The value of source data verification in a cancer clinical trial

Background Source data verification (SDV) is a resource intensive method of quality assurance frequently used in clinical trials. There is no empirical evidence to suggest that SDV would impact on comparative treatment effect results from a clinical trial. Methods Data discrepancies and comparative treatment effects obtained following 100% SDV were compared to those based on data without SDV. Overall survival (OS) and Progression-free survival (PFS) were compared using Kaplan-Meier curves, log-rank tests and Cox models. Tumour response classifications and comparative treatment Odds Ratios (ORs) for the outcome objective response rate, and number of Serious Adverse Events (SAEs) were compared. OS estimates based on SDV data were compared against estimates obtained from centrally monitored data. Findings Data discrepancies were identified between different monitoring procedures for the majority of variables examined, with some variation in discrepancy rates. There were no systematic patterns to discrepancies and their impact was negligible on OS, the primary outcome of the trial (HR (95% CI): 1.18(0.99 to 1.41), p = 0.064 with 100% SDV; 1.18(0.99 to 1.42), p = 0.068 without SDV; 1.18(0.99 to 1.40), p = 0.073 with central monitoring). Results were similar for PFS. More extreme discrepancies were found for the subjective outcome overall objective response (OR (95% CI): 1.67(1.04 to 2.68), p = 0.03 with 100% SDV; 2.45(1.49 to 4.04), p = 0.0003 without any SDV) which was mostly due to differing CT scans. Interpretation Quality assurance methods used in clinical trials should be informed by empirical evidence. In this empirical comparison, SDV was expensive and identified random errors that made little impact on results and clinical conclusions of the trial. Central monitoring using an external data source was a more efficient approach for the primary outcome of OS. For the subjective outcome objective response, an independent blinded review committee and tracking system to monitor missing scan data could be more efficient than SDV

Quaternary structure of a G-protein coupled receptor heterotetramer in complex with Gi and Gs

Background: G-protein-coupled receptors (GPCRs), in the form of monomers or homodimers that bind heterotrimeric G proteins, are fundamental in the transfer of extracellular stimuli to intracellular signaling pathways. Different GPCRs may also interact to form heteromers that are novel signaling units. Despite the exponential growth in the number of solved GPCR crystal structures, the structural properties of heteromers remain unknown. Results: We used single-particle tracking experiments in cells expressing functional adenosine A1-A2A receptors fused to fluorescent proteins to show the loss of Brownian movement of the A1 receptor in the presence of the A2A receptor, and a preponderance of cell surface 2:2 receptor heteromers (dimer of dimers). Using computer modeling, aided by bioluminescence resonance energy transfer assays to monitor receptor homomerization and heteromerization and G-protein coupling, we predict the interacting interfaces and propose a quaternary structure of the GPCR tetramer in complex with two G proteins. Conclusions: The combination of results points to a molecular architecture formed by a rhombus-shaped heterotetramer, which is bound to two different interacting heterotrimeric G proteins (Gi and Gs). These novel results constitute an important advance in understanding the molecular intricacies involved in GPCR function

Compensatory ingestion upon dietary restriction in Drosophila melanogaster

Dietary restriction extends the lifespan of numerous, evolutionarily diverse species. In D. melanogaster, a prominent model for research on the interaction between nutrition and longevity, dietary restriction is typically based on medium dilution, with possible compensatory ingestion commonly being neglected. Possible problems with this approach are revealed by using a method for direct monitoring of D. melanogaster feeding behavior. This demonstrates that dietary restriction elicits robust compensatory changes in food consumption. As a result, the effect of medium dilution is overestimated and, in certain cases, even fully compensated for. Our results strongly indicate that feeding behavior and nutritional composition act concertedly to determine fly lifespan. Feeding behavior thus emerges as a central element in D. melanogaster aging

The JCMT Transient Survey: Identifying Submillimeter Continuum Variability over Several Year Timescales Using Archival JCMT Gould Belt Survey Observations

This is the final version of the article. Available from American Astronomical Society via the DOI in this record.Investigating variability at the earliest stages of low-mass star formation is fundamental in understanding how a protostar assembles mass. While many simulations of protostellar disks predict non-steady accretion onto protostars, deeper investigation requires robust observational constraints on the frequency and amplitude of variability events characterized across the observable SED. In this study, we develop methods to robustly analyze repeated observations of an area of the sky for submillimeter variability in order to determine constraints on the magnitude and frequency of deeply embedded protostars. We compare 850 μm JCMT Transient Survey data with archival JCMT Gould Belt Survey data to investigate variability over 2–4 year timescales. Out of 175 bright, independent emission sources identified in the overlapping fields, we find seven variable candidates, five of which we classify as Strong, and the remaining two we classify as Extended to indicate that the latter are associated with larger-scale structure. For the Strong variable candidates, we find an average fractional peak brightness change per year of $| 4.0| \% \,{\mathrm{yr}}^{-1}$, with a standard deviation of $2.7 \% \,{\mathrm{yr}}^{-1}$. In total, 7% of the protostars associated with 850 μm emission in our sample show signs of variability. Four of the five Strong sources are associated with a known protostar. The remaining source is a good follow-up target for an object that is anticipated to contain an enshrouded, deeply embedded protostar. In addition, we estimate the 850 μm periodicity of the submillimeter variable source, EC 53, to be 567 ± 32 days, based on the archival Gould Belt Survey data.Steve Mairs was partially supported by the Natural Sciences and Engineering Research Council (NSERC) of Canada graduate scholarship program. Doug Johnstone is supported by the National Research Council of Canada and by an NSERC Discovery Grant. Gregory Herczeg is supported by general grant 11473005 awarded by the National Science Foundation of China. Andy Pon received partial salary support from a Canadian Institute for Theoretical Astrophysics (CITA) National Fellowship. Miju Kang was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT, & Future Planning (No. NRF-2015R1C1A1A01052160). J.-E. Lee was supported by the Basic Science Research Program through the National Research Foundation of Korea (grant No. NRF-2015R1A2A2A01004769) and the Korea Astronomy and Space Science Institute under the R&D program (Project No. 2015-1-320-18) supervised by the Ministry of Science and ICT. The authors wish to recognize and acknowledge the very significant cultural role and reverence that the summit of Maunakea has always had within the indigenous Hawaiian community. We are most fortunate to have the opportunity to conduct observations from this mountain. The James Clerk Maxwell Telescope is operated by the East Asian Observatory on behalf of the National Astronomical Observatory of Japan, Academia Sinica Institute of Astronomy and Astrophysics, the Korea Astronomy and Space Science Institute, the National Astronomical Observatories of China, and the Chinese Academy of Sciences (Grant No. XDB09000000), with additional funding support from the Science and Technology Facilities Council of the United Kingdom and participating universities in the United Kingdom and Canada. The James Clerk Maxwell Telescope has historically been operated by the Joint Astronomy Centre on behalf of the Science and Technology Facilities Council of the United Kingdom, the National Research Council of Canada, and the Netherlands Organisation for Scientific Research. Additional funds for the construction of SCUBA-2 were provided by the Canada Foundation for Innovation. The identification number for the JCMT Transient Survey data used in this paper is M16AL001. The identification numbers for the archival Gould Belt Survey data used in this paper are MJLSG31, MJLSG32, MJLSG33, MJLSG38, and MJLSG41. The authors thank the JCMT staff for their support of the data collection and reduction efforts. This research has made use of NASA's Astrophysics Data System and the facilities of the Canadian Astronomy Data Centre operated by the National Research Council of Canada, with the support of the Canadian Space Agency. The authors would especially like to thank Chang Won Lee and Harriet Parsons for their useful insights and suggestions, along with the extended JCMT Transient Team21 for their support. This research used the services of the Canadian Advanced Network for Astronomy Research (CANFAR), which in turn is supported by CANARIE, Compute Canada, University of Victoria, the National Research Council of Canada, and the Canadian Space Agency. This research made use of APLpy, an open-source plotting package for Python hosted at http://aplpy.github.com, and matplotlib, a 2D plotting library for Python (Hunter 2007)

The JCMT Transient Survey: Stochastic and Secular Variability of Protostars and Disks In the Submillimeter Region Observed over 18 Months

This is the final version of the article. Available from American Astronomical Society via the DOI in this record.We analyze results from the first 18 months of monthly submillimeter monitoring of eight star-forming regions in the JCMT Transient Survey. In our search for stochastic variability in 1643 bright peaks, only the previously identified source, EC 53, shows behavior well above the expected measurement uncertainty. Another four sources—two disks and two protostars—show moderately enhanced standard deviations in brightness, as expected for stochastic variables. For the two protostars, this apparent variability is the result of single epochs that are much brighter than the mean. In our search for secular brightness variations that are linear in time, we measure the fractional brightness change per year for 150 bright peaks, 50 of which are protostellar. The ensemble distribution of slopes is well fit by a normal distribution with σ ~ 0.023. Most sources are not rapidly brightening or fading at submillimeter wavelengths. Comparison against time-randomized realizations shows that the width of the distribution is dominated by the uncertainty in the individual brightness measurements of the sources. A toy model for secular variability reveals that an underlying Gaussian distribution of linear fractional brightness change σ = 0.005 would be unobservable in the present sample, whereas an underlying distribution with σ = 0.02 is ruled out. Five protostellar sources, 10% of the protostellar sample, are found to have robust secular measures deviating from a constant flux. The sensitivity to secular brightness variations will improve significantly with a sample over a longer time duration, with an improvement by factor of two expected by the conclusion of our 36 month survey.The JCMT is operated by the East Asian Observatory on behalf of The National Astronomical Observatory of Japan, Academia Sinica Institute of Astronomy and Astrophysics, the Korea Astronomy and Space Science Institute, the National Astronomical Observatories of China and the Chinese Academy of Sciences (Grant No. XDB09000000), with additional funding support from the Science and Technology Facilities Council of the United Kingdom and participating universities in the United Kingdom and Canada. The identification number for the JCMT Transient Survey under which the SCUBA-2 data used in this paper can be found is M16AL001. The authors thank the JCMT staff for their support of the GBS team in data collection and reduction efforts. The Starlink software (Currie et al. 2014) is supported by the East Asian Observatory. This research has made use of NASA's Astrophysics Data System and the facilities of the Canadian Astronomy Data Centre operated by the National Research Council of Canada with the support of the Canadian Space Agency. This research used the services of the Canadian Advanced Network for Astronomy Research (CANFAR), which in turn is supported by CANARIE, Compute Canada, University of Victoria, the National Research Council of Canada, and the Canadian Space Agency

Anaerobic utilization of pectinous substrates at extremely haloalkaline conditions by Natranaerovirga pectinivora gen. nov., sp. nov., and Natranaerovirga hydrolytica sp. nov., isolated from hypersaline soda lakes

Anaerobic enrichments at pH 10, with pectin and polygalacturonates as substrates and inoculated with samples of sediments of hypersaline soda lakes from the Kulunda Steppe (Altai, Russia) demonstrated the potential for microbial pectin degradation up to soda-saturating conditions. The enrichments resulted in the isolation of six strains of obligately anaerobic fermentative bacteria, which represented a novel deep lineage within the order Clostridiales loosely associated with the family Lachnospiraceae. The isolates were rod-shaped and formed terminal round endospores. One of the striking features of the novel group is a very narrow substrate spectrum for growth, restricted to galacturonic acid and its polymers (e.g. pectin). Acetate and formate were the final fermentation products. Growth was possible in a pH range from 8 to 10.5, with an optimum at pH 9.5–10, and in a salinity range from 0.2 to 3.5 M Na+. On the basis of unique phenotypic properties and distinct phylogeny, the pectinolytic isolates are proposed to be assigned to a new genus Natranaerovirga with two species N. hydrolytica (APP2T=DSM24176T=UNIQEM U806T) and N. pectinivora (AP3T=DSM24629T=UNIQEM U805T)

What we talk about when we talk about "global mindset": managerial cognition in multinational corporations

Recent developments in the global economy and in multinational corporations have placed significant emphasis on the cognitive orientations of managers, giving rise to a number of concepts such as “global mindset” that are presumed to be associated with the effective management of multinational corporations (MNCs). This paper reviews the literature on global mindset and clarifies some of the conceptual confusion surrounding the construct. We identify common themes across writers, suggesting that the majority of studies fall into one of three research perspectives: cultural, strategic, and multidimensional. We also identify two constructs from the social sciences that underlie the perspectives found in the literature: cosmopolitanism and cognitive complexity and use these two constructs to develop an integrative theoretical framework of global mindset. We then provide a critical assessment of the field of global mindset and suggest directions for future theoretical and empirical research

Categorial Compositionality: A Category Theory Explanation for the Systematicity of Human Cognition

Classical and Connectionist theories of cognitive architecture seek to explain systematicity (i.e., the property of human cognition whereby cognitive capacity comes in groups of related behaviours) as a consequence of syntactically and functionally compositional representations, respectively. However, both theories depend on ad hoc assumptions to exclude specific instances of these forms of compositionality (e.g. grammars, networks) that do not account for systematicity. By analogy with the Ptolemaic (i.e. geocentric) theory of planetary motion, although either theory can be made to be consistent with the data, both nonetheless fail to fully explain it. Category theory, a branch of mathematics, provides an alternative explanation based on the formal concept of adjunction, which relates a pair of structure-preserving maps, called functors. A functor generalizes the notion of a map between representational states to include a map between state transformations (or processes). In a formal sense, systematicity is a necessary consequence of a higher-order theory of cognitive architecture, in contrast to the first-order theories derived from Classicism or Connectionism. Category theory offers a re-conceptualization for cognitive science, analogous to the one that Copernicus provided for astronomy, where representational states are no longer the center of the cognitive universe—replaced by the relationships between the maps that transform them

Changes in Inflammatory Biomarkers Across Weight Classes in a Representative US Population: A Link Between Obesity and Inflammation

Obesity has been linked with a chronic state of inflammation which may be involved in the development of metabolic syndrome, cardiovascular disease, non-alcoholic steatohepatitis, and even cancer. The objective of this study was to examine the association between obesity class and levels of inflammatory biomarkers from men and women who participated in the 1999–2004 National Health and Nutrition Examination Survey (NHANES). Serum concentrations of C-reactive protein (CRP) and fibrinogen were measured among US participants of the 1999–2004 NHANES. We examined biomarker levels across different weight classes with normal weight, overweight, and obesity classes 1, 2, and 3 were defined as BMI of <25.0, 25.0–29.9, 30.0–34.9, 35.0–39.9, and ≥40.0, respectively. With CRP levels for normal weight individuals as a reference, CRP levels nearly doubled with each increase in weight class: +0.11 mg/dl (95% CI, 0.06–0.16) for overweight, +0.21 mg/dl (95% CI, 0.16–0.27) for obesity class 1, +0.43 mg/dl (95% CI, 0.26–0.61) for obesity class 2, and +0.73 mg/dl (95% CI, 0.55–0.90) for obesity class 3. With normal weight individuals as a reference, fibrinogen levels increase with increasing weight class and were highest for obesity class 3 individuals, +93.5 mg/dl (95% CI, 72.9–114.1). Individuals with hypertension or diabetes have higher levels of CRP and fibrinogen levels compared to individuals without hypertension or diabetes, even when stratified according to BMI. There is a direct association between increasing obesity class and the presence of obesity-related comorbidities such as diabetes and hypertension with high levels of inflammatory biomarkers