bluuebunny/crossref_metadata_2025 huggingface dataset:
Sustainability from a Performance‐Oriented Architecture Perspective – Alternative Approaches to Questions regarding the Sustainability of the Built Environment
Authors: Hensel Michael U.
Published: June 2012

This article introduces and discusses a series of alternative and interrelated concepts and approaches regarding questions of the sustainability of the built environment and architectural design. The need for this discussion arises from the realization that the majority of current approaches to questions of sustainability in architectural design tend to considerably stifle complexity in approach, problem analysis and definition. This development is characterized by isolated and partial aspects of environmental problems, instead of a more holistic systems approach, often present in the approaches of other disciplines or interdisciplinary efforts.

The shortage of alternative approaches in architectural design requires a critical rethinking of the question of sustainability of the built environment and its relation to other domains in and outside the anthroposphere. To address this problem is the goal of this article. In doing so, it introduces and discusses concepts and approaches that are rooted in a systems approach and aims for more complex problem definitions, while taking longer‐term perspectives into consideration. This is done from a performance‐oriented architecture perspective, which operates on the dynamic interactions between local ecosystems (including humans), environment and the spatial–material organization complex of architecture. Copyright © 2012 John Wiley & Sons, Ltd and ERP Environment.
Innovative Foresights in Sustainable Design and Architecture – How to Promote Seemingly Impossible, but Still Crucial, Radical Changes
Authors: Edeholt Håkan
Published: June 2012

Scientific warnings of an escalation of climate disaster become more severe by the day. Seemingly, the magnitude of the alarms increases at a pace that outcompetes the concerns it seems to generate in public policies and discourses. Are we perhaps, as some suggest, in the middle of a huge public denial? Why is this so? What could design and design research possibly do about it?

This paper briefly discusses some characteristic features within the domains of society, science and design (including architecture) and how these three domains interrelate when it comes to the challenge of climate change and global sustainability. The intention is to create a creative analytical field of tensions, with complementary actors. The paper then especially focuses on possible contributions from the domain of design. One of the conclusions is that the challenge is so huge that we need to utilize a variety of professional domains of competence and that all should contribute where their involvement will make most difference. We therefore suggest that perhaps the most important contribution that design can make is to suggest new possible, preferable and radically different alternatives of living. Here the intention is to facilitate creative discourses rather than creating creative solutions that direct solve all the complex problems at hand.

A master course in design, entitled ‘Shaping futures’, where students are required to come up with plausible scenarios that address possible climate changes, is used as an illustrative example. In order to address climate change the course joins the domains of foresight, innovation and design. The course reveals both opportunities for design work, and also areas where design as a discipline needs further development. Copyright © 2012 John Wiley & Sons, Ltd and ERP Environment.
Sustainability Through Design Science: Re‐Imagining Option Spaces Beyond Eco‐Efficiency
Authors: Frye‐Levine Laura Alex
Published: June 2012

Ecological resource efficiency, implemented as a market mechanism within a neoclassical economy, shoulders the burden of providing a worldview for sustainable development: continuous GDP growth to provide for the expansion of human needs, and dematerialization through resource efficiency to accommodate ecological limits.

However, resource efficiency does not equal resource conservation. Empirical evidence confirms that the emergent rebound effects of efficiency gains overpower their first‐order intention, creating counterintuitive feedback effects at larger scales. Backfire, the collective product of individual scale resource efficiencies, is little recognized as a key driver of resource depletion. However, the acknowledgement of rebound effects as emergent properties of eco‐efficiency systems also opens an opportunity space.

This paper introduces the paradigm of design science for sustainable development, a qualitatively different epistemology in which the emergent effects of throughput growth and social rebound are collectively negotiated within a sustainable area budget. Multiple‐alternative scenario building within this budget outlines a process within which emergent properties are negotiated relative to the resilience of social and ecological systems. Design science provides the crucial outlines for the negotiation of a common future inscribed within ecological limits. Copyright © 2012 John Wiley & Sons, Ltd and ERP Environment.
Sustainable Design: A Brief Appraisal of its Main Concepts
Authors: Keitsch Martina
Published: June 2012

Research linking design to sustainability surfaced in the 1970s and has since received broad attention in academic and professional literature. Rachel Carson's book Silent Spring from 1962 and the Gaia hypothesis of James Lovelock and Lynn Margulis from 1974 inspired design, among many other disciplines, to search for an appropriate balance between industrial cultures and natural surroundings. This article tracks a brief idea‐historical account of sustainable design theories. Main concepts in the field are consolidated under three criteria: ethics, technology fixes and social interaction. These criteria are considered as the main motivators for research and theory development in sustainable design. Following the Introduction, which gives an overview of concept development in design in general and sustainable design in particular, the second section explains the methodological onset for the analysis and introduces three concepts that represent important trends in sustainable design theory. The three concepts: Papanek's socially and ecologically responsible design, the Design for the Environment approach, and Manzini's sustainable everyday philosophy, are analysed in the third section according to the role they assign to the criteria. Further, the section reviews the concepts within a wider debate on sustainable development. The article concludes with a proposal as to how conceptualization in sustainable design could proceed, to meet the complexity of sustainability issues in present society. Copyright © 2012 John Wiley & Sons, Ltd and ERP Environment.
On the use of Biomimicry as a Useful Tool for the Industrial Designer
Authors: Volstad Nina Louise , Boks Casper
Published: June 2012

Designers and engineers are constantly searching for inspiration to solve their problems. One source of inspiration that has been used for centuries is nature. This practice is often referred to as ‘biomimicry’; innovation inspired by nature. This paper reviews existing literature and explores biomimicry information relevant for industrial design. Perceived benefits and pitfalls of using biomimicry in design are critically discussed. The paper stipulates that when used reductively – with the goal of finding a solution, not to necessarily create an ecologically sound product – biomimicry can be seen as a supplement to the designer's existing toolkit. However, it should not be used bombastically as if only nature can provide the panacea for all (sustainable) design challenges. Based on the review, a new biomimicry tool is presented in the form of a card deck, displaying categorized sources of inspiration towards design solutions. This provides industrial designers with an easy starting point to work with this subject. Copyright © 2012 John Wiley & Sons, Ltd and ERP Environment.
An Overview of Chinese Green Building Standards
Authors: Geng Yong , Dong Huijuan , Xue Bing , Fu Jia
Published: June 2012

With rapid urbanization and industrialization, China is now facing a great challenge in meeting the soaring demand for new buildings and the corresponding energy consumption. Under such circumstances, the setting of a national standard on green buildings would be an effective way to respond. In fact, China has made significant progress in developing national green building standards. But such progress is not explicitly released to the international societies. Therefore, the aim of this paper is to introduce such progress. China's green building efforts are first discussed in detail with the various provisions of the national indicator system. By conducting a comparison with other countries' green building standards, a critical analysis of such a national standard is presented. The comparison indicates benefits to be gained and challenges to be met, such as lack of indicators on responding climate change, lack of region‐specific indicators, lack of quantitative indicators, higher costs for receiving certification and lack of applying innovative green technologies. So, substantive revision is critically needed. The knowledge gained from Chinese efforts on green building indicators are valuable to both developed and developing nations seeking to implement sustainable development measures within their regulatory policies. Copyright © 2012 John Wiley & Sons, Ltd and ERP Environment.
Utilizing Societal Engagement as a Vehicle for Enhancing the Image and Sustainability of the Construction Industry
Authors: Wong Kelwin K.W. , Kumaraswamy Mohan , Mahesh Gangadhar , Thomas Ng S.
Published: June 2012

A construction industry encountering uncertain workload, difficulty in workforce renewal, and ultimately endangering its own sustainability jeopardizes not only the long‐term health of the industry, but also the sustainable development of a city's infrastructures. Hong Kong is a city facing this problem and there are growing concerns within the industry that there will be an inadequate workforce to meet future demand and that the industry is unable to attract sufficient young talent, in part because of the negative image of the construction industry. This paper aims to examine the role and impact of societal engagement in infrastructure projects. The notion of using societal engagement as a vehicle for enhancing the image and sustainability of the construction industry, thereby also improving the ability to attract new entrants, is proposed in this paper. It is also suggested that the construction industry's interaction with the public should be a continuous process on a daily basis through a professional workforce that promotes safety, environmental responsibility and caring for the needs of society, rather than only during public engagement events for individual projects. Copyright © 2012 John Wiley & Sons, Ltd and ERP Environment.
Cultural Traditions for the Sake of Innovation: the Concept of Scandinavian Design as a Potential Tool in the Development of a Sustainable China
Authors: Skjerven Astrid
Published: June 2012

China is currently undergoing rapid changes on a vast scale in the form of urban development and industrialization based on Western technology. Traditional methods of production have been abandoned, and cultural traditions are being marginalized. In this way not only natural resources, but also habitual ways of living and thereby a meaningful life are threatened. Some of the most important means for the creation of meaning are the objects of everyday life, a fact that makes the field of product design of crucial importance to the development. The question at stake is how cultural traditions can be re‐established and used as an innovative force in product development to secure coherence with the past and the creation of a sustainable yet modern China. The rationale of this article is that interpretations of Scandinavian design might contribute to such a development. The article first discusses the subject of cultural sustainability and the significance of product design. It then presents the history of the concept of Scandinavian design and its relevance as a possible tool in changing today's situation. In addition to historical research it is based on experience from an educational cooperation project between one Chinese and two Norwegian universities, and an investigation of a Norwegian firm's engagement in the country. The findings of the project, which is still in its initial stage, have so far indicated that the concept of what characterizes Scandinavian design has the potential to contribute to product design approaches that can stimulate sustainability. Copyright © 2012 John Wiley & Sons, Ltd and ERP Environment
Extending the c‐statistic to nominal polytomous outcomes: the Polytomous Discrimination Index
Authors: Van Calster Ben , Van Belle Vanya , Vergouwe Yvonne , Timmerman Dirk , Van Huffel Sabine , Steyerberg Ewout W.
Published: June 2012

Diagnostic problems in medicine are sometimes polytomous, meaning that the outcome has more than two distinct categories. For example, ovarian tumors can be benign, borderline, primary invasive, or metastatic. Extending the main measure of binary discrimination, the c‐statistic or area under the ROC curve, to nominal polytomous settings is not straightforward. This paper reviews existing measures and presents the polytomous discrimination index (PDI) as an alternative. The PDI assesses all sets of k cases consisting of one case from each outcome category. For each category i (i = 1, … ,k), it is assessed whether the risk of category i is highest for the case from category i. A score of 1∕k is given per category for which this holds, yielding a set score between 0 and 1 to indicate the level of discrimination. The PDI is the average set score and is interpreted as the probability to correctly identify a case from a randomly selected category within a set of k cases. This probability can be split up by outcome category, yielding k category‐specific values that result in the PDI when averaged. We demonstrate the measures on two diagnostic problems (residual mass histology after chemotherapy for testicular cancer; diagnosis of ovarian tumors). We compare the behavior of the measures on theoretical data, showing that PDI is more strongly influenced by simultaneous discrimination between all categories than by partial discrimination between pairs of categories. In conclusion, the PDI is attractive because it better matches the requirements of a measure to summarize polytomous discrimination. Copyright © 2012 John Wiley & Sons, Ltd.
Adaptive extensions of a two‐stage group sequential procedure for testing primary and secondary endpoints (II): sample size re‐estimation
Authors: Tamhane Ajit C. , Wu Yi , Mehta Cyrus R.
Published: June 2012

In this part II of the paper on adaptive extensions of a two‐stage group sequential procedure (GSP) for testing primary and secondary endpoints, we focus on the second stage sample size re‐estimation based on the first stage data. First, we show that if we use the Cui–Huang–Wang statistics at the second stage, then we can use the same primary and secondary boundaries as for the original procedure (without sample size re‐estimation) and still control the type I familywise error rate. This extends their result for the single endpoint case. We further show that the secondary boundary can be sharpened in this case by taking the unknown correlation coefficient ρ between the primary and secondary endpoints into account through the use of the confidence limit method proposed in part I of this paper. If we use the sufficient statistics instead of the CHW statistics, then we need to modify both the primary and secondary boundaries; otherwise, the error rate can get inflated. We show how to modify the boundaries of the original group sequential procedure to control the familywise error rate. We provide power comparisons between competing procedures. We illustrate the procedures with a clinical trial example. Copyright © 2012 John Wiley & Sons, Ltd.
Variable selection in semiparametric cure models based on penalized likelihood, with application to breast cancer clinical trials
Authors: Liu Xiang , Peng Yingwei , Tu Dongsheng , Liang Hua
Published: June 2012

Survival data with a sizable cure fraction are commonly encountered in cancer research. The semiparametric proportional hazards cure model has been recently used to analyze such data. As seen in the analysis of data from a breast cancer study, a variable selection approach is needed to identify important factors in predicting the cure status and risk of breast cancer recurrence. However, no specific variable selection method for the cure model is available. In this paper, we present a variable selection approach with penalized likelihood for the cure model. The estimation can be implemented easily by combining the computational methods for penalized logistic regression and the penalized Cox proportional hazards models with the expectation–maximization algorithm. We illustrate the proposed approach on data from a breast cancer study. We conducted Monte Carlo simulations to evaluate the performance of the proposed method. We used and compared different penalty functions in the simulation studies. Copyright © 2012 John Wiley & Sons, Ltd.
Multivariate multilevel spline models for parallel growth processes: application to weight and mean arterial pressure in pregnancy
Authors: Macdonald‐Wallis Corrie , Lawlor Debbie A. , Palmer Tom , Tilling Kate
Published: June 2012

Growth models are commonly used in life course epidemiology to describe growth trajectories and their determinants or to relate particular patterns of change to later health outcomes. However, methods to analyse relationships between two or more change processes occurring in parallel, in particular to assess evidence for causal influences of change in one variable on subsequent changes in another, are less developed. We discuss linear spline multilevel models with a multivariate response and show how these can be used to relate rates of change in a particular time period in one variable to later rates of change in another variable by using the variances and covariances of individual‐level random effects for each of the splines. We describe how regression coefficients can be calculated for these associations and how these can be adjusted for other parameters such as random effect variables relating to baseline values or rates of change in earlier time periods, and compare different methods for calculating the standard errors of these regression coefficients. We also show that these models can equivalently be fitted in the structural equation modelling framework and apply each method to weight and mean arterial pressure changes during pregnancy, obtaining similar results for multilevel and structural equation models. This method improves on the multivariate linear growth models, which have been used previously to model parallel processes because it enables nonlinear patterns of change to be modelled and the temporal sequence of multivariate changes to be determined, with adjustment for change in earlier time periods. Copyright © 2012 John Wiley & Sons, Ltd.
Homogeneity tests of clustered diagnostic markers with applications to the BioCycle Study
Authors: Tang Liansheng Larry , Liu Aiyi , Schisterman Enrique F. , Zhou Xiao‐Hua , Liu Catherine Chun‐ling
Published: June 2012

Diagnostic trials often require the use of a homogeneity test among several markers. Such a test may be necessary to determine the power both during the design phase and in the initial analysis stage. However, no formal method is available for the power and sample size calculation when the number of markers is greater than two and marker measurements are clustered in subjects. This article presents two procedures for testing the accuracy among clustered diagnostic markers. The first procedure is a test of homogeneity among continuous markers based on a global null hypothesis of the same accuracy. The result under the alternative provides the explicit distribution for the power and sample size calculation. The second procedure is a simultaneous pairwise comparison test based on weighted areas under the receiver operating characteristic curves. This test is particularly useful if a global difference among markers is found by the homogeneity test. We apply our procedures to the BioCycle Study designed to assess and compare the accuracy of hormone and oxidative stress markers in distinguishing women with ovulatory menstrual cycles from those without. Copyright © 2012 John Wiley & Sons, Ltd.
A latent‐variable marginal method for multi‐level incomplete binary data
Authors: Chen Baojiang , Zhou Xiao‐Hua
Published: June 2012

Incomplete multi‐level data arise commonly in many clinical trials and observational studies. Because of multi‐level variations in this type of data, appropriate data analysis should take these variations into account. A random effects model can allow for the multi‐level variations by assuming random effects at each level, but the computation is intensive because high‐dimensional integrations are often involved in fitting models. Marginal methods such as the inverse probability weighted generalized estimating equations can involve simple estimation computation, but it is hard to specify the working correlation matrix for multi‐level data. In this paper, we introduce a latent variable method to deal with incomplete multi‐level data when the missing mechanism is missing at random, which fills the gap between the random effects model and marginal models. Latent variable models are built for both the response and missing data processes to incorporate the variations that arise at each level. Simulation studies demonstrate that this method performs well in various situations. We apply the proposed method to an Alzheimer's disease study. Copyright © 2012 John Wiley & Sons, Ltd.
Group sequential and discretized sample size re‐estimation designs: a comparison of flexibility
Authors: Wu Xiaoru , Cui Lu
Published: June 2012

In clinical trials, researchers usually determine a study sample size prior to the start of the study to provide a sufficient power at a targeted treatment difference. When the targeted treatment difference deviates from the true one, the study may either have insufficient power or use more subjects than necessary. To address the difficulty in sample size planning, researchers have developed various flexible sample size designs and compared their performances. Some previous work suggests that re‐estimation designs are inefficient and that one can improve uniformly by using standard group sequential likelihood ratio tests, although more interim analyses are involved. However, researchers need to further study the statement and the minimal number of tests needed before a standard group sequential test might outperform a re‐estimation design. In this paper, we conducted simulation studies to answer these questions using various optimality criteria. Copyright © 2012 John Wiley & Sons, Ltd.
NHLBI clinical trials workshop: an executive summary
Authors: Zheng Gang , Wu Colin O. , Yang Song , Waclawiw Myron A. , DeMets David L. , Geller Nancy L.
Published: June 2012

On September 13–14, 2010, the National Heart, Lung and Blood Institute (NHLBI) organized a workshop: ‘Clinical Trials: Past, Present and Future’. The workshop covered many areas in clinical trials, including the history of clinical trials at NHLBI, Bayesian clinical trials, surrogate endpoints, reporting clinical trials, handling missing data, flexible designs and adaptive trials, personalized medicine and genomic clinical trials, and comparative effectiveness research. In this report, we summarize the main discussions and conclusions based on the presentations of the invited speakers at the workshop. Copyright © 2012 John Wiley & Sons, Ltd.
Dichotomizing a continuous outcome in cluster randomized trials: impact on power
Authors: Caille Agnès , Leyrat Clémence , Giraudeau Bruno
Published: June 2012

In cluster randomized trials (CRTs), clusters of individuals are randomized rather than the individuals themselves. For such trials, power depends in part on the degree of similarity among responses within a cluster, which is quantified by the intaclass correlation coefficient (ICC). Thus, for a fixed sample size, power decreases with increasing ICC. In reliability studies with two observers, dichotomizing a continuous outcome variable has been shown to reduce the ICC. We checked (by a simulation study) that this property still applies to CRTs, in which cluster sizes are variable and usually greater than in reliability studies and observations (within clusters) are exchangeable. Then, in a CRT, dichotomizing a continuous outcome actually induces two antagonistic effects: decreased power because of loss of information and increased power induced by attenuation of the ICC. Therefore, we aimed to assess the impact of dichotomizing a continuous outcome on power in a CRT. We derived an analytical formula for power based on a generalized estimating equation approach after dichotomizing a continuous outcome. This theoretical result was obtained by considering equal cluster sizes, and we then assessed its accuracy (by a simulation study) in the more realistic situation of varying cluster sizes. We showed that dichotomization is associated with decreased power: attenuation of the ICC does not compensate for the loss of power induced by loss of information. Loss of power is reduced with increased initial continuous‐outcome ICC and/or prevalence of success for the dichotomized outcome approaching 50%. Copyright © 2012 John Wiley & Sons, Ltd.
Aggregating published prediction models with individual participant data: a comparison of different approaches
Authors: Debray Thomas P.A. , Koffijberg Hendrik , Vergouwe Yvonne , Moons Karel G.M. , Steyerberg Ewout W.
Published: June 2012

During the recent decades, interest in prediction models has substantially increased, but approaches to synthesize evidence from previously developed models have failed to keep pace. This causes researchers to ignore potentially useful past evidence when developing a novel prediction model with individual participant data (IPD) from their population of interest. We aimed to evaluate approaches to aggregate previously published prediction models with new data. We consider the situation that models are reported in the literature with predictors similar to those available in an IPD dataset. We adopt a two‐stage method and explore three approaches to calculate a synthesis model, hereby relying on the principles of multivariate meta‐analysis. The former approach employs a naive pooling strategy, whereas the latter accounts for within‐study and between‐study covariance. These approaches are applied to a collection of 15 datasets of patients with traumatic brain injury, and to five previously published models for predicting deep venous thrombosis. Here, we illustrated how the generally unrealistic assumption of consistency in the availability of evidence across included studies can be relaxed. Results from the case studies demonstrate that aggregation yields prediction models with an improved discrimination and calibration in a vast majority of scenarios, and result in equivalent performance (compared with the standard approach) in a small minority of situations. The proposed aggregation approaches are particularly useful when few participant data are at hand. Assessing the degree of heterogeneity between IPD and literature findings remains crucial to determine the optimal approach in aggregating previous evidence into new prediction models. Copyright © 2012 John Wiley & Sons, Ltd.
Hierarchical modeling of agreement
Authors: Vanbelle Sophie , Mutsvari Timothy , Declerck Dominique , Lesaffre Emmanuel
Published: June 2012

Kappa‐like agreement indexes are often used to assess the agreement among examiners on a categorical scale. They have the particularity of correcting the level of agreement for the effect of chance. In the present paper, we first define two agreement indexes belonging to this family in a hierarchical context. In particular, we consider the cases of a random and fixed set of examiners. Then, we develop a method to evaluate the influence of factors on these indexes. Agreement indexes are directly related to a set of covariates through a hierarchical model. We obtain the posterior distribution of the model parameters in a Bayesian framework. We apply the proposed approach on dental data and compare it with the generalized estimating equations approach. Copyright © 2012 John Wiley & Sons, Ltd.
Estimating associations of mobile phone use and brain tumours taking into account laterality: a comparison and theoretical evaluation of applied methods
Authors: Frederiksen Kirsten , Deltour Isabelle , Schüz Joachim
Published: June 2012

Estimating exposure–outcome associations using laterality information on exposure and on outcome is an issue, when estimating associations of mobile phone use and brain tumour risk. The exposure is localized; therefore, a potential risk is expected to exist primarily on the side of the head, where the phone is usually held (ipsilateral exposure), and to a lesser extent at the opposite side of the head (contralateral exposure). Several measures of the associations with ipsilateral and contralateral exposure, dealing with different sampling designs, have been presented in the literature. This paper presents a general framework for the analysis of such studies using a likelihood‐based approach in a competing risks model setting. The approach clarifies the implicit assumptions required for the validity of the presented estimators, particularly that in some approaches the risk with contralateral exposure is assumed to be zero. The performance of the estimators is illustrated in a simulation study showing for instance that while in some scenarios there is a loss of statistical power, others — in case of a positive ipsilateral exposure–outcome association — would result in a negatively biased estimate of the contralateral exposure parameter, irrespective of any additional recall bias. In conclusion, our theoretical evaluations and results from the simulation study emphasize the importance of setting up a formal model, which furthermore allows for estimation in more complicated and perhaps more realistic exposure settings, such as taking into account exposure to both sides of the head. Copyright © 2012 John Wiley & Sons, Ltd.
On Bayesian methods of exploring qualitative interactions for targeted treatment
Authors: Chen Wei , Ghosh Debashis , Raghunathan Trivellore E. , Norkin Maxim , Sargent Daniel J. , Bepler Gerold
Published: June 2012

Providing personalized treatments designed to maximize benefits and minimizing harms is of tremendous current medical interest. One problem in this area is the evaluation of the interaction between the treatment and other predictor variables. Treatment effects in subgroups having the same direction but different magnitudes are called quantitative interactions, whereas those having opposite directions in subgroups are called qualitative interactions (QIs). Identifying QIs is challenging because they are rare and usually unknown among many potential biomarkers. Meanwhile, subgroup analysis reduces the power of hypothesis testing and multiple subgroup analyses inflate the type I error rate. We propose a new Bayesian approach to search for QI in a multiple regression setting with adaptive decision rules. We consider various regression models for the outcome. We illustrate this method in two examples of phase III clinical trials. The algorithm is straightforward and easy to implement using existing software packages. We provide a sample code in Appendix A. Copyright © 2012 John Wiley & Sons, Ltd.
Variable selection for covariate‐adjusted semiparametric inference in randomized clinical trials
Authors: Yuan Shuai , Zhang Hao Helen , Davidian Marie
Published: June 2012

Extensive baseline covariate information is routinely collected on participants in randomized clinical trials, and it is well recognized that a proper covariate‐adjusted analysis can improve the efficiency of inference on the treatment effect. However, such covariate adjustment has engendered considerable controversy, aspost hocselection of covariates may involve subjectivity and may lead to biased inference, whereas prior specification of the adjustment may exclude important variables from consideration. Accordingly, how to select covariates objectively to gain maximal efficiency is of broad interest. We propose and study the use of modern variable selection methods for this purpose in the context of a semiparametric framework, under which variable selection in modeling the relationship between outcome and covariates is separated from estimation of the treatment effect, circumventing the potential for selection bias associated with standard analysis of covariance methods. We demonstrate that such objective variable selection techniques combined with this framework can identify key variables and lead to unbiased and efficient inference on the treatment effect. A critical issue in finite samples is validity of estimators of uncertainty, such as standard errors and confidence intervals for the treatment effect. We propose an approach to estimation of sampling variation of estimated treatment effect and show its superior performance relative to that of existing methods. Copyright © 2012 John Wiley & Sons, Ltd.
Using multiple risk models with preventive interventions
Authors: Gail Mitchell H.
Published: June 2012

An ideal preventive intervention would have negligible side effects and could be applied to the entire population, thus achieving maximal preventive impact. Unfortunately, many interventions have adverse effects and beneficial effects. For example, tamoxifen reduces the risk of breast cancer by about 50% and the risk of hip fracture by 45%, but increases the risk of stroke by about 60%; other serious adverse effects include endometrial cancer and pulmonary embolus. Hence, tamoxifen should only be given to the subset of the population with high enough risks of breast cancer and hip fracture such that the preventive benefits outweigh the risks. Recommendations for preventive use of tamoxifen have been based primarily on breast cancer risk. Age‐specific and race‐specific rates were considered for other health outcomes, but not risk models. In this paper, we investigate the extent to which modeling not only the risk of breast cancer, but also the risk of stroke, can improve the decision to take tamoxifen. These calculations also give insight into the relative benefits of improving the discriminatory accuracy of such risk models versus improving the preventive effectiveness or reducing the adverse risks of the intervention. Depending on the discriminatory accuracies of the risk models, there may be considerable advantage to modeling the risks of more than one health outcome. Published 2012. This article is a US Government work and is in the public domain in the USA.
Anticancer Efficacy and Subcellular Site of Action Investigated by Real‐Time Monitoring of Cellular Responses to Localized Drug Delivery in Single Cells
Authors: Zheng Xin Ting , Chen Peng , Li Chang Ming
Published: June 2012

Subcellular‐targeted drug delivery has much potential to defeat infectious diseases and cancers. Medical and/or biochemical effects of drugs/bioactive molecules delivered to subcellular compartments and their subcellular sites of action need to be investigated but have not been explored. Here the subcellular location‐dependent biochemical responses of a potent anticancer drug, β‐lapachone (β‐lap), is investigated by a reduced graphene oxide (rGO)‐functionalized optical nanoprobe, which can deliver and simultaneously monitor the drug effects at nanoscales. For the first time, distinct oxidative responses and calcium alterations in three selected subcellular domains are observed and clearly pinpoint that the perinuclear region is the optimal subcellular site for β‐lap to have the best anticancer efficacy. The results presented here provide not only scientific insights of subcellular drug–cell interaction that is not obtainable from conventional methods, but they also provide valuable knowledge for rational design of subcellular‐targeted delivery or spatially resolved signal intervention.
Carbon Nanotube Rope with Electrical Stimulation Promotes the Differentiation and Maturity of Neural Stem Cells
Authors: Huang Yu‐Jie , Wu Hsi‐Chin , Tai Nyan‐Hwa , Wang Tzu‐Wei
Published: July 2012

In recent years, the utilization of nanomaterials such as carbon nanotubes (CNTs) in the field of neuroscience has forever changed the approach to nerve‐related research. The array of novel properties CNTs possess allows them to interact with neurons at the nanodimensional scale. In this study, a CNT rope substrate is developed to allow the electrical stimulation of neural stem cells (NSCs) in culture medium and the in situ observation of the response of these stem cells after stimulation. CNTs are synthesized by chemical vapor deposition and prepared into a ropelike structure with a diameter of 1 mm and length of 1.5 cm. NSCs are differentiated on the CNT rope substrate while the direction of neurite outgrowth, phenotype, and maturity of the NSCs are analyzed. Fluorescence and scanning electron microscopy demonstrate that neurite extension favors the direction of the spiral topography on the CNT rope. NSCs plated on CNT ropes are boosted towards differentiated neurons in the early culture stage when compared to conventional tissue culture plates via the analysis of neuronal gene and protein expressions by quantitative polymerase chain reaction and immunostaining, respectively. Furthermore, a set of electrical stimulation parameters (5 mV, 0.5 mA, 25 ms intermittent stimulation) promotes neuronal maturity while also increasing the speed of neurite outgrowth. These results indicate that an electroconductive CNT rope substrate along with electrical stimulation may have a synergistic effect on promoting neurite elongation and boosting effects on the differentiation of NSCs into mature neuronal cells for therapeutic application in neural regeneration.
Determination of the Rate of CO2–CO Reaction with Magnetite by Isotope Exchange Technique
Authors: HU Xiaojun , Zhang Teng , Chou Kuo‐Chih , Matsuura Hiroyuki , Tsukihashi Fumitaka
Published: June 2012

To clarify the mechanism and get the accurate kinetic parameters of CO2–CO reaction with magnetite, 13CO2–CO isotope exchange technique was used to determine the rate constants of CO2 dissociation on the surface of magnetite from 1073 to 1373 K. The real interfacial rate constant was estimated by considering the gas phase mass transfer along a plate. The relationship of the rate constant and CO2/CO ratio was expressed by the formula of kc = k0 (CO2/CO)−1−m, m represents the effect of CO2/CO ratio on the activity of oxygen in iron oxide. The apparent activation energy of the reaction between CO2–CO gas and magnetite was calculated to 161, 175 ± 15, 198, and 197 ± 16 kJ mol−1 for CO2/CO ratios of 4.0, 5.0, 6.0, and 10.0, respectively. This dependence relationship may be caused by the decrease of free electron in magnetite phase with the increase of CO2/CO ratio.
Influence of Cold Forming and Heat Treatment on the Microstructure and Mechanical Properties of an Air‐Hardening Steel
Authors: Grydin Olexandr , Rodman Dmytro , Schaper Mirko
Published: June 2012

The use of air‐hardening steels in the manufacture of automobile body components shortens the corresponding process chain by means of eliminating the immersion or gas quenching operation since hardening occurs in still air. To choose the optimal forming and heat‐treatment parameters, the development of the microstructure needs to be considered as a consequence of the thermomechanical production processes. The object of this work is to investigate the effects of forming and the subsequent heat‐treating on the changes of the microstructural parameters for the air‐hardening steel LH800. For this purpose, specimens were processed under different forming and heat‐treating conditions and subsequently examined by means of SEM and mechanically tested using tensile tests. Based on this, an empirical equation was derived which describes the influence of both the martensite's bundle thickness and the original austenite's grain size on the yield stress. In this way, microstructural parameters can be identified which lead to good mechanical properties. The measured correlation can thus be used for modeling the LH800 steel's forming and heat‐treatment processes.
Differential role of serotonin projections from the dorsal and median raphe nuclei in phencyclidine‐induced hyperlocomotion and fos‐like immunoreactivity in rats
Authors: Kusljic Snezana , Van Den Buuse Maarten
Published: June 2012

Altered brain serotonin activity is implicated in schizophrenia. We have previously shown differential involvement of serotonergic projections from the dorsal or median raphe nucleus in phencyclidine‐induced hyperlocomotion in rats, a behavioral model of aspects of schizophrenia. Here we further investigated the effects of serotonergic lesions of the raphe nuclei on phencyclidine‐induced hyperlocomotion by parallel assessment of Fos‐like immunoreactivity (FLI), a marker of neuronal activation in the brain. Male Sprague‐Dawley rats were anesthetized with pentobarbitone and stereotaxically microinjected with 5 μg of the serotonergic neurotoxin, 5,7‐dihydroxytryptamine (5,7‐DHT), into either the dorsal raphe (DRN) or median raphe nucleus (MRN). Two weeks after the surgery, rats with lesions of the MRN, but not those with lesions of the DRN, showed significant enhancement of the hyperlocomotion induced by injection of 2.5 mg/kg of phencyclidine. Rats with MRN lesions also showed significantly higher levels of FLI in the polymorphic layer of the dentate gyrus in the dorsal hippocampus (PoDG) when compared with sham‐operated controls. Rats with lesions of the DRN showed significantly higher levels of FLI in the nucleus accumbens (NAcc). These results indicate that FLI in the PoDG, but not the NAcc, correlates with enhanced phencyclidine‐induced locomotor hyperactivity in MRN‐lesioned rats. These results support our previous studies suggesting a role of serotonergic projections from the MRN to the dorsal hippocampus in some of the symptoms of schizophrenia. Synapse, 2012. © 2012 Wiley Periodicals, Inc.
The impact of acetylcholinesterase inhibitors on the extracellular acetylcholine concentrations in the adult rat brain: A meta‐analysis
Authors: Noori Hamid R. , Fliegel Sarah , Brand Ines , Spanagel Rainer
Published: June 2012

In vivo microdialysis has become a key method in investigating the dynamics of different neurotransmitter systems such as acetylcholine in the extracellular fluid. Depending on the sensitivity of the analytical method applied for measuring acetylcholine levels in brain dialysates, acetylcholinesterase (AChE) inhibitors are often used to increase the basal acetylcholine level up to a detectable magnitude. This artificial manipulation of the system questions the outcome of pharmacological studies and has led to a large number of experiments pursuing the appropriate physiological and pharmacological concentration of the AChE inhibitors in a range between 0.01 and 100 μM. However, the complexity of the action of these substances, particularly through the involvement of muscarinic autoreceptors and the induction of an autoinhibitory effect on acetylcholine release, did not allow this quest to be resolved completely and suggests the application of advanced mathematical methods for the evaluation of acetylcholine baseline levels. Here we performed a meta‐analysis on published datasets of in vivo microdialysis measurements to assess the concentration‐dependent effects of various AChE inhibitors on acetylcholine levels within the prefrontal cortex, nucleus accumbens, caudate putamen, and hippocampus in adult rats. In total 3255 rats were analyzed and we found that when compared with the minority of studies (14%) that did not use AChE inhibitors (these studies yielded basal levels between 0.55 and 2.71 nM depending on the brain site) an up to 350‐fold increase in baseline values after the application of an inhibitor could be detected. Especially, the derivates neostigmine bromide and physostigmine sulfate seem to produce dramatic effects. Furthermore, concentration‐dependent effects after the application of AChE inhibitors could not be established. In the case of neostigmine bromide an inverted concentration (0.1–10 μM)–response relationship was even detected. We conclude that although the presynaptic action of AChE inhibitors is well understood the nonphysiological and concentration‐independent augmentation of the acetylcholine system requires the use of a standard protocol in order to produce replicable and comparable results. Our meta‐analysis suggests the use of 0.1 μM neostigmine which produces an approximately 10‐fold boost of brain baseline levels. Synapse 2012. © 2012 Wiley Periodicals, Inc.
Conceptions of time in (paleo)climate science and some implications
Authors: Caseldine Chris
Published: June 2012

Palaeoscientists of necessity deal with time as a fundamental part of the research process and have developed understandings within the discipline of how to deal with a range of timescales from the deep time of Archaean geology to recent time, that is the last few centuries. Time has however largely been seen as providing a chronology, the ability to place events in sequence and through the implementation of various dating techniques to relate these sequences across space, providing fundamental information toward understanding cause and effect within the Earth system. Variability in the units of time, the differences between radiometric and sidereal or calendrical years is accounted for and not deemed significant. When dealing with other disciplines, either through research into the relationship of past societies to climate change, or when contributing to the concerns over future directions of climate problems arise in attempting to communicate the nature of timescales. The real issue is to reinforce the idea of change as a basic quality of the climate system, something that can occur very rapidly. It is open to question whether a concentration on timescales of climate change is proving a distraction in terms of communication from the most important issue. Change is a fundamental property of the global climate system, and from our paleoscience knowledge it is clear that change will continue into the future and could well be very rapid. WIREs Clim Change 2012 doi: 10.1002/wcc.178

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