Book review - Richard Goldberg, Medicinal Product Liability and Regulation (Hart Publishing, Oxford, 2013) 214pp

In December 2013, settlement was reached between approximately 100 Australian and New Zealand Thalidomide victims and the company which had acted as the Australian distributor of the infamous drug, thus putting to rest the possibility of litigation. Around the same time, Thalidomide victims in the United Kingdom (UK) launched a similar bid for compensation against the manufacturer and distributor. It is clear that despite a lengthy amount of time having passed ever since the thalidomide disaster commenced in 1962, the controversy over compensation continues. Indeed, the author of Medicinal Product Liability and Regulation (published before the announcement of the British legal claim), Professor Goldberg, notes that claims for resulting birth defects continue to emerge right into the present day. His prescient insight into the contemporary relevance of compensation for pharmaceutical injuries thus makes Medicinal Product Liability and Regulation a very relevant addition to the small body of scholarship that is available on this rather specific and complex issue.

Chondrocyte redifferentiation and construct mechanical property development in single-component photocrosslinkable hydrogels

Hydrogels are promising materials for cartilage repair, but the properties required for optimal functional outcomes are not yet known. In this study, we functionalized four materials that are commonly used in cartilage tissue engineering and evaluated them using in vitro cultures. Gelatin, hyaluronic acid, polyethylene glycol, and alginate were functionalized with methacrylic anhydride to make them photocrosslinkable. We found that the responses of encapsulated human chondrocytes were highly dependent on hydrogel type. Gelatin hydrogels supported cell proliferation and the deposition of a glycosaminoglycan rich matrix with significant mechanical functionality. However, cells had a dedifferentiated phenotype, with high expression of collagen type I. Chondrocytes showed the best redifferentiation in hyaluronic acid hydrogels, but the newly formed matrix was highly localized to the pericellular regions, and these gels degraded rapidly. Polyethylene glycol hydrogels, as a bioinert control, did not promote any strong responses. Alginate hydrogels did not support the deposition of new matrix, and the stiffness decreased during culture. The markedly different response of chondrocytes to these four photocrosslinkable hydrogels demonstrates the importance of material properties for chondrogenesis and extracellular matrix production, which are critical for effective cartilage repair.

Ecosystem management along ephemeral rivers: Trading off socio-economic water supply and vegetation conservation under flood regime uncertainty

In ecosystems driven by water availability, plant community dynamics depend on complex interactions between vegetation, hydrology, and human water resources use. Along ephemeral rivers—where water availability is erratic—vegetation and people are particularly vulnerable to changes in each other's water use. Sensible management requires that water supply be maintained for people, while preserving ecosystem health. Meeting such requirements is challenging because of the unpredictable water availability. We applied information gap decision theory to an ecohydrological system model of the Kuiseb River environment in Namibia. Our aim was to identify the robustness of ecosystem and water management strategies to uncertainties in future flood regimes along ephemeral rivers. We evaluated the trade-offs between alternative performance criteria and their robustness to uncertainty to account for both (i) human demands for water supply and (ii) reducing the risk of species extinction caused by water mining. Increasing uncertainty of flood regime parameters reduced the performance under both objectives. Remarkably, the ecological objective (species coexistence) was more sensitive to uncertainty than the water supply objective. However, within each objective, the relative performance of different management strategies was insensitive to uncertainty. The ‘best’ management strategy was one that is tuned to the competitive species interactions in the Kuiseb environment. It regulates the biomass of the strongest competitor and, thus, at the same time decreases transpiration, thereby increasing groundwater storage and reducing pressure on less dominant species. This robust mutually acceptable strategy enables species persistence without markedly reducing the water supply for humans. This study emphasises the utility of ecohydrological models for resource management of water-controlled ecosystems. Although trade-offs were identified between alternative performance criteria and their robustness to uncertain future flood regimes, management strategies were identified that help to secure an ecologically sustainable water supply.

Responding to black markets: Role of IT and network structures

This paper presents the unique black markets of asset pooling and leasing services, which exposes the nature and extent of industry-specific threats. We explore how firms providing such services together with their network structures that constitute the foundations of asset pooling and leasing respond to the threat of black markets. We encapsulate detecting and encountering the threat of black markets through the theoretical lens of agility, which encompasses the elements of sensing and responding (Overby et al. 2006; Roberts and Grover 2012). This novel concept of responding to threats using the agility lens has not been adequately addressed by past studies on enterprise agility. Through a case study of a global asset pooling and leasing company, we reveal the criticality of network structures, the impracticality of IT and inadequate tracking mechanisms that challenge firms in minimizing such threats.

Solo holiday travellers: Motivators and drivers of satisfaction and dissatisfaction

A growing number of people are travelling alone for holidays, yet limited research addresses this topic. This paper explores the main motivators and drivers of satisfaction and dissatisfaction for solo holiday travellers using a critical incident technique (CIT) to collect and analyse data. The findings show that drivers of satisfaction for solo holiday travellers are more related to personal feelings of freedom, relaxation and discovery (personal factors), and interaction with other people (human interaction factors), than with holiday destination factors. Safety (a destination factor) and unfriendly service providers (a human interaction factor) are the main sources of dissatisfaction for solo holiday travellers.

Case Studies in Bayesian Statistical Modelling and Analysis

Provides an accessible foundation to Bayesian analysis using real world models This book aims to present an introduction to Bayesian modelling and computation, by considering real case studies drawn from diverse fields spanning ecology, health, genetics and finance. Each chapter comprises a description of the problem, the corresponding model, the computational method, results and inferences as well as the issues that arise in the implementation of these approaches. Case Studies in Bayesian Statistical Modelling and Analysis: •Illustrates how to do Bayesian analysis in a clear and concise manner using real-world problems. •Each chapter focuses on a real-world problem and describes the way in which the problem may be analysed using Bayesian methods. •Features approaches that can be used in a wide area of application, such as, health, the environment, genetics, information science, medicine, biology, industry and remote sensing. Case Studies in Bayesian Statistical Modelling and Analysis is aimed at statisticians, researchers and practitioners who have some expertise in statistical modelling and analysis, and some understanding of the basics of Bayesian statistics, but little experience in its application. Graduate students of statistics and biostatistics will also find this book beneficial.

Financial Accounting: Reporting, Analysis and Decision Making [5th ed.]

In recent years accounting education has seen numerous changes to the way financial accounting is taught. These changes reflect the demands of an ever-changing business world, opportunities created by new technology and instructional technologies, and an increased understanding of how students learn. The foundation of Financial Accounting is based on a number of unique principles and innovations in accounting education. The objective of Financial Accounting is to provide students with an understanding of those concepts that are fundamental to the preparation and use of accounting information. Most students will forget procedural details within a short period of time. On the other hand, concepts, if well taught, should be remembered for a lifetime. Concepts are especially important in a world where the details are constantly changing. Students learn best when they are actively engaged. The overriding pedagogical objective of Financial Accounting is to provide students with continual opportunities for active learning. One of the best tools for active learning is strategically placed questions. Discussions are framed by questions, often beginning with rhetorical questions and ending with review questions, and our analytical devices, called decision-making toolkits, use key questions to demonstrate the purpose of each.

Combination inhaled corticosteroids and long-acting beta2-agonists for children and adults with bronchiectasis

BACKGROUND Bronchiectasis is a major contributor to chronic respiratory morbidity and mortality worldwide. Wheeze and other asthma-like symptoms and bronchial hyperreactivity may occur in people with bronchiectasis. Physicians often use asthma treatments in patients with bronchiectasis. OBJECTIVES To assess the effects of inhaled long-acting beta2-agonists (LABA) combined with inhaled corticosteroids (ICS) in children and adults with bronchiectasis during (1) acute exacerbations and (2) stable state. SEARCH METHODS The Cochrane Airways Group searched the the Cochrane Airways Group Specialised Register of Trials, which includes records identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and other databases. The Cochrane Airways Group performed the latest searches in October 2013. SELECTION CRITERIA All randomised controlled trials (RCTs) of combined ICS and LABA compared with a control (placebo, no treatment, ICS as monotherapy) in children and adults with bronchiectasis not related to cystic fibrosis (CF). DATA COLLECTION AND ANALYSIS Two review authors extracted data independently using standard methodological procedures as expected by The Cochrane Collaboration. MAIN RESULTS We found no RCTs comparing ICS and LABA combination with either placebo or usual care. We included one RCT that compared combined ICS and LABA with high-dose ICS in 40 adults with non-CF bronchiectasis without co-existent asthma. All participants received three months of high-dose budesonide dipropionate treatment (1600 micrograms). After three months, participants were randomly assigned to receive either high-dose budesonide dipropionate (1600 micrograms per day) or a combination of budesonide with formoterol (640 micrograms of budesonide and 18 micrograms of formoterol) for three months. The study was not blinded. We assessed it to be an RCT with overall high risk of bias. Data analysed in this review showed that those who received combined ICS-LABA (in stable state) had a significantly better transition dyspnoea index (mean difference (MD) 1.29, 95% confidence interval (CI) 0.40 to 2.18) and cough-free days (MD 12.30, 95% CI 2.38 to 22.2) compared with those receiving ICS after three months of treatment. No significant difference was noted between groups in quality of life (MD -4.57, 95% CI -12.38 to 3.24), number of hospitalisations (odds ratio (OR) 0.26, 95% CI 0.02 to 2.79) or lung function (forced expiratory volume in one second (FEV1) and forced vital capacity (FVC)). Investigators reported 37 adverse events in the ICS group versus 12 events in the ICS-LABA group but did not mention the number of individuals experiencing adverse events. Hence differences between groups were not included in the analyses. We assessed the overall evidence to be low quality. AUTHORS' CONCLUSIONS In adults with bronchiectasis without co-existent asthma, during stable state, a small single trial with a high risk of bias suggests that combined ICS-LABA may improve dyspnoea and increase cough-free days in comparison with high-dose ICS. No data are provided for or against, the use of combined ICS-LABA in adults with bronchiectasis during an acute exacerbation, or in children with bronchiectasis in a stable or acute state. The absence of high quality evidence means that decisions to use or discontinue combined ICS-LABA in people with bronchiectasis may need to take account of the presence or absence of co-existing airway hyper-responsiveness and consideration of adverse events associated with combined ICS-LABA.

Mathematical modeling for improved greenhouse gas balances, agro-ecosystems, and policy development: Lessons from the Australian experience

If the land sector is to make significant contributions to mitigating anthropogenic greenhouse gas (GHG) emissions in coming decades, it must do so while concurrently expanding production of food and fiber. In our view, mathematical modeling will be required to provide scientific guidance to meet this challenge. In order to be useful in GHG mitigation policy measures, models must simultaneously meet scientific, software engineering, and human capacity requirements. They can be used to understand GHG fluxes, to evaluate proposed GHG mitigation actions, and to predict and monitor the effects of specific actions; the latter applications require a change in mindset that has parallels with the shift from research modeling to decision support. We compare and contrast 6 agro-ecosystem models (FullCAM, DayCent, DNDC, APSIM, WNMM, and AgMod), chosen because they are used in Australian agriculture and forestry. Underlying structural similarities in the representations of carbon flows though plants and soils in these models are complemented by a diverse range of emphases and approaches to the subprocesses within the agro-ecosystem. None of these agro-ecosystem models handles all land sector GHG fluxes, and considerable model-based uncertainty exists for soil C fluxes and enteric methane emissions. The models also show diverse approaches to the initialisation of model simulations, software implementation, distribution, licensing, and software quality assurance; each of these will differentially affect their usefulness for policy-driven GHG mitigation prediction and monitoring. Specific requirements imposed on the use of models by Australian mitigation policy settings are discussed, and areas for further scientific development of agro-ecosystem models for use in GHG mitigation policy are proposed.

Bayesian predictive modeling and comparison of oil samples

Statistical comparison of oil samples is an integral part of oil spill identification, which deals with the process of linking an oil spill with its source of origin. In current practice, a frequentist hypothesis test is often used to evaluate evidence in support of a match between a spill and a source sample. As frequentist tests are only able to evaluate evidence against a hypothesis but not in support of it, we argue that this leads to unsound statistical reasoning. Moreover, currently only verbal conclusions on a very coarse scale can be made about the match between two samples, whereas a finer quantitative assessment would often be preferred. To address these issues, we propose a Bayesian predictive approach for evaluating the similarity between the chemical compositions of two oil samples. We derive the underlying statistical model from some basic assumptions on modeling assays in analytical chemistry, and to further facilitate and improve numerical evaluations, we develop analytical expressions for the key elements of Bayesian inference for this model. The approach is illustrated with both simulated and real data and is shown to have appealing properties in comparison with both standard frequentist and Bayesian approaches

Click functionalization of methacrylate-based hydrogels and their cellular response

Methacrylate-based hydrogels, such as homo- and copolymers of 2-hydroxyethyl methacrylate (HEMA), have demonstrated significant potential for use in biomedical applications. However, many of these hydrogels tend to resist cell attachment and growth at their surfaces, which can be detrimental for certain applications. In this article, glycidyl methacrylate (GMA) was copolymerized with HEMA to generate gels functionalized with epoxide groups. The epoxides were then functionalized by two sequential click reactions, namely, nucleophilic ring opening of epoxides with sodium azide and then coupling of small molecules and peptides via Huisgen's copper catalyzed 1,3-dipolar cycloaddition of azides with alkynes. Using this strategy it was possible to control the degree of functionalization by controlling the feed ratio of monomers during polymerization. In vitro cell culture of human retinal pigment epithelial cell line (ARPE-19) with the hydrogels showed improved cell adhesion, growth and proliferation for hydrogels that were functionalized with a peptide containing the RGD sequence. In addition, the cell attachment progressively decreased with increasing densities of the RGD containing peptide. In summary, a facile methodology has been presented that gives rise to hydrogels with controlled degrees of functionality, such that the cell response is directly related to the levels and nature of that functionality.

A simple and fast two-locus quality control test to detect false positives due to batch effects in genome-wide association studies

The impact of erroneous genotypes having passed standard quality control (QC) can be severe in genome-wide association studies, genotype imputation, and estimation of heritability and prediction of genetic risk based on single nucleotide polymorphisms (SNP). To detect such genotyping errors, a simple two-locus QC method, based on the difference in test statistic of association between single SNPs and pairs of SNPs, was developed and applied. The proposed approach could detect many problematic SNPs with statistical significance even when standard single SNP QC analyses fail to detect them in real data. Depending on the data set used, the number of erroneous SNPs that were not filtered out by standard single SNP QC but detected by the proposed approach varied from a few hundred to thousands. Using simulated data, it was shown that the proposed method was powerful and performed better than other tested existing methods. The power of the proposed approach to detect erroneous genotypes was approximately 80% for a 3% error rate per SNP. This novel QC approach is easy to implement and computationally efficient, and can lead to a better quality of genotypes for subsequent genotype-phenotype investigations.

Common genetic influences underlie comorbidity of migraine and endometriosis

We examined the co-occurrence of migraine and endometriosis within the largest known collection of families containing multiple women with surgically confirmed endometriosis and in an independent sample of 815 monozygotic and 457 dizygotic female twin pairs. Within the endometriosis families, a significantly increased risk of migrainous headache was observed in women with endometriosis compared to women without endometriosis (odds ratio [OR] 1.57, 95% confidence interval [CI]: 1.12-2.21, P=0.009). Bivariate heritability analyses indicated no evidence for common environmental factors influencing either migraine or endometriosis but significant genetic components for both traits, with heritability estimates of 69 and 49%, respectively. Importantly, a significant additive genetic correlation (r(G) = 0.27, 95% CI: 0.06-0.47) and bivariate heritability (h(2)=0.17, 95% CI: 0.08-0.27) was observed between migraine and endometriosis. Controlling for the personality trait neuroticism made little impact on this association. These results confirm the previously reported comorbidity between migraine and endometriosis and indicate common genetic influences completely explain their co-occurrence within individuals. Given pharmacological treatments for endometriosis typically target hormonal pathways and a number of findings provide support for a relationship between hormonal variations and migraine, hormone-related genes and pathways are highly plausible candidates for both migraine and endometriosis. Therefore, taking into account the status of both migraine and endometriosis may provide a novel opportunity to identify the genes underlying them. Finally, we propose that the analysis of such genetically correlated comorbid traits can increase power to detect genetic risk loci through the use of more specific, homogenous and heritable phenotypes.