The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials

Flaws in the design, conduct, analysis, and reporting of randomised trials can cause the effect of an intervention to be underestimated or overestimated. The Cochrane Collaboration’s tool for assessing risk of bias aims to make the process clearer and more accurat

Default Risk and Equity Returns: A Comparison of the Bank-Based German and the U.S. Financial System

In this paper, we address the question whether the impact of default risk on equity returns depends on the financial system firms operate in. Using an implementation of Merton's option-pricing model for the value of equity to estimate firms' default risk, we construct a factor that measures the excess return of firms with low default risk over firms with high default risk. We then compare results from asset pricing tests for the German and the U.S. stock markets. Since Germany is the prime example of a bank-based financial system, where debt is supposedly a major instrument of corporate governance, we expect that a systematic default risk effect on equity returns should be more pronounced for German rather than U.S. firms. Our evidence suggests that a higher firm default risk systematically leads to lower returns in both capital markets. This contradicts some previous results for the U.S. by Vassalou/Xing (2004), but we show that their default risk factor looses its explanatory power if one includes a default risk factor measured as a factor mimicking portfolio. It further turns out that the composition of corporate debt affects equity returns in Germany. Firms' default risk sensitivities are attenuated the more a firm depends on bank debt financing

The ELF Honest Data Broker:Informatics enabling public-private collaboration in a precompetitive arena

New precompetitive ways of working in the pharmaceutical industry are driving the development of new informatics systems to enable their execution and management. The European Lead Factory (ELF) is a precompetitive, 30-partner collaboration between academic groups, small–medium enterprises and pharmaceutical companies created to discover small molecule hits against novel biological targets. A unique HTS screening and triage workflow has been developed to balance the intellectual property and scientific requirements of all the partners. Here, we describe the ELF Honest Data Broker, a cloud-based informatics system providing the scientific triage tools, fine-grained permissions and management tools required to implement the workflow

The nomenclature, definition and classification of discordant atrioventricular connections

Congenitally corrected transposition is a complex cardiac lesion that is often associated with ventricular septal defect, obstruction of the outflow tract of the morphologically left ventricle, and abnormalities of the morphologically tricuspid valve.1,2Nomenclature for this lesion has been variable and confusing.1In this review, we define, and hopefully clarify this terminology. The lesion is a combination of discordant union of the atrial chambers with the ventricles, and the ventricles with the arterial trunks.1,2In rare circumstances, discordant atrioventricular connections can be associated with concordant ventriculo-arterial connections. This malformation has been called "isolated ventricular inversion". The term is less than precise, and the descriptive approach using the phrase "discordant atrioventricular connections with concordant ventriculo-arterial connections" is preferred, as discussed below

Role of the androgen receptor in breast cancer and preclinical analysis of enzalutamide

INTRODUCTION: The androgen receptor (AR) is widely expressed in breast cancers and has been proposed as a therapeutic target in estrogen receptor alpha (ER) negative breast cancers that retain AR. However, controversy exists regarding the role of AR, particularly in ER + tumors. Enzalutamide, an AR inhibitor that impairs nuclear localization of AR, was used to elucidate the role of AR in preclinical models of ER positive and negative breast cancer. METHODS: We examined nuclear AR to ER protein ratios in primary breast cancers in relation to response to endocrine therapy. The effects of AR inhibition with enzalutamide were examined in vitro and in preclinical models of ER positive and negative breast cancer that express AR. RESULTS: In a cohort of 192 women with ER + breast cancers, a high ratio of AR:ER (≥2.0) indicated an over four fold increased risk for failure while on tamoxifen (HR = 4.43). The AR:ER ratio had an independent effect on risk for failure above ER % staining alone. AR:ER ratio is also an independent predictor of disease-free survival (HR = 4.04, 95% CI: 1.68, 9.69; p = 0.002) and disease specific survival (HR = 2.75, 95% CI: 1.11, 6.86; p = 0.03). Both enzalutamide and bicalutamide inhibited 5-alpha-dihydrotestosterone (DHT)-mediated proliferation of breast cancer lines in vitro; however, enzalutamide uniquely inhibited estradiol (E2)-mediated proliferation of ER+/AR + breast cancer cells. In MCF7 xenografts (ER+/AR+) enzalutamide inhibited E2-driven tumor growth as effectively as tamoxifen by decreasing proliferation. Enzalutamide also inhibited DHT- driven tumor growth in both ER positive (MCF7) and negative (MDA-MB-453) xenografts, but did so by increasing apoptosis. CONCLUSIONS: AR to ER ratio may influence breast cancer response to traditional endocrine therapy. Enzalutamide elicits different effects on E2-mediated breast cancer cell proliferation than bicalutamide. This preclinical study supports the initiation of clinical studies evaluating enzalutamide for treatment of AR(+) tumors regardless of ER status, since it blocks both androgen- and estrogen- mediated tumor growth

Climate change adaptation and cross-sectoral policy coherence in southern Africa

To be effective, climate change adaptation needs to be mainstreamed across multiple sectors and greater policy coherence is essential. Using the cases of Malawi, Tanzania and Zambia, this paper investigates the extent of coherence in national policies across the water and agriculture sectors and to climate change adaptation goals outlined in national development plans. A two-pronged qualitative approach is applied using Qualitative Document Analysis of relevant policies and plans, combined with expert interviews from non-government actors in each country. Findings show that sector policies have differing degrees of coherence on climate change adaptation, currently being strongest in Zambia and weakest in Tanzania. We also identify that sectoral policies remain more coherent in addressing immediate-term disaster management issues of floods and droughts rather than longer-term strategies for climate adaptation. Coherence between sector and climate policies and strategies is strongest when the latter has been more recently developed. However to date, this has largely been achieved by repackaging of existing sectoral policy statements into climate policies drafted by external consultants to meet international reporting needs and not by the establishment of new connections between national sectoral planning processes. For more effective mainstreaming of climate change adaptation, governments need to actively embrace longer-term cross-sectoral planning through cross-Ministerial structures, such as initiated through Zambia’s Interim Climate Change Secretariat, to foster greater policy coherence and integrated adaptation planning

Neural processing of criticism and positive comments from relatives in individuals with schizotypal personality traits

Objectives. High negative expressed emotion by family members towards schizophrenia patients increases the risk of subsequent relapse. The study aimed to determine whether individuals with high schizotypy (HS) and low schizotypy (LS) would differ in activation of brain areas involved in cognitive control when listening to relative criticism

Neonatal head and torso vibration exposure during inter-hospital transfer

Inter-hospital transport of premature infants is increasingly common, given the centralisation of neonatal intensive care. However, it is known to be associated with anomalously increased morbidity, most notably brain injury, and with increased mortality from multifactorial causes. Surprisingly, there have been relatively few previous studies investigating the levels of mechanical shock and vibration hazard present during this vehicular transport pathway. Using a custom inertial datalogger, and analysis software, we quantify vibration and linear head acceleration. Mounting multiple inertial sensing units on the forehead and torso of neonatal patients and a preterm manikin, and on the chassis of transport incubators over the duration of inter-site transfers, we find that the resonant frequency of the mattress and harness system currently used to secure neonates inside incubators is ~9Hz. This couples to vehicle chassis vibration, increasing vibration exposure to the neonate. The vibration exposure per journey (A(8) using the ISO 2631 standard) was at least 20% of the action point value of current European Union regulations over all 12 neonatal transports studied, reaching 70% in two cases. Direct injury risk from linear head acceleration (HIC15) was negligible. Although the overall hazard was similar, vibration isolation differed substantially between sponge and air mattresses, with a manikin. Using a Global Positioning System datalogger alongside inertial sensors, vibration increased with vehicle speed only above 60 km/h. These preliminary findings suggest there is scope to engineer better systems for transferring sick infants, thus potentially improving their outcomes

Design Principles for Ligand-Sensing, Conformation-Switching Ribozymes

Nucleic acid sensor elements are proving increasingly useful in biotechnology and biomedical applications. A number of ligand-sensing, conformational-switching ribozymes (also known as allosteric ribozymes or aptazymes) have been generated by some combination of directed evolution or rational design. Such sensor elements typically fuse a molecular recognition domain (aptamer) with a catalytic signal generator (ribozyme). Although the rational design of aptazymes has begun to be explored, the relationships between the thermodynamics of aptazyme conformational changes and aptazyme performance in vitro and in vivo have not been examined in a quantitative framework. We have therefore developed a quantitative and predictive model for aptazymes as biosensors in vitro and as riboswitches in vivo. In the process, we have identified key relationships (or dimensionless parameters) that dictate aptazyme performance, and in consequence, established equations for precisely engineering aptazyme function. In particular, our analysis quantifies the intrinsic trade-off between ligand sensitivity and the dynamic range of activity. We were also able to determine how in vivo parameters, such as mRNA degradation rates, impact the design and function of aptazymes when used as riboswitches. Using this theoretical framework we were able to achieve quantitative agreement between our models and published data. In consequence, we are able to suggest experimental guidelines for quantitatively predicting the performance of aptazyme-based riboswitches. By identifying factors that limit the performance of previously published systems we were able to generate immediately testable hypotheses for their improvement. The robust theoretical framework and identified optimization parameters should now enable the precision design of aptazymes for biotechnological and clinical applications