Cuesta, Miguel A; Gerhards, Michael F; van Geloven, Anna A W; van der Zaag, Edwin S; van der Hoeven, Joost A B; Klicks, Rutger; Cense, Huib A; Roumen, Rudi M H; Eijsbouts, Quirijn A J; Lange, Johan F; Fockens, Paul; de Borgie, Corianne A J M; Bemelman, Wilem A; Reitsma, Johannes B; Stockmann, Hein B A C; Vrouenraets, Bart C; Boermeester, Marja A

2010-07-20

Conservative treatment of uncomplicated or mild diverticulitis usually includes antibiotic therapy. It is, however, uncertain whether patients with acute diverticulitis indeed benefit from antibiotics. In most guidelines issued by professional organizations antibiotics are considered mandatory in the treatment of mild diverticulitis. This advice lacks evidence and is merely based on experts' opinion. Adverse effects of the use of antibiotics are well known, including allergic reactions, development of bacterial resistance to antibiotics and other side-effects. A randomized multicenter pragmatic clinical trial comparing two treatment strategies for uncomplicated acute diverticulitis. I) A conservative strategy with antibiotics: hospital admission, supportive measures and at least 48 hours of intravenous antibiotics which subsequently are switched to oral, if tolerated (for a total duration of antibiotic treatment of 10 days). II) A liberal strategy without antibiotics: admission only if needed on clinical grounds, supportive measures only. Patients are eligible for inclusion if they have a diagnosis of acute uncomplicated diverticulitis as demonstrated by radiological imaging. Only patients with stages 1a and 1b according to Hinchey's classification or "mild" diverticulitis according to the Ambrosetti criteria are included. The primary endpoint is time-to-full recovery within a 6-month follow-up period. Full recovery is defined as being discharged from the hospital, with a return to pre-illness activities, and VAS score below 4 without the use of daily pain medication. Secondary endpoints are proportion of patients who develop complicated diverticulitis requiring surgery or non-surgical intervention, morbidity, costs, health-related quality of life, readmission rate and acute diverticulitis recurrence rate. In a non-inferiority design 264 patients are needed in each study arm to detect a difference in time-to-full recovery of 5 days or more with a power of 85% and a

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.

Patient dissatisfaction with acute stroke care.

PubMed

Asplund, Kjell; Jonsson, Fredrik; Eriksson, Marie; Stegmayr, Birgitta; Appelros, Peter; Norrving, Bo; Terént, Andreas; Asberg, Kerstin Hulter

2009-12-01

Riks-Stroke, the Swedish Stroke Register, was used to explore patient characteristics and stroke services as determinants of patient dissatisfaction with acute in-hospital care. All 79 hospitals in Sweden admitting acute stroke patients participate in Riks-Stroke. During 2001 to 2007, 104,876 patients (87% of survivors) responded to a follow-up questionnaire 3 months after acute stroke; this included questions on satisfaction with various aspects of stroke care. The majority (>90%) were satisfied with acute in-hospital stroke care. Dissatisfaction was closely associated with outcome at 3 months. Patient who were dependent regarding activities of daily living, felt depressed, or had poor self-perceived general health were more likely to be dissatisfied. Dissatisfaction with global acute stroke care was linked to dissatisfaction with other aspects of care, including rehabilitation and support by community services. Patients treated in stroke units were less often dissatisfied than patients in general wards, as were patients who had been treated in a small hospital (vs medium or large hospitals) and patient who had participated in discharge planning. In multivariate analyses, the strongest predictor of dissatisfaction with acute care was poor outcome (dependency regarding activities of daily living, depressed mood, poor self-perceived health). Dissatisfaction with in-hospital acute stroke care is part of a more extensive complex comprising poor functional outcome, depressive mood, poor self-perceived general health, and dissatisfaction not only with acute care but also with health care and social services at large. Several aspects of stroke care organization are associated with a lower risk of dissatisfaction.

Positive psychological states and health behaviors in acute coronary syndrome patients: A qualitative study.

PubMed

Huffman, Jeff C; DuBois, Christina M; Mastromauro, Carol A; Moore, Shannon V; Suarez, Laura; Park, Elyse R

2016-06-01

Positive psychological states are linked to superior cardiac outcomes, possibly mediated through increased participation in health behaviors. Trained study staff conducted in-depth semi-structured interviews in the hospital and 3 months later for 34 patients diagnosed with an acute coronary syndrome. These interviews focused on positive psychological states, cardiac health behaviors, and their connection; the interviews were transcribed and independently coded using directed content analysis. Both optimism and positive affect were associated with completion of physical activity and healthy eating in a bidirectional manner. In contrast, gratitude, while common, was infrequently linked to completion of health behaviors. © The Author(s) 2014.

Health insurance system and payments provided to patients for the management of severe acute pancreatitis in Japan.

PubMed

Yoshida, Masahiro; Takada, Tadahiro; Kawarada, Yoshifumi; Hirata, Koichi; Mayumi, Toshihiko; Sekimoto, Miho; Hirota, Masahiko; Kimura, Yasutoshi; Takeda, Kazunori; Isaji, Shuji; Koizumi, Masaru; Otsuki, Makoto; Matsuno, Seiki

2006-01-01

The health insurance system in Japan is based upon the Universal Medical Care Insurance System, which gives all citizens the right to join an insurance scheme of their own choice, as guaranteed by the provisions of Article 25 of the Constitution of Japan, which states: "All people shall have the right to maintain the minimum standards of wholesome and cultured living." The health care system in Japan includes national medical insurance, nursing care for the elderly, and government payments for the treatment of intractable diseases. Medical insurance provisions are handled by Employee's Health Insurance (Social Insurance), which mainly covers employees of private companies and their families, and by National Health Insurance, which provides for the needs of self-employed people. Both schemes have their own medical care service programs for retired persons and their families. The health care system for the elderly covers people 75 years of age and over and bedridden people 65 years of age and over. There is also a system under which the government pays all or part of medical expenses, and/or pays medical expenses not covered by insurance. This is referred to collectively as the "medical expenses payment system" and includes the provision of medical assistance for specified intractable diseases. Because severe acute pancreatitis has a high mortality rate, it is specified as an intractable disease. In order to lower the mortality rate of various diseases, including severe acute pancreatitis, the specification system has been adopted by the government. The cost of treatment for severe acute pancreatitis is paid in full by the government from the date the application is made for a certificate verifying that the patient has an intractable disease.

Pharmacogenetic meta-analysis of baseline risk factors, pharmacodynamic, efficacy and tolerability endpoints from two large global cardiovascular outcomes trials for darapladib.

PubMed

Yeo, Astrid; Li, Li; Warren, Liling; Aponte, Jennifer; Fraser, Dana; King, Karen; Johansson, Kelley; Barnes, Allison; MacPhee, Colin; Davies, Richard; Chissoe, Stephanie; Tarka, Elizabeth; O'Donoghue, Michelle L; White, Harvey D; Wallentin, Lars; Waterworth, Dawn

2017-01-01

Darapladib, a lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor, failed to demonstrate efficacy for the primary endpoints in two large phase III cardiovascular outcomes trials, one in stable coronary heart disease patients (STABILITY) and one in acute coronary syndrome (SOLID-TIMI 52). No major safety signals were observed but tolerability issues of diarrhea and odor were common (up to 13%). We hypothesized that genetic variants associated with Lp-PLA2 activity may influence efficacy and tolerability and therefore performed a comprehensive pharmacogenetic analysis of both trials. We genotyped patients within the STABILITY and SOLID-TIMI 52 trials who provided a DNA sample and consent (n = 13,577 and 10,404 respectively, representing 86% and 82% of the trial participants) using genome-wide arrays with exome content and performed imputation using a 1000 Genomes reference panel. We investigated baseline and change from baseline in Lp-PLA2 activity, two efficacy endpoints (major coronary events and myocardial infarction) as well as tolerability parameters at genome-wide and candidate gene level using a meta-analytic approach. We replicated associations of published loci on baseline Lp-PLA2 activity (APOE, CELSR2, LPA, PLA2G7, LDLR and SCARB1) and identified three novel loci (TOMM5, FRMD5 and LPL) using the GWAS-significance threshold P≤5E-08. Review of the PLA2G7 gene (encoding Lp-PLA2) within these datasets identified V279F null allele carriers as well as three other rare exonic null alleles within various ethnic groups, however none of these variants nor any other loci associated with Lp-PLA2 activity at baseline were associated with any of the drug response endpoints. The analysis of darapladib efficacy endpoints, despite low power, identified six low frequency loci with main genotype effect (though with borderline imputation scores) and one common locus (minor allele frequency 0.24) with genotype by treatment interaction effect passing the GWAS

EPHECT III: Health risk assessment of exposure to household consumer products.

PubMed

Trantallidi, M; Dimitroulopoulou, C; Wolkoff, P; Kephalopoulos, S; Carrer, P

2015-12-01

In the framework of the EU EPHECT project (Emissions, Exposure Patterns and Health Effects of Consumer Products in the EU), irritative and respiratory effects were assessed in relation to acute (30-min) and long-term (24-h) inhalation exposure to key and emerging indoor air pollutants emitted during household use of selected consumer products. A detailed Health Risk Assessment (HRA) was performed for five selected pollutants of respiratory health relevance, namely acrolein, formaldehyde, naphthalene, d-limonene and α-pinene. For each pollutant, the Critical Exposure Limit (CEL) was compared to indoor air concentrations and exposure estimates for the use of 15 selected consumer products by two population groups (housekeepers and retired people) in the four geographical regions of Europe (North, West, South, East), which were derived previously based on microenvironmental modelling. For the present HRA, health-based CELs were derived for certain compounds in case indoor air quality guidelines were not available by the World Health Organization for end-points relevant to the current study. For each pollutant, the highest indoor air concentrations in each microenvironment and exposure estimates across home microenvironments during the day were lower than the corresponding acute and long-term CELs. However, considerable contributions, especially to acute exposures, were obtained in some cases, such as formaldehyde emissions resulting from single product use of a floor cleaning agent (82% CEL), a candle (10% CEL) and an electric air freshener (17% CEL). Regarding multiple product use, the case of 30-min formaldehyde exposure reaching 34% CEL when eight product classes were used across home microenvironments, i.e. all-purpose/kitchen/floor cleaning agents, furniture/floor polish, combustible/electric air fresheners, and perfume, needs to be highlighted. Such estimated values should be evaluated with caution, as these may be attributed to the exposure scenarios

Relative Biological Effectiveness of HZE Particles for Chromosomal Exchanges and Other Surrogate Cancer Risk Endpoints.

PubMed

Cacao, Eliedonna; Hada, Megumi; Saganti, Premkumar B; George, Kerry A; Cucinotta, Francis A

2016-01-01

The biological effects of high charge and energy (HZE) particle exposures are of interest in space radiation protection of astronauts and cosmonauts, and estimating secondary cancer risks for patients undergoing Hadron therapy for primary cancers. The large number of particles types and energies that makeup primary or secondary radiation in HZE particle exposures precludes tumor induction studies in animal models for all but a few particle types and energies, thus leading to the use of surrogate endpoints to investigate the details of the radiation quality dependence of relative biological effectiveness (RBE) factors. In this report we make detailed RBE predictions of the charge number and energy dependence of RBE's using a parametric track structure model to represent experimental results for the low dose response for chromosomal exchanges in normal human lymphocyte and fibroblast cells with comparison to published data for neoplastic transformation and gene mutation. RBE's are evaluated against acute doses of γ-rays for doses near 1 Gy. Models that assume linear or non-targeted effects at low dose are considered. Modest values of RBE (<10) are found for simple exchanges using a linear dose response model, however in the non-targeted effects model for fibroblast cells large RBE values (>10) are predicted at low doses <0.1 Gy. The radiation quality dependence of RBE's against the effects of acute doses γ-rays found for neoplastic transformation and gene mutation studies are similar to those found for simple exchanges if a linear response is assumed at low HZE particle doses. Comparisons of the resulting model parameters to those used in the NASA radiation quality factor function are discussed.

Relative Biological Effectiveness of HZE Particles for Chromosomal Exchanges and Other Surrogate Cancer Risk Endpoints

DOE PAGES

Cacao, Eliedonna; Hada, Megumi; Saganti, Premkumar B.; ...

2016-04-25

The biological effects of high charge and energy (HZE) particle exposures are of interest in space radiation protection of astronauts and cosmonauts, and estimating secondary cancer risks for patients undergoing Hadron therapy for primary cancers. The large number of particles types and energies that makeup primary or secondary radiation in HZE particle exposures precludes tumor induction studies in animal models for all but a few particle types and energies, thus leading to the use of surrogate endpoints to investigate the details of the radiation quality dependence of relative biological effectiveness (RBE) factors. In this report we make detailed RBE predictionsmore » of the charge number and energy dependence of RBE’s using a parametric track structure model to represent experimental results for the low dose response for chromosomal exchanges in normal human lymphocyte and fibroblast cells with comparison to published data for neoplastic transformation and gene mutation. RBE’s are evaluated against acute doses of γ-rays for doses near 1 Gy. Models that assume linear or non-targeted effects at low dose are considered. Modest values of RBE (<10) are found for simple exchanges using a linear dose response model, however in the non-targeted effects model for fibroblast cells large RBE values (>10) are predicted at low doses <0.1 Gy. The radiation quality dependence of RBE’s against the effects of acute doses γ-rays found for neoplastic transformation and gene mutation studies are similar to those found for simple exchanges if a linear response is assumed at low HZE particle doses. Finally, we discuss comparisons of the resulting model parameters to those used in the NASA radiation quality factor function.« less

Relative Biological Effectiveness of HZE Particles for Chromosomal Exchanges and Other Surrogate Cancer Risk Endpoints

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

Cacao, Eliedonna; Hada, Megumi; Saganti, Premkumar B.

The biological effects of high charge and energy (HZE) particle exposures are of interest in space radiation protection of astronauts and cosmonauts, and estimating secondary cancer risks for patients undergoing Hadron therapy for primary cancers. The large number of particles types and energies that makeup primary or secondary radiation in HZE particle exposures precludes tumor induction studies in animal models for all but a few particle types and energies, thus leading to the use of surrogate endpoints to investigate the details of the radiation quality dependence of relative biological effectiveness (RBE) factors. In this report we make detailed RBE predictionsmore » of the charge number and energy dependence of RBE’s using a parametric track structure model to represent experimental results for the low dose response for chromosomal exchanges in normal human lymphocyte and fibroblast cells with comparison to published data for neoplastic transformation and gene mutation. RBE’s are evaluated against acute doses of γ-rays for doses near 1 Gy. Models that assume linear or non-targeted effects at low dose are considered. Modest values of RBE (<10) are found for simple exchanges using a linear dose response model, however in the non-targeted effects model for fibroblast cells large RBE values (>10) are predicted at low doses <0.1 Gy. The radiation quality dependence of RBE’s against the effects of acute doses γ-rays found for neoplastic transformation and gene mutation studies are similar to those found for simple exchanges if a linear response is assumed at low HZE particle doses. Finally, we discuss comparisons of the resulting model parameters to those used in the NASA radiation quality factor function.« less

Exploring the Relationships between the Electronic Health Record System Components and Patient Outcomes in an Acute Hospital Setting

ERIC Educational Resources Information Center

Wiggley, Shirley L.

2011-01-01

Purpose: The purpose of this study was to examine the relationship between the electronic health record system components and patient outcomes in an acute hospital setting, given that the current presidential administration has earmarked nearly $50 billion to the implementation of the electronic health record. The relationship between the…

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.

Economic evaluation of exercise-based cardiac rehabilitation in patients with a recent acute coronary syndrome.

PubMed

Hautala, A J; Kiviniemi, A M; Mäkikallio, T; Koistinen, P; Ryynänen, O-P; Martikainen, J A; Seppänen, T; Huikuri, H V; Tulppo, M P

2017-11-01

Health care decision-making requires evidence of the cost-effectiveness of medical therapies. We evaluated the cost-effectiveness of exercise-based cardiac rehabilitation (ECR) implemented according to guidelines. All the patients (n = 204) had experienced a recent acute coronary syndrome and were randomized to a 1-year ECR (n = 109) or usual care (UC) group (n = 95). The patients' health-related quality of life was followed using the 15D instrument and health care costs were collected from electronic health registries. The cost-effectiveness of ECR was estimated based on intervention and health care costs and quality-adjusted life years (QALYs) gained. The total average cost per patient was lower in ECR than in UC. The incremental cost was divided by the baseline-adjusted incremental QALYs (0.045), yielding an incremental cost-effectiveness ratio of -€24511/QALYs. A combined endpoint of mortality, recurrent coronary event, or hospitalization for a heart failure occurred for five patients in ECR and 16 patients in UC (HR 3.9, 95% CI 1.4-10.6, P = 0.004, relative risk reduction 73%, number needed to treat eight). ECR is a dominant treatment option and decreases the occurrence of adverse cardiac events. These results are useful for decision-making when planning optimal utilization of resources in Finnish health care. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Imputation of a true endpoint from a surrogate: application to a cluster randomized controlled trial with partial information on the true endpoint.

PubMed

Nixon, Richard M; Duffy, Stephen W; Fender, Guy R K

2003-09-24

The Anglia Menorrhagia Education Study (AMES) is a randomized controlled trial testing the effectiveness of an education package applied to general practices. Binary data are available from two sources; general practitioner reported referrals to hospital, and referrals to hospital determined by independent audit of the general practices. The former may be regarded as a surrogate for the latter, which is regarded as the true endpoint. Data are only available for the true end point on a sub set of the practices, but there are surrogate data for almost all of the audited practices and for most of the remaining practices. The aim of this paper was to estimate the treatment effect using data from every practice in the study. Where the true endpoint was not available, it was estimated by three approaches, a regression method, multiple imputation and a full likelihood model. Including the surrogate data in the analysis yielded an estimate of the treatment effect which was more precise than an estimate gained from using the true end point data alone. The full likelihood method provides a new imputation tool at the disposal of trials with surrogate data.

Acute and Subchronic Toxicity of Inhaled Toluene in Male ...

EPA Pesticide Factsheets

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 and one subchronic, were conducted to seek effects of the VOC, toluene, in rats and to compare the effects between acute and subchronic exposures. Adult male Long-Evans rats were exposed to toluene vapor (n = 6 per group) at a concentration of 0 or l 019 ± 14 ppm for 6 h in the acute study and at 0 ± 0, 10 ± 1.4, 97 ± 7, or 995 ± 43 ppm for 6 h/d, 5 d/week for 13 weeksin the subchronic study. For the acute study, brains were dissected on ice within 30 min of the end of exposure, while for the subchronic study, brains were dissected 18 h after the last exposure. Frontal cortex, hippocampus, cerebellum, and striatum were assayed for a variety of oxidative stress (OS) parameters including total aconitase (TA), protein carbonyls, glutathione peroxidase (GPX), glutathione reductase (GRD), glutathione transferase (GST), y-­glutamylcysteine synthetase (GCS), superoxide dismutase (SOD), total antioxidants (TAS), NADPH quinone oxidoreductase- 1 (NQO1 ), and NADH ubiquinone reductase (UBIQ-RD) activities using commercially available kits. Following acute exposure, UBIQ-RD, GCS and GRD were increased significantly only in the cerebellum, while TAS was increased in frontal cortex. On the other

Multisite Comparison of Anti-Human Immunodeficiency Virus Microbicide Activity in Explant Assays Using a Novel Endpoint Analysis ▿ †

PubMed Central

Richardson-Harman, Nicola; Lackman-Smith, Carol; Fletcher, Patricia S.; Anton, Peter A.; Bremer, James W.; Dezzutti, Charlene S.; Elliott, Julie; Grivel, Jean-Charles; Guenthner, Patricia; Gupta, Phalguni; Jones, Maureen; Lurain, Nell S.; Margolis, Leonid B.; Mohan, Swarna; Ratner, Deena; Reichelderfer, Patricia; Roberts, Paula; Shattock, Robin J.; Cummins, James E.

2009-01-01

Microbicide candidates with promising in vitro activity are often advanced for evaluations using human primary tissue explants relevant to the in vivo mucosal transmission of human immunodeficiency virus type 1 (HIV-1), such as tonsil, cervical, or rectal tissue. To compare virus growth or the anti-HIV-1 efficacies of candidate microbicides in tissue explants, a novel soft-endpoint method was evaluated to provide a single, objective measurement of virus growth. The applicability of the soft endpoint is shown across several different ex vivo tissue types, with the method performed in different laboratories, and for a candidate microbicide (PRO 2000). The soft-endpoint method was compared to several other endpoint methods, including (i) the growth of virus on specific days after infection, (ii) the area under the virus growth curve, and (iii) the slope of the virus growth curve. Virus growth at the assay soft endpoint was compared between laboratories, methods, and experimental conditions, using nonparametric statistical analyses. Intra-assay variability determinations using the coefficient of variation demonstrated higher variability for virus growth in rectal explants. Significant virus inhibition by PRO 2000 and significant differences in the growth of certain primary HIV-1 isolates were observed by the majority of laboratories. These studies indicate that different laboratories can provide consistent measurements of anti-HIV-1 microbicide efficacy when (i) the soft endpoint or another standardized endpoint is used, (ii) drugs and/or virus reagents are centrally sourced, and (iii) the same explant tissue type and method are used. Application of the soft-endpoint method reduces the inherent variability in comparisons of preclinical assays used for microbicide development. PMID:19726602

Impact of integrated health system changes, accelerated due to an earthquake, on emergency department attendances and acute admissions: a Bayesian change-point analysis.

PubMed

Schluter, Philip J; Hamilton, Greg J; Deely, Joanne M; Ardagh, Michael W

2016-05-11

To chart emergency department (ED) attendance and acute admission following a devastating earthquake in 2011 which lead to Canterbury's rapidly accelerated integrated health system transformations. Interrupted time series analysis, modelling using Bayesian change-point methods, of ED attendance and acute admission rates over the 2008-2014 period. ED department within the Canterbury District Health Board; with comparison to two other district health boards unaffected by the earthquake within New Zealand. Canterbury's health system services ∼500 000 people, with around 85 000 ED attendances and 37 000 acute admissions per annum. De-seasoned standardised population ED attendance and acute admission rates overall, and stratified by age and sex, compared before and after the earthquake. Analyses revealed five global patterns: (1) postearthquake, there was a sudden and persisting decrease in the proportion of the population attending the ED; (2) the growth rate of ED attendances per head of population did not change between the pre-earthquake and postearthquake periods; (3) postearthquake, there was a sudden and persisting decrease in the proportion of the population admitted to hospital; (4) the growth rate of hospital admissions per head of the population declined between pre-earthquake and postearthquake periods and (5) the most dramatic reduction in hospital admissions growth after the earthquake occurred among those aged 65+ years. Extrapolating from the projected and fitted deseasoned rates for December 2014, ∼676 (16.8%) of 4035 projected hospital admissions were avoided. While both necessarily and opportunistically accelerated, Canterbury's integrated health systems transformations have resulted in a dramatic and sustained reduction in ED attendances and acute hospital admissions. This natural intervention experiment, triggered by an earthquake, demonstrated that integrated health systems with high quality out-of-hospital care models are likely to

Exposure to traffic pollution, acute inflammation and autonomic response in a panel of car commuters.

PubMed

Sarnat, Jeremy A; Golan, Rachel; Greenwald, Roby; Raysoni, Amit U; Kewada, Priya; Winquist, Andrea; Sarnat, Stefanie E; Dana Flanders, W; Mirabelli, Maria C; Zora, Jennifer E; Bergin, Michael H; Yip, Fuyuen

2014-08-01

Exposure to traffic pollution has been linked to numerous adverse health endpoints. Despite this, limited data examining traffic exposures during realistic commutes and acute response exists. We conducted the Atlanta Commuters Exposures (ACE-1) Study, an extensive panel-based exposure and health study, to measure chemically-resolved in-vehicle exposures and corresponding changes in acute oxidative stress, lipid peroxidation, pulmonary and systemic inflammation and autonomic response. We recruited 42 adults (21 with and 21 without asthma) to conduct two 2-h scripted highway commutes during morning rush hour in the metropolitan Atlanta area. A suite of in-vehicle particulate components were measured in the subjects' private vehicles. Biomarker measurements were conducted before, during, and immediately after the commutes and in 3 hourly intervals after commutes. At measurement time points within 3h after the commute, we observed mild to pronounced elevations relative to baseline in exhaled nitric oxide, C-reactive-protein, and exhaled malondialdehyde, indicative of pulmonary and systemic inflammation and oxidative stress initiation, as well as decreases relative to baseline levels in the time-domain heart-rate variability parameters, SDNN and rMSSD, indicative of autonomic dysfunction. We did not observe any detectable changes in lung function measurements (FEV1, FVC), the frequency-domain heart-rate variability parameter or other systemic biomarkers of vascular injury. Water soluble organic carbon was associated with changes in eNO at all post-commute time-points (p<0.0001). Our results point to measureable changes in pulmonary and autonomic biomarkers following a scripted 2-h highway commute. Copyright © 2014 Elsevier Inc. All rights reserved.

Exposure to traffic pollution, acute inflammation and autonomic response in a panel of car commuters

PubMed Central

Sarnat, Jeremy A.; Golan, Rachel; Greenwald, Roby; Raysoni, Amit U.; Kewada, Priya; Winquist, Andrea; Sarnat, Stefanie E.; Flanders, W. Dana; Mirabelli, Maria C.; Zora, Jennifer E.; Bergin, Michael H.; Yip, Fuyuen

2015-01-01

Background Exposure to traffic pollution has been linked to numerous adverse health endpoints. Despite this, limited data examining traffic exposures during realistic commutes and acute response exists. Objectives: We conducted the Atlanta Commuters Exposures (ACE-1) Study, an extensive panel-based exposure and health study, to measure chemically-resolved in-vehicle exposures and corresponding changes in acute oxidative stress, lipid peroxidation, pulmonary and systemic inflammation and autonomic response. Methods We recruited 42 adults (21 with and 21 without asthma) to conduct two 2-h scripted highway commutes during morning rush hour in the metropolitan Atlanta area. A suite of in-vehicle particulate components were measured in the subjects’ private vehicles. Biomarker measurements were conducted before, during, and immediately after the commutes and in 3 hourly intervals after commutes. Results At measurement time points within 3 h after the commute, we observed mild to pronounced elevations relative to baseline in exhaled nitric oxide, C-reactive-protein, and exhaled malondialdehyde, indicative of pulmonary and systemic inflammation and oxidative stress initiation, as well as decreases relative to baseline levels in the time-domain heart-rate variability parameters, SDNN and rMSSD, indicative of autonomic dysfunction. We did not observe any detectable changes in lung function measurements (FEV1, FVC), the frequency-domain heart-rate variability parameter or other systemic biomarkers of vascular injury. Water soluble organic carbon was associated with changes in eNO at all post-commute time-points (p < 0.0001). Conclusions Our results point to measureable changes in pulmonary and autonomic biomarkers following a scripted 2-h highway commute. PMID:24906070

Impact of Acute Metal Stress in Saccharomyces cerevisiae

PubMed Central

Lichtenberg-Fraté, Hella; Glaser, Walter; Schüller, Christoph; Klipp, Edda

2014-01-01

Although considered as essential cofactors for a variety of enzymatic reactions and for important structural and functional roles in cell metabolism, metals at high concentrations are potent toxic pollutants and pose complex biochemical problems for cells. We report results of single dose acute toxicity testing in the model organism S. cerevisiae. The effects of moderate toxic concentrations of 10 different human health relevant metals, Ag+, Al3+, As3+, Cd2+, Co2+, Hg2+, Mn2+, Ni2+, V3+, and Zn2+, following short-term exposure were analyzed by transcription profiling to provide the identification of early-on target genes or pathways. In contrast to common acute toxicity tests where defined endpoints are monitored we focused on the entire genomic response. We provide evidence that the induction of central elements of the oxidative stress response by the majority of investigated metals is the basic detoxification process against short-term metal exposure. General detoxification mechanisms also comprised the induction of genes coding for chaperones and those for chelation of metal ions via siderophores and amino acids. Hierarchical clustering, transcription factor analyses, and gene ontology data further revealed activation of genes involved in metal-specific protein catabolism along with repression of growth-related processes such as protein synthesis. Metal ion group specific differences in the expression responses with shared transcriptional regulators for both, up-regulation and repression were also observed. Additionally, some processes unique for individual metals were evident as well. In view of current concerns regarding environmental pollution our results may support ongoing attempts to develop methods to monitor potentially hazardous areas or liquids and to establish standardized tests using suitable eukaryotic a model organism. PMID:24416162

Impact of acute metal stress in Saccharomyces cerevisiae.

PubMed

Hosiner, Dagmar; Gerber, Susanne; Lichtenberg-Fraté, Hella; Glaser, Walter; Schüller, Christoph; Klipp, Edda

2014-01-01

Although considered as essential cofactors for a variety of enzymatic reactions and for important structural and functional roles in cell metabolism, metals at high concentrations are potent toxic pollutants and pose complex biochemical problems for cells. We report results of single dose acute toxicity testing in the model organism S. cerevisiae. The effects of moderate toxic concentrations of 10 different human health relevant metals, Ag(+), Al(3+), As(3+), Cd(2+), Co(2+), Hg(2+), Mn(2+), Ni(2+), V(3+), and Zn(2+), following short-term exposure were analyzed by transcription profiling to provide the identification of early-on target genes or pathways. In contrast to common acute toxicity tests where defined endpoints are monitored we focused on the entire genomic response. We provide evidence that the induction of central elements of the oxidative stress response by the majority of investigated metals is the basic detoxification process against short-term metal exposure. General detoxification mechanisms also comprised the induction of genes coding for chaperones and those for chelation of metal ions via siderophores and amino acids. Hierarchical clustering, transcription factor analyses, and gene ontology data further revealed activation of genes involved in metal-specific protein catabolism along with repression of growth-related processes such as protein synthesis. Metal ion group specific differences in the expression responses with shared transcriptional regulators for both, up-regulation and repression were also observed. Additionally, some processes unique for individual metals were evident as well. In view of current concerns regarding environmental pollution our results may support ongoing attempts to develop methods to monitor potentially hazardous areas or liquids and to establish standardized tests using suitable eukaryotic a model organism.

Role of central obesity in risk stratification after an acute coronary event: does central obesity add prognostic value to the Global Registry of Acute Coronary Events (GRACE) risk score in patients with acute coronary syndrome?

PubMed

Martins, Albino; Ribeiro, Sílvia; Gonçalves, Pierre; Correia, Adelino

2013-10-01

Accurate risk stratification is an important step in the initial management of acute coronary syndrome (ACS), and current guidelines recommend the use of risk scores, such as the Global Registry of Acute Coronary Events risk score (GRACE RS). Recent studies have suggested that abdominal obesity is associated with cardiovascular events in patients with ACS. However, little is known about the additional value of abdominal obesity beyond risk scores. The aim of our study was thus to assess whether waist circumference, a surrogate of abdominal adiposity, adds prognostic information to the GRACE RS. This was a retrospective cohort study of ACS patients admitted consecutively to a cardiac care unit between June 2009 and July 2010. The composite of all-cause mortality or myocardial reinfarction within six months of index hospitalization was used as the endpoint for the analysis. A total of 285 patients were studied, 96.1% admitted for myocardial infarction (with or without ST elevation) and 3.9% for unstable angina. At the end of the follow-up period, 10 patients had died and the composite endpoint had been reached in 27 patients (9.5%). More than 70% of the study population were obese or overweight, and abdominal obesity was present in 44.6%. The GRACE RS showed poor predictive accuracy (area under the curve 0.60), and most of the GRACE variables did not reach statistical significance in multivariate analysis. The addition of waist circumference to the GRACE RS did not improve its discriminatory performance. Abdominal obesity does not add prognostic information to the GRACE RS to predict six-month mortality or myocardial reinfarction.

Challenge of improving postoperative pain management: case studies of three acute pain services in the UK National Health Service.

PubMed

Powell, A E; Davies, H T O; Bannister, J; Macrae, W A

2009-06-01

Previous national survey research has shown significant deficits in routine postoperative pain management in the UK. This study used an organizational change perspective to explore in detail the organizational challenges faced by three acute pain services in improving postoperative pain management. Case studies were conducted comprising documentary review and semi-structured interviews (71) with anaesthetists, surgeons, nurses, other health professionals, and managers working in and around three broadly typical acute pain services. Although the precise details differed to some degree, the three acute pain services all faced the same broad range of inter-related challenges identified in the organizational change literature (i.e. structural, political, cultural, educational, emotional, and physical/technological challenges). The services were largely isolated from wider organizational objectives and activities and struggled to engage other health professionals in improving postoperative pain management against a background of limited resources, turbulent organizational change, and inter- and intra-professional politics. Despite considerable efforts they struggled to address these challenges effectively. The literature on organizational change and quality improvement in health care suggests that it is only by addressing the multiple challenges in a comprehensive way across all levels of the organization and health-care system that sustained improvements in patient care can be secured. This helps to explain why the hard work and commitment of acute pain services over the years have not always resulted in significant improvements in routine postoperative pain management for all surgical patients. Using this literature and adopting a whole-organization quality improvement approach tailored to local circumstances may produce a step-change in the quality of routine postoperative pain management.

Confirming mental health care in acute psychiatric wards, as narrated by persons experiencing psychotic illness: an interview study.

PubMed

Sebergsen, Karina; Norberg, Astrid; Talseth, Anne-Grethe

2016-01-01

It is important that mental health nurses meet the safety, security and care needs of persons suffering from psychotic illness to enhance these persons' likelihood of feeling better during their time in acute psychiatric wards. Certain persons in care describe nurses' mental health care as positive, whereas others report negative experiences and express a desire for improvements. There is limited research on how persons with psychotic illness experience nurses' mental health care acts and how such acts help these persons feel better. Therefore, the aim of this study was to explore, describe and understand how the mental health nurses in acute psychiatric wards provide care that helps persons who experienced psychotic illness to feel better, as narrated by these persons. This study had a qualitative design; 12 persons participated in qualitative interviews. The interviews were transcribed, content analysed and interpreted using Martin Buber's concept of confirmation. The results of this study show three categories of confirming mental health care that describe what helped the participants to feel better step-by-step: first, being confirmed as a person experiencing psychotic illness in need of endurance; second, being confirmed as a person experiencing psychotic illness in need of decreased psychotic symptoms; and third, being confirmed as a person experiencing psychotic illness in need of support in daily life. The underlying meaning of the categories and of subcategories were interpreted and formulated as the theme; confirming mental health care to persons experiencing psychotic illness. Confirming mental health care acts seem to help persons to feel better in a step-wise manner during psychotic illness. Nurses' openness and sensitivity to the changing care needs of persons who suffer from psychotic illness create moments of confirmation within caring acts that concretely help the persons to feel better and that may enhance their health. The results show the

Refractory Graft-Versus-Host Disease-Free, Relapse-Free Survival as an Accurate and Easy-to-Calculate Endpoint to Assess the Long-Term Transplant Success.

PubMed

Kawamura, Koji; Nakasone, Hideki; Kurosawa, Saiko; Yoshimura, Kazuki; Misaki, Yukiko; Gomyo, Ayumi; Hayakawa, Jin; Tamaki, Masaharu; Akahoshi, Yu; Kusuda, Machiko; Kameda, Kazuaki; Wada, Hidenori; Ishihara, Yuko; Sato, Miki; Terasako-Saito, Kiriko; Kikuchi, Misato; Kimura, Shun-Ichi; Tanihara, Aki; Kako, Shinichi; Kanamori, Heiwa; Mori, Takehiko; Takahashi, Satoshi; Taniguchi, Shuichi; Atsuta, Yoshiko; Kanda, Yoshinobu

2018-02-21

The aim of this study was to develop a new composite endpoint that accurately reflects the long-term success of allogeneic hematopoietic stem cell transplantation (allo-HSCT), as the conventional graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) overestimates the impact of GVHD. First, we validated current GRFS (cGRFS), which recently was proposed as a more accurate endpoint of long-term transplant success. cGRFS was defined as survival without disease relapse/progression or active chronic GVHD at a given time after allo-HSCT, calculated using 2 distinct methods: a linear combination of a Kaplan-Meier estimates approach and a multistate modelling approach. Next, we developed a new composite endpoint, refractory GRFS (rGRFS). rGRFS was calculated similarly to conventional GRFS treating grade III to IV acute GVHD, chronic GVHD requiring systemic treatment, and disease relapse/progression as events, except that GVHD that resolved and did not require systemic treatment at the last evaluation was excluded as an event in rGRFS. The 2 cGRFS curves obtained using 2 different approaches were superimposed and both were superior to that of conventional GRFS, reflecting the proportion of patients with resolved chronic GVHD. Finally, the curves of cGRFS and rGRFS overlapped after the first 2 years of post-transplant follow-up. These results suggest that cGRFS and rGRFS more accurately reflect transplant success than conventional GRFS. Especially, rGRFS can be more easily calculated than cGRFS and analyzed with widely used statistical approaches, whereas cGRFS more accurately represents the burden of GVHD-related morbidity in the first 2 years after transplantation. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

M-Health for Improving Screening Accuracy of Acute Malnutrition in a Community-Based Management of Acute Malnutrition Program in Mumbai Informal Settlements.

PubMed

Chanani, Sheila; Wacksman, Jeremy; Deshmukh, Devika; Pantvaidya, Shanti; Fernandez, Armida; Jayaraman, Anuja

2016-12-01

Acute malnutrition is linked to child mortality and morbidity. Community-Based Management of Acute Malnutrition (CMAM) programs can be instrumental in large-scale detection and treatment of undernutrition. The World Health Organization (WHO) 2006 weight-for-height/length tables are diagnostic tools available to screen for acute malnutrition. Frontline workers (FWs) in a CMAM program in Dharavi, Mumbai, were using CommCare, a mobile application, for monitoring and case management of children in combination with the paper-based WHO simplified tables. A strategy was undertaken to digitize the WHO tables into the CommCare application. To measure differences in diagnostic accuracy in community-based screening for acute malnutrition, by FWs, using a mobile-based solution. Twenty-seven FWs initially used the paper-based tables and then switched to an updated mobile application that included a nutritional grade calculator. Human error rates specifically associated with grade classification were calculated by comparison of the grade assigned by the FW to the grade each child should have received based on the same WHO tables. Cohen kappa coefficient, sensitivity and specificity rates were also calculated and compared for paper-based grade assignments and calculator grade assignments. Comparing FWs (N = 14) who completed at least 40 screenings without and 40 with the calculator, the error rates were 5.5% and 0.7%, respectively (p < .0001). Interrater reliability (κ) increased to an almost perfect level (>.90), from .79 to .97, after switching to the mobile calculator. Sensitivity and specificity also improved significantly. The mobile calculator significantly reduces an important component of human error in using the WHO tables to assess acute malnutrition at the community level. © The Author(s) 2016.

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.

Enhancing adult therapeutic interpersonal relationships in the acute health care setting: an integrative review

PubMed Central

Kornhaber, Rachel; Walsh, Kenneth; Duff, Jed; Walker, Kim

2016-01-01

Therapeutic interpersonal relationships are the primary component of all health care interactions that facilitate the development of positive clinician–patient experiences. Therapeutic interpersonal relationships have the capacity to transform and enrich the patients’ experiences. Consequently, with an increasing necessity to focus on patient-centered care, it is imperative for health care professionals to therapeutically engage with patients to improve health-related outcomes. Studies were identified through an electronic search, using the PubMed, Cumulative Index to Nursing and Allied Health Literature, and PsycINFO databases of peer-reviewed research, limited to the English language with search terms developed to reflect therapeutic interpersonal relationships between health care professionals and patients in the acute care setting. This study found that therapeutic listening, responding to patient emotions and unmet needs, and patient centeredness were key characteristics of strategies for improving therapeutic interpersonal relationships. PMID:27789958

Enhancing adult therapeutic interpersonal relationships in the acute health care setting: an integrative review.

PubMed

Kornhaber, Rachel; Walsh, Kenneth; Duff, Jed; Walker, Kim

2016-01-01

Therapeutic interpersonal relationships are the primary component of all health care interactions that facilitate the development of positive clinician-patient experiences. Therapeutic interpersonal relationships have the capacity to transform and enrich the patients' experiences. Consequently, with an increasing necessity to focus on patient-centered care, it is imperative for health care professionals to therapeutically engage with patients to improve health-related outcomes. Studies were identified through an electronic search, using the PubMed, Cumulative Index to Nursing and Allied Health Literature, and PsycINFO databases of peer-reviewed research, limited to the English language with search terms developed to reflect therapeutic interpersonal relationships between health care professionals and patients in the acute care setting. This study found that therapeutic listening, responding to patient emotions and unmet needs, and patient centeredness were key characteristics of strategies for improving therapeutic interpersonal relationships.

Restraint use in acute and extended mental health services for older persons.

PubMed

Gerace, Adam; Mosel, Krista; Oster, Candice; Muir-Cochrane, Eimear

2013-12-01

Restraint of older persons in inpatient and residential care is used to control aggression, and prevent falls and other adverse outcomes. Initiatives to reduce these practices are being implemented worldwide. However, there has been little examination of restraint practice in psychiatric services for older persons. This paper reports a retrospective comparative analysis of restraint use in three acute and two extended care psychiatric inpatient wards in Australia. The analysis involved examination of restraint incidents and comparison of restrained and non-restrained patients. There was significant variation in restraint use between wards. On one acute ward, 12.74% of patients were restrained, although restraint use declined during the data collection period. Patients with dementia were restrained at higher rates than patients with other diagnoses, and restrained patients stayed in hospital for a longer duration. Restraint occurred early in admission, and few differences emerged between those restrained once or multiple times. Mechanical restraint was more prevalent than physical restraint, with restraint predominantly used to manage aggression and falls. Findings provide new data on restraint in older persons' psychiatric services. Greater conceptual understandings of behaviours associated with dementia and the unique needs of patients with these disorders may assist in reducing restraint use in these settings. © 2012 The Authors; International Journal of Mental Health Nursing © 2012 Australian College of Mental Health Nurses Inc.

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.

QSAR modeling of cumulative environmental end-points for the prioritization of hazardous chemicals.

PubMed

Gramatica, Paola; Papa, Ester; Sangion, Alessandro

2018-01-24

The hazard of chemicals in the environment is inherently related to the molecular structure and derives simultaneously from various chemical properties/activities/reactivities. Models based on Quantitative Structure Activity Relationships (QSARs) are useful to screen, rank and prioritize chemicals that may have an adverse impact on humans and the environment. This paper reviews a selection of QSAR models (based on theoretical molecular descriptors) developed for cumulative multivariate endpoints, which were derived by mathematical combination of multiple effects and properties. The cumulative end-points provide an integrated holistic point of view to address environmentally relevant properties of chemicals.

A New Test Unit for Disintegration End-Point Determination of Orodispersible Films.

PubMed

Low, Ariana; Kok, Si Ling; Khong, Yuet Mei; Chan, Sui Yung; Gokhale, Rajeev

2015-11-01

No standard time or pharmacopoeia disintegration test method for orodispersible films (ODFs) exists. The USP disintegration test for tablets and capsules poses significant challenges for end-point determination when used for ODFs. We tested a newly developed disintegration test unit (DTU) against the USP disintegration test. The DTU is an accessory to the USP disintegration apparatus. It holds the ODF in a horizontal position, allowing top-view of the ODF during testing. A Gauge R&R study was conducted to assign relative contributions of the total variability from the operator, sample or the experimental set-up. Precision was compared using commercial ODF products in different media. Agreement between the two measurement methods was analysed. The DTU showed improved repeatability and reproducibility compared to the USP disintegration system with tighter standard deviations regardless of operator or medium. There is good agreement between the two methods, with the USP disintegration test giving generally longer disintegration times possibly due to difficulty in end-point determination. The DTU provided clear end-point determination and is suitable for quality control of ODFs during product developmental stage or manufacturing. This may facilitate the development of a standardized methodology for disintegration time determination of ODFs. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

PREDICTING TOXICOLOGICAL ENDPOINTS OF CHEMICALS USING QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS (QSARS)

EPA Science Inventory

Quantitative structure-activity relationships (QSARs) are being developed to predict the toxicological endpoints for untested chemicals similar in structure to chemicals that have known experimental toxicological data. Based on a very large number of predetermined descriptors, a...

Complexity of bioindicator selection for ecological, human, and cultural health: Chinook salmon and red knot as case studies

PubMed Central

Burger, Joanna; Gochfeld, Michael; Niles, Lawrence; Powers, Charles; Brown, Kevin; Clarke, James; Dey, Amanda; Kosson, David

2015-01-01

There is considerable interest in developing bioindicators of ecological health that are also useful indicators for human health. Yet, human health assessment usually encompasses physical/chemical exposures and not cultural well-being. In this paper, we propose that bioindicators can be selected for all three purposes. We use Chinook or king salmon (Oncorhynchus tshawytscha) and red knot (Calidris canutus rufa, a sandpiper) as examples of indicators that can be used to assess human, ecological, and cultural health. Even so, selecting endpoints or metrics for each indicator species is complex and is explored in this paper. We suggest that there are several endpoint types to examine for a given species, including physical environment, environmental stressors, habitat, life history, demography, population counts, and cultural/societal aspects. Usually cultural endpoints are economic indicators (e.g., number of days fished, number of hunting licenses), rather than the importance of a fishing culture. Development of cultural/societal endpoints must include the perceptions of local communities, cultural groups, and tribal nations, as well as governmental and regulatory communities (although not usually so defined, the latter have cultures as well). Endpoint selection in this category is difficult because the underlying issues need to be identified and used to develop endpoints that tribes and stakeholders themselves see as reasonable surrogates of the qualities they value. We describe several endpoints for salmon and knots that can be used for ecological, human, and cultural/societal health. PMID:25666646

Complexity of bioindicator selection for ecological, human, and cultural health: Chinook salmon and red knot as case studies

DOE PAGES

Burger, Joanna; Gochfeld, Michael; Niles, Lawrence; ...

2015-02-10

There is considerable interest in developing bioindicators of ecological health that are also useful indicators for human health. Yet, human health assessment usually encompasses physical/chemical exposures and not cultural well-being. In this paper, we propose that bioindicators can be selected for all three purposes. We use Chinook or king salmon (Oncorhynchus tshawytscha) and red knot (Calidris canutus rufa, a sandpiper) as examples of indicators that can be used to assess human, ecological, and cultural health. Even so, selecting endpoints or metrics for each indicator species is complex and is explored in this paper. Here, we suggest that there are severalmore » endpoint types to examine for a given species, including physical environment, environmental stressors, habitat, life history, demography, population counts, and cultural/societal aspects. Usually cultural endpoints are economic indicators (e.g., number of days fished, number of hunting licenses), rather than the importance of a fishing culture. Development of cultural/societal endpoints must include the perceptions of local communities, cultural groups, and tribal nations, as well as governmental and regulatory communities (although not usually so defined, the latter have cultures as well). Endpoint selection in this category is difficult because the underlying issues need to be identified and used to develop endpoints that tribes and stakeholders themselves see as reasonable surrogates of the qualities they value. We describe several endpoints for salmon and knots that can be used for ecological, human, and cultural/societal health.« less

Complexity of bioindicator selection for ecological, human, and cultural health: Chinook salmon and red knot as case studies

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

Burger, Joanna; Gochfeld, Michael; Niles, Lawrence

There is considerable interest in developing bioindicators of ecological health that are also useful indicators for human health. Yet, human health assessment usually encompasses physical/chemical exposures and not cultural well-being. In this paper, we propose that bioindicators can be selected for all three purposes. We use Chinook or king salmon (Oncorhynchus tshawytscha) and red knot (Calidris canutus rufa, a sandpiper) as examples of indicators that can be used to assess human, ecological, and cultural health. Even so, selecting endpoints or metrics for each indicator species is complex and is explored in this paper. Here, we suggest that there are severalmore » endpoint types to examine for a given species, including physical environment, environmental stressors, habitat, life history, demography, population counts, and cultural/societal aspects. Usually cultural endpoints are economic indicators (e.g., number of days fished, number of hunting licenses), rather than the importance of a fishing culture. Development of cultural/societal endpoints must include the perceptions of local communities, cultural groups, and tribal nations, as well as governmental and regulatory communities (although not usually so defined, the latter have cultures as well). Endpoint selection in this category is difficult because the underlying issues need to be identified and used to develop endpoints that tribes and stakeholders themselves see as reasonable surrogates of the qualities they value. We describe several endpoints for salmon and knots that can be used for ecological, human, and cultural/societal health.« less

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.

A quality-of-life-oriented endpoint for comparing therapies.

PubMed

Gelber, R D; Gelman, R S; Goldhirsch, A

1989-09-01