Duplicated network meta-analysis in advanced prostate cancer: a case study and recommendations for change

Background: Research overlap and duplication is a recognised problem in the context of both pairwise and network systematic reviews and meta-analyses. As a case study, we carried out a scoping review to identify and examine duplicated network meta-analyses (NMAs) in a specific disease setting where several novel therapies have recently emerged: hormone-sensitive metastatic prostate cancer (mHSPC). Methods: MEDLINE and EMBASE were systematically searched, in January 2020, for indirect or mixed treatment comparisons or network meta-analyses of the systemic treatments docetaxel and abiraterone acetate in the mHSPC setting, with a time-to-event outcome reported on the hazard-ratio scale. Eligibility decisions were made, and data extraction performed, by two independent reviewers. Results: A total of 13 eligible reviews were identified, analysing between 3 and 8 randomised comparisons, and comprising between 1773 and 7844 individual patients. Although the included trials and treatments showed a high degree of overlap, we observed considerable variation between identified reviews in terms of review aims, eligibility criteria and included data, statistical methodology, reporting and inference. Furthermore, crucial methodological details and specific source data were often unclear. Conclusions and recommendations: Variation across duplicated NMAs, together with reporting inadequacies, may compromise identification of best-performing treatments. Particularly in fast-moving fields, review authors should be aware of all relevant studies, and of other reviews with potential for overlap or duplication. We recommend that review protocols be published in advance, with greater clarity regarding the specific aims or scope of the project, and that reports include information on how the work builds upon existing knowledge. Source data and results should be clearly and completely presented to allow unbiased interpretation

Identifying inconsistency in network meta-analysis: Is the net heat plot a reliable method?

One of the biggest challenges for network meta-analysis is inconsistency, which occurs when the direct and indirect evidence conflict. Inconsistency causes problems for the estimation and interpretation of treatment effects and treatment contrasts. Krahn and colleagues proposed the net heat approach as a graphical tool for identifying and locating inconsistency within a network of randomized controlled trials. For networks with a treatment loop, the net heat plot displays statistics calculated by temporarily removing each design one at a time, in turn, and assessing the contribution of each remaining design to the inconsistency. The net heat plot takes the form of a matrix which is displayed graphically with coloring indicating the degree of inconsistency in the network. Applied to a network of individual participant data assessing overall survival in 7531 patients with lung cancer, we were surprised to find no evidence of important inconsistency from the net heat approach; this contradicted other approaches for assessing inconsistency such as the Bucher approach, Cochran's Q statistic, node-splitting, and the inconsistency parameter approach, which all suggested evidence of inconsistency within the network at the 5% level. Further theoretical work shows that the calculations underlying the net heat plot constitute an arbitrary weighting of the direct and indirect evidence which may be misleading. We illustrate this further using a simulation study and a network meta-analysis of 10 treatments for diabetes. We conclude that the net heat plot does not reliably signal inconsistency or identify designs that cause inconsistency

Possible scale invariant linear magnetoresistance in pyrochlore iridates Bi2Ir2O7

We report the observation of a linear magnetoresistance in single crystals and epitaxial thin films of the pyrochlore iridate Bi2Ir2O7. The linear magnetoresistance is positive and isotropic at low temperatures, without any sign of saturation up to 35 T. As temperature increases, the linear field dependence gradually evolves to a quadratic field dependence. The temperature and field dependence of magnetoresistance of Bi2Ir2O7 bears strikingly resemblance to the scale invariant magnetoresistance observed in the strange metal phase in high Tc cuprates. However, the residual resistivity of Bi2Ir2O7 is more than two orders of magnitude higher than the curpates. Our results suggest that the correlation between linear magnetoresistance and quantum fluctuations may exist beyond high temperature superconductors

What happens in the Lab: Applying Midstream Modulation to Enhance Critical Reflection in the Laboratory

In response to widespread policy prescriptions for responsible innovation, social scientists and engineering ethicists, among others, have sought to engage natural scientists and engineers at the ‘midstream’: building interdisciplinary collaborations to integrate social and ethical considerations with research and development processes. Two ‘laboratory engagement studies’ have explored how applying the framework of midstream modulation could enhance the reflections of natural scientists on the socio-ethical context of their work. The results of these interdisciplinary collaborations confirm the utility of midstream modulation in encouraging both first- and second-order reflective learning. The potential for second-order reflective learning, in which underlying value systems become the object of reflection, is particularly significant with respect to addressing social responsibility in research practices. Midstream modulation served to render the socio-ethical context of research visible in the laboratory and helped enable research participants to more critically reflect on this broader context. While lab-based collaborations would benefit from being carried out in concert with activities at institutional and policy levels, midstream modulation could prove a valuable asset in the toolbox of interdisciplinary methods aimed at responsible innovation

Principles of crystal growth of intermetallic and oxide compounds from molten solutions

We present a tutorial on the principles of crystal growth of intermetallic and oxide compounds from molten solutions, with an emphasis on the fundamental principles governing the underlying phase equilibria and phase diagrams of multicomponent systems.Comment: 43 pages, 24 figures; Philosophical Magazine, 201

Clinical biological and genetic heterogeneity of the inborn errors of pulmonary surfactant metabolism

Pulmonary surfactant is a multimolecular complex located at the air-water interface within the alveolus to which a range of physical (surface-active properties) and immune functions has been assigned. This complex consists of a surface-active lipid layer (consisting mainly of phospholipids), and of an aqueous subphase. From discrete surfactant sub-fractions one can isolate strongly hydrophobic surf acta nt proteins B (SP-B) and C (SP-C) as well as collectins SP-A and SP-D, which were shown to have specific structural, metabolic, or immune properties. Inborn or acquired abnormalities of the surfactant, qualitative or quantitative in nature, account for a number of human diseases. Beside hyaline membrane disease of the preterm neonate, a cluster of hereditary or acquired lung diseases has been characterized by periodic acid-Schiff-positive material filling the alveoli. From this heterogeneous nosologic group, at least two discrete entities presently emerge. The first is the SP-B deficiency, in which an essentially proteinaceous material is stored within the alveoli, and which represents an autosomal recessive Mendelian entity linked to the SFTPB gene (MIM 1786640). The disease usually generally entails neonatal respiratory distress with rapid fatal outcome, although partial or transient deficiencies have also been observed. The second is alveolar proteinosis, characterized by the storage of a mixed protein and lipid material, which constitutes a relatively heterogeneous clinical and biological syndrome, especially with regard to age at onset (from the neonate through to adulthood) as well as the severity of associated signs. Murine models, with a targeted mutation of the gene encoding granulocyte macrophage colony-stimulating factor (GM-CSF) (Csfgm) or the beta subunit of its receptor (II3rb1) support the hypothesis of an abnormality of surfactant turnover in which the alveolar macrophage is a key player. Apart from SP-B deficiency, in which a near-consensus diagnostic chart can be designed, the ascertainment of other abnormalities of surfactant metabolism is not straightforward. The disentanglement of this disease cluster is however essential to propose specific therapeutic procedures: repeated broncho-alveolar ravages, GM-CSF replacement, bone marrow grafting or lung transplantation

Momentum Dependence of the Nematic Order Parameter in Iron-Based Superconductors.

The momentum dependence of the nematic order parameter is an important ingredient in the microscopic description of iron-based high-temperature superconductors. While recent reports on FeSe indicate that the nematic order parameter changes sign between electron and hole bands, detailed knowledge is still missing for other compounds. Combining angle-resolved photoemission spectroscopy with uniaxial strain tuning, we measure the nematic band splitting in both FeSe and BaFe_{2}As_{2} without interference from either twinning or magnetic order. We find that the nematic order parameter exhibits the same momentum dependence in both compounds with a sign change between the Brillouin center and the corner. This suggests that the same microscopic mechanism drives the nematic order in spite of the very different phase diagrams

Sign-reversal of the in-plane resistivity anisotropy in hole-doped iron pnictides

The in-plane anisotropy of the electrical resistivity across the coupled orthorhombic and magnetic transitions of the iron pnictides has been extensively studied in the parent and electron-doped compounds. All these studies universally show that the resistivity $\rho_{a}$ across the long orthorhombic axis $a_{O}$ - along which the spins couple antiferromagnetically below the magnetic transition temperature - is smaller than the resistivity $\rho_{b}$ of the short orthorhombic axis $b_{O}$, i. e. $\rho_{a}<\rho_{b}$. Here we report that in the hole-doped compounds Ba$_{1-x}$K$_{x}$Fe$_{2}$As$_{2}$, as the doping level increases, the resistivity anisotropy initially becomes vanishingly small, and eventually changes sign for sufficiently large doping, i. e. $\rho_{b}<\rho_{a}$. This observation is in agreement with a recent theoretical prediction that considers the anisotropic scattering of electrons by spin-fluctuations in the orthorhombic/nematic state.Comment: This paper has been replaced by the new version offering new explanation of the experimental results first reported her

F-theory on Genus-One Fibrations

We argue that M-theory compactified on an arbitrary genus-one fibration, that is, an elliptic fibration which need not have a section, always has an F-theory limit when the area of the genus-one fiber approaches zero. Such genus-one fibrations can be easily constructed as toric hypersurfaces, and various $SU(5)\times U(1)^n$ and $E_6$ models are presented as examples. To each genus-one fibration one can associate a $\tau$-function on the base as well as an $SL(2,\mathbb{Z})$ representation which together define the IIB axio-dilaton and 7-brane content of the theory. The set of genus-one fibrations with the same $\tau$-function and $SL(2,\mathbb{Z})$ representation, known as the Tate-Shafarevich group, supplies an important degree of freedom in the corresponding F-theory model which has not been studied carefully until now. Six-dimensional anomaly cancellation as well as Witten's zero-mode count on wrapped branes both imply corrections to the usual F-theory dictionary for some of these models. In particular, neutral hypermultiplets which are localized at codimension-two fibers can arise. (All previous known examples of localized hypermultiplets were charged under the gauge group of the theory.) Finally, in the absence of a section some novel monodromies of Kodaira fibers are allowed which lead to new breaking patterns of non-Abelian gauge groups.Comment: 53 pages, 9 figures, 6 tables. v2: references adde