Transactional Memory in a Dynamic Language

Concurrency control is mostly based on locks and is therefore notoriously difficult to use. Even though some programming languages provide high-level constructs, these add complexity and potentially hard-to-detect bugs to the application. Transactional memory is an attractive mechanism that does not have the drawbacks of locks, however the underlying implementation is often difficult to integrate into an existing language. In this paper we show how we have introduced transactional semantics into Smalltalk by using the reflective facilities of the language. Our approach is based on method annotations, incremental parse tree transformations and an optimistic commit protocol. The implementation does not depend on modifications to the virtual machine and therefore can be changed at the language level. We report on a practical case study, benchmarks and further and on-going work.

Combining follow-up and change data is valid in meta-analyses of continuous outcomes: a meta-epidemiological study

OBJECTIVE To investigate whether it is valid to combine follow-up and change data when conducting meta-analyses of continuous outcomes. STUDY DESIGN AND SETTING Meta-epidemiological study of randomized controlled trials in patients with osteoarthritis of the knee/hip, which assessed patient-reported pain. We calculated standardized mean differences (SMDs) based on follow-up and change data, and pooled within-trial differences in SMDs. We also derived pooled SMDs indicating the largest treatment effect within a trial (optimistic selection of SMDs) and derived pooled SMDs from the estimate indicating the smallest treatment effect within a trial (pessimistic selection of SMDs). RESULTS A total of 21 meta-analyses with 189 trials with 292 randomized comparisons in 41,256 patients were included. On average, SMDs were 0.04 standard deviation units more beneficial when follow-up values were used (difference in SMDs: -0.04; 95% confidence interval: -0.13, 0.06; P=0.44). In 13 meta-analyses (62%), there was a relevant difference in clinical and/or significance level between optimistic and pessimistic pooled SMDs. CONCLUSION On average, there is no relevant difference between follow-up and change data SMDs, and combining these estimates in meta-analysis is generally valid. Decision on which type of data to use when both follow-up and change data are available should be prespecified in the meta-analysis protocol.

Testing for Measurement Equivalence in Surveys: Dimensions of Social Trust across Cultural Contexts

Our study evaluates the dimensionality and equivalence of social trust across cultural contexts, using new data from Switzerland and the World Values Survey 2005–2008. Whereas some scholars assert that trust should be regarded as a coherent concept, others claim that trust is better conceived of as a multidimensional concept. In contrast to the conventional dichotomy of the forms of social trust, we identify three distinct forms of trust, namely, particularized, generalized, and identity-based trust. Moreover, we dispute the view that respondents understand the wording of survey questions regarding social trust differently between different cultural contexts, which would imply that comparative research on trust is a pointless endeavor. Applying multiple-group confirmatory factor analysis to the various constructs of social trust, we conclude that one may study relationships among the three forms of trust and other theoretical constructs as well as compare latent means across cultural contexts. Our analyses therefore provide an optimistic outlook for future comparative analyses that investigate forms of social trust across cultural contexts.

Robust meta-analytic-predictive priors in clinical trials with historical control information.

Historical information is always relevant for clinical trial design. Additionally, if incorporated in the analysis of a new trial, historical data allow to reduce the number of subjects. This decreases costs and trial duration, facilitates recruitment, and may be more ethical. Yet, under prior-data conflict, a too optimistic use of historical data may be inappropriate. We address this challenge by deriving a Bayesian meta-analytic-predictive prior from historical data, which is then combined with the new data. This prospective approach is equivalent to a meta-analytic-combined analysis of historical and new data if parameters are exchangeable across trials. The prospective Bayesian version requires a good approximation of the meta-analytic-predictive prior, which is not available analytically. We propose two- or three-component mixtures of standard priors, which allow for good approximations and, for the one-parameter exponential family, straightforward posterior calculations. Moreover, since one of the mixture components is usually vague, mixture priors will often be heavy-tailed and therefore robust. Further robustness and a more rapid reaction to prior-data conflicts can be achieved by adding an extra weakly-informative mixture component. Use of historical prior information is particularly attractive for adaptive trials, as the randomization ratio can then be changed in case of prior-data conflict. Both frequentist operating characteristics and posterior summaries for various data scenarios show that these designs have desirable properties. We illustrate the methodology for a phase II proof-of-concept trial with historical controls from four studies. Robust meta-analytic-predictive priors alleviate prior-data conflicts ' they should encourage better and more frequent use of historical data in clinical trials.

Comprehensive validation of published immunohistochemical prognostic biomarkers of prostate cancer-what has gone wrong? A blueprint for the way forward in biomarker studies

BACKGROUND Treatment planning of localised prostate cancer remains challenging. Besides conventional parameters, a wealth of prognostic biomarkers has been proposed so far. None of which, however, have successfully been implemented in a routine setting so far. The aim of our study was to systematically verify a set of published prognostic markers for prostate cancer. METHODS Following an in-depth PubMed search, 28 markers were selected that have been proposed as multivariate prognostic markers for primary prostate cancer. Their prognostic validity was examined in a radical prostatectomy cohort of 238 patients with a median follow-up of 60 months and biochemical progression as endpoint of the analysis. Immunohistochemical evaluation was performed using previously published cut-off values, but allowing for optimisation if necessary. Univariate and multivariate Cox regression were used to determine the prognostic value of biomarkers included in this study. RESULTS Despite the application of various cut-offs in the analysis, only four (14%) markers were verified as independently prognostic (AKT1, stromal AR, EZH2, and PSMA) for PSA relapse following radical prostatectomy. CONCLUSIONS Apparently, many immunohistochemistry-based studies on prognostic markers seem to be over-optimistic. Codes of best practice, such as the REMARK guidelines, may facilitate the performance of conclusive and transparent future studies.

What are the metacognitive costs of young children's overconfidence?

Children typically hold very optimistic views of their own skills but so far, only a few studies have investigated possible correlates of the ability to predict performance accurately. Therefore, this study examined the role of individual differences in performance estimation accuracy as a global metacognitive index for different monitoring and control skills (item-level judgments of learning [JOLs] and confidence judgments [CJs]), metacognitive control processes (allocation of study time and control of answers), and executive functions (cognitive flexibility, inhibition, working memory) in 6-year-olds (N=93). The three groups of under estimators, realists and over estimators differed significantly in their monitoring and control abilities: the under estimators outperformed the over estimators by showing a higher discrimination in CJs between correct and incorrect recognition. Also, the under estimators scored higher on the adequate control of incorrectly recognized items. Regarding the interplay of monitoring and control processes, under estimators spent more time studying items with low JOLs, and relied more systematically on their monitoring when controlling their recognition compared to over estimators. At the same time, the three groups did not differ significantly from each other in their executive functions. Overall, results indicate that differences in performance estimation accuracy are systematically related to other global and item-level metacognitive monitoring and control abilities in children as young as six years of age, while no meaningful association between performance estimation accuracy and executive functions was found.

Intervertebral Disc Repair using Fleece-Membrane Composite Silk Material and Genipin-enhanced Fibrin Hydrogel

Introduction: Treating low back pain (LBP) has become an increasing challenge, as it is one of the main factors causing pain and is accompanied by high costs for the individual and the society. LBP can be caused by trauma of the intervertebral disc (IVD) or IVD degeneration. In the case of disc herniation the inner gelatinous part of the IVD, called nucleus pulposus, is pressed through the fibrous, annulus fibrosus that forms the outer part of the IVD. Today’s gold standard for treatment is extensive surgery as removal of the IVD and fusion of the vertebrae. In order to find a more gentle way to treat LBP and restore the native IVD we use a novel silk fleece-membrane composite from genetically modified silk worms whose silk contains a growth factor (GDF-6) that is associated with pushing stem cells towards a disc like phenotype (1). By combining it with a genipin-enhanced fibrin hydrogel we tested its suitability in organ culture on prior injured bovine IVD in our custom built two-degree of freedom bioreactor to mimic natural loading conditions. Material & Methods: Bovine IVDs of 12-17 months old animals were isolated by first removing all surrounding tissue followed by cutting out the IVDs as previously described (2). Culturing of discs occurred in high glucose Dulbecco's Modified Eagle Medium (HG-DMEM) supplemented with 5% serum as previously described (2). On the next day injury was induced using a 2mm biopsy punch (Polymed, Switzerland). The formed cavity was filled with (0.4%) genipin-enhanced human based fibrin hydrogel (35-55mg/mL human fibrinogen, Baxter, Austria) and sealed with a silk fleece-membrane composite (Spintec Engineering, Germany). Different culture conditions were applied: free swelling, static diurnal load of 0.2MPa for 8h/d and complex loading at 0.2MPa compression combined with ± 2° torsion at 0.2Hz for 8h/d (2). After 14 days of culture cell activity was determined with resazurin assay. Additionally, glycosaminoglycan (dimethyl-methylene blue), DNA (Hoechst) and collagen content (hydroxy- proline) were determined. Finally, real-time qPCR of major IVD marker and inflammation genes was performed to judge integrity of IVDs. Results: The fibrin hydrogel is able to keep the silk seal in place throughout the 14 days of in organ culture under all conditions. Additionally, cell activity showed optimistic results and we could not confirm negative effects of the repaired discs regarding overexpression of inflammation markers. Conclusions: The genipin-enhanced fibrin hydrogel in combination with the silk fleece- membrane composite seems to be a promising approach for IVD repair. Currently we assess the capability of GDF-6 incorporated in our silk composites on human mesenchymal stem cells and later on in organ culture. References 1. Clarke LE, McConnell JC, Sherratt MJ, Derby B, Richardson SM, Hoyland JA. Growth differentiation factor 6 and transforming growth factor-beta differentially mediate mesenchymal stem cell differentiation, composition and micromechanical properties of nucleus pulposus constructs. Arthritis Res Ther 2014, Mar 12;16(2):R67. 2. Chan SC, Gantenbein-Ritter B. Preparation of intact bovine tail intervertebral discs for organ culture. J Vis Exp 2012, Feb 2;60(60):e3490. Acknowledgements. This work is funded by the Gebert Rüf Foundation, project number GRS-028/13.

Using technology to enhance decision making

We focus here on decision making in the everyday clinical situation and do not address decision making in politics and administration, although obviously it affects clinical practice and vice versa. For example, decisions against providing sufficient face-to-face psychotherapy is one factor that may increase the demand for Internet therapy, and vice versa—that is, the use of technology for therapy, as in Internet therapy, might influence to what extent face-to-face therapy needs to be provided. It is obvious that the aggregation of information for political and administrative decisions can take advantage of technology. If technology is used professionally, this should contribute to better informed decisions and less dependency on information provided by lobbyists who might not work in the interest of high-quality service for those who need it. An optimistic view is thus that technology works in favor of patients on this level as well. In the interest of keeping the focus of this chapter manageable, we also do not address treatments fully delivered over the Internet or computers, as for the example described in Comer and Barlow (2014), although such treatments, as they unfold, of course also include decision making.

Effects of stereotypic behaviour and chronic mild stress on judgement bias in laboratory mice

Cognitive processes are influenced by underlying affective states, and tests of cognitive bias have recently been developed to assess the valence of affective states in animals. These tests are based on the fact that individuals in a negative affective state interpret ambiguous stimuli more pessimistically than individuals in a more positive state. Using two strains of mice we explored whether unpredictable chronic mild stress (UCMS) can induce a negative judgement bias and whether variation in the expression of stereotypic behaviour is associated with variation in judgement bias. Sixteen female CD-1 and 16 female C57BL/6 mice were trained on a tactile conditional discrimination test with grade of sandpaper as a cue for differential food rewards. Once they had learned the discrimination, half of the mice were subjected to UCMS for three weeks to induce a negative affective state. Although UCMS induced a reduced preference for the higher value reward in the judgement bias test, it did not affect saccharine preference or hypothalamic–pituitary–adrenal (HPA) activity. However, UCMS affected responses to ambiguous (intermediate) cues in the judgement bias test. While control mice showed a graded response to ambiguous cues, UCMS mice of both strains did not discriminate between ambiguous cues and tended to show shorter latencies to the ambiguous cues and the negative reference cue. UCMS also increased bar-mouthing in CD-1, but not in C57BL/6 mice. Furthermore, mice with higher levels of stereotypic behaviour made more optimistic choices in the judgement bias test. However, no such relationship was found for stereotypic bar-mouthing, highlighting the importance of investigating different types of stereotypic behaviour separately.

Should I Stay or Should I Go? Career Choice Intentions of Students with Family Business Background

Personal and motivational patterns of intentional founders have been researched in great depth; however, antecedents to career choices of intentional successors have been conspicuously missing in entrepreneurship research. By drawing on theory of planned behavior, we investigate how intentional founders, successors, and employees differ in terms of locus of control and entrepreneurial self-efficacy as well as independence and innovation motives. We find that transitive likelihood of career intent depends on degree of entrepreneurial self-efficacy and the independence motive. Unexpectedly, we see that high levels of internal locus of control lead to a preference of employment, which challenges traditional entrepreneurship research and suggests that the feasibility of an entrepreneurial career path does not automatically make it desirable. Our findings suggest that students with family business background are pessimistic about being in control in an entrepreneurial career, but optimistic about their efficacy to pursue an entrepreneurial career.