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

The Late Quaternary tephrostratigraphy of annually laminated sediments from Meerfelder Maar, Germany

© 2015 Elsevier Ltd.The record of Late Quaternary environmental change within the sediments of Meerfelder Maar in the Eifel region of Germany is renowned for its high precision chronology, which is annually laminated throughout the Last Glacial to Interglacial transition (LGIT) and most of the Holocene. Two visible tephra layers are prominent within the floating varve chronology of Meerfelder Maar. An Early Holocene tephra layer, the Ulmener Maar Tephra (~11,000 varve years BP), provides a tie-line of the Meerfelder Maar record to the varved Holocene record of nearby Lake Holzmaar. The Laacher See Tephra provides another prominent time marker for the late Allerød, ~200 varve years before the transition into the Younger Dryas at 12,680 varve years BP. Further investigation has now shown that there are also 15 cryptotephra layers within the Meerfelder Maar LGIT-Holocene stratigraphy and these layers hold the potential to make direct comparisons between the Meerfelder Maar record and other palaeoenvironmental archives from across Europe and the North Atlantic. Most notable is the presence of the Vedde Ash, the most widespread Icelandic eruption known from the Late Quaternary, which occurred midway through the Younger Dryas. The Vedde Ash has also been found in the Greenland ice cores and can be used as an isochron around which the GICC05 and Meerfelder Maar annual chronologies can be compared. Near the base of the annual laminations in Meerfelder Maar a cryptotephra is found that correlates to the Neapolitan Yellow Tuff, erupted from Campi Flegrei in southern Italy, 1200km away. This is the furthest north that the Neapolitan Yellow Tuff has been found, highlighting its importance in the construction of a European-wide tephrostratigraphic framework. The co-location of cryptotephra layers from Italian, Icelandic and Eifel volcanic sources, within such a precise chronological record, makes Meerfelder Maar one of the most important tephrostratotype records for continental Europe during the Last Glacial to Interglacial transition

Folding model analysis of elastic and inelastic proton scattering on Sulfur isotopes

The folding formalism for the nucleon-nucleus optical potential and inelastic form factor is applied to study elastic and inelastic proton scattering on 30-40S isotopes. A recently developed realistic density dependent M3Y interaction, well tested in the folding analysis of nucleus-nucleus elastic and inelastic scattering, is used as effective NN interaction. The nuclear ground state and transition densities (for the 2+ excitations in Sulfur isotopes) are obtained in the Hartree-Fock-BCS and QRPA approaches, respectively. The best fit ratios of transition moments Mn/Mp for the lowest 2+ states in Sulfur isotopes are compared to those obtained earlier in the DWBA analysis of the same data using the same structure model and inelastic form factors obtained with the JLM effective interaction. Our folding+DWBA analysis has shown quite a strong isovector mixing in the elastic and inelastic scattering channels for the neutron rich 38,40S nuclei. In particular, the relative strength of the isovector part of the transition potential required by the inelastic p+38S data is significantly stronger than that obtained with the corresponding QRPA transition density.Comment: 24 pages, 11 figures, accepted for publication in Nucl. Phys.

Knowledge integration in One Health policy formulation, implementation and evaluation

The One Health concept covers the interrelationship between human, animal and environmental health and requires multistakeholder collaboration across many cultural, disciplinary, institutional and sectoral boundaries. Yet, the implementation of the One Health approach appears hampered by shortcomings in the global framework for health governance. Knowledge integration approaches, at all stages of policy development, could help to address these shortcomings. The identification of key objectives, the resolving of trade-offs and the creation of a common vision and a common direction can be supported by multicriteria analyses. Evidence-based decision-making and transformation of observations into narratives detailing how situations emerge and might unfold in the future can be achieved by systems thinking. Finally, transdisciplinary approaches can be used both to improve the effectiveness of existing systems and to develop novel networks for collective action. To strengthen One Health governance, we propose that knowledge integration becomes a key feature of all stages in the development of related policies. We suggest several ways in which such integration could be promoted

Bounded and unitary elements in pro-C^*-algebras

A pro-C^*-algebra is a (projective) limit of C^*-algebras in the category of topological *-algebras. From the perspective of non-commutative geometry, pro-C^*-algebras can be seen as non-commutative k-spaces. An element of a pro-C^*-algebra is bounded if there is a uniform bound for the norm of its images under any continuous *-homomorphism into a C^*-algebra. The *-subalgebra consisting of the bounded elements turns out to be a C^*-algebra. In this paper, we investigate pro-C^*-algebras from a categorical point of view. We study the functor (-)_b that assigns to a pro-C^*-algebra the C^*-algebra of its bounded elements, which is the dual of the Stone-\v{C}ech-compactification. We show that (-)_b is a coreflector, and it preserves exact sequences. A generalization of the Gelfand-duality for commutative unital pro-C^*-algebras is also presented.Comment: v2 (accepted

Association between body-mass index and quality of split bowel preparation

BACKGROUND & AIMS: Little is known about the association between obesity and bowel preparation. We investigated whether body mass index (BMI) is an independent risk factor for inadequate bowel preparation in patients who receive split preparation regimens. METHODS: We performed a retrospective study of data from 2163 consecutive patients (mean age, 60.6 ± 10.5 y; 93.8% male) who received outpatient colonoscopies in 2009 at the Veterans Affairs Medical Center in Indianapolis, Indiana. All patients received a split preparation, categorized as adequate (excellent or good, based on the Aronchick scale) or inadequate. We performed a multivariable analysis to identify factors independently associated with inadequate preparation. RESULTS: Bowel preparation quality was inadequate for 44.2% of patients; these patients had significantly higher mean BMIs than patients with adequate preparation (31.2 ± 6.5 vs 29.8 ± 5.9, respectively; P < .0001) and Charlson comorbidity scores (1.5 ± 1.6 vs 1.1 ± 1.4; P < .0001). Independent risk factors for inadequate preparation were a BMI of 30 kg/m(2) or greater (odds ratio [OR], 1.46; 95% confidence interval [CI], 1.21-1.75; P < .0001), use of tobacco (OR, 1.28; 95% CI, 1.07-1.54; P = .0084) or narcotics (OR, 1.28; 95% CI, 1.04-1.57; P = .0179), hypertension (OR, 1.30; 95% CI, 1.07-1.57; P = .0085), diabetes (OR, 1.38; 95% CI, 1.12-1.69; P = .0021), and dementia (OR, 3.02; 95% CI, 1.22-7.49; P = .0169). CONCLUSIONS: BMI is an independent factor associated with inadequate split bowel preparation for colonoscopy. Additional factors associated with quality of bowel preparation include diabetes, hypertension, dementia, and use of tobacco and narcotics. Patients with BMIs of 30 kg/m(2) or greater should be considered for more intensive preparation regimens

Analysis of a quenched lattice-QCD dressed-quark propagator

Quenched lattice-QCD data on the dressed-quark Schwinger function can be correlated with dressed-gluon data via a rainbow gap equation so long as that equation's kernel possesses enhancement at infrared momenta above that exhibited by the gluon alone. The required enhancement can be ascribed to a dressing of the quark-gluon vertex. The solutions of the rainbow gap equation exhibit dynamical chiral symmetry breaking and are consistent with confinement. The gap equation and related, symmetry-preserving ladder Bethe-Salpeter equation yield estimates for chiral and physical pion observables that suggest these quantities are materially underestimated in the quenched theory: |<bar-q q>| by a factor of two and f_pi by 30%.Comment: 9 pages, LaTeX2e, REVTEX4, 6 figure

PGB pair production at LHC and ILC as a probe of the topcolor-assisted technicolor models

The topcolor-assisted technicolor (TC2) model predicts some light pseudo goldstone bosons (PGBs), which may be accessible at the LHC or ILC. In this work we study the pair productions of the charged or neutral PGBs at the LHC and ILC. For the productions at the LHC we consider the processes proceeding through gluon-gluon fusion and quark-antiquark annihilation, while for the productions at the ILC we consider both the electron-positron collision and the photon-photon collision. We find that in a large part of parameter space the production cross sections at both colliders can be quite large compared with the low standard model backgrounds. Therefore, in future experiments these productions may be detectable and allow for probing TC2 model.Comment: 26 pages, 16 figures. slight changes in the text; notations for curves changed; references adde

Defending the genome from the enemy within:mechanisms of retrotransposon suppression in the mouse germline

The viability of any species requires that the genome is kept stable as it is transmitted from generation to generation by the germ cells. One of the challenges to transgenerational genome stability is the potential mutagenic activity of transposable genetic elements, particularly retrotransposons. There are many different types of retrotransposon in mammalian genomes, and these target different points in germline development to amplify and integrate into new genomic locations. Germ cells, and their pluripotent developmental precursors, have evolved a variety of genome defence mechanisms that suppress retrotransposon activity and maintain genome stability across the generations. Here, we review recent advances in understanding how retrotransposon activity is suppressed in the mammalian germline, how genes involved in germline genome defence mechanisms are regulated, and the consequences of mutating these genome defence genes for the developing germline

Syrosingopine sensitizes cancer cells to killing by metformin

We report that the anticancer activity of the widely used diabetic drug metformin is strongly potentiated by syrosingopine. Synthetic lethality elicited by combining the two drugs is synergistic and specific to transformed cells. This effect is unrelated to syrosingopine's known role as an inhibitor of the vesicular monoamine transporters. Syrosingopine binds to the glycolytic enzyme α-enolase in vitro, and the expression of the γ-enolase isoform correlates with nonresponsiveness to the drug combination. Syrosingopine sensitized cancer cells to metformin and its more potent derivative phenformin far below the individual toxic threshold of each compound. Thus, combining syrosingopine and codrugs is a promising therapeutic strategy for clinical application for the treatment of cancer