P-hacking in clinical trials and how incentives shape the distribution of results across phases

Clinical research should conform to high standards of ethical and scientific integrity, given that human lives are at stake. However, economic incentives can generate conflicts of interest for investigators, who may be inclined to withhold unfavorable results or even tamper with data in order to achieve desired outcomes. To shed light on the integrity of clinical trial results, this paper systematically analyzes the distribution of p-values of primary outcomes for phase II and phase III drug trials reported to the ClinicalTrials.gov registry. First, we detect no bunching of results just above the classical 5% threshold for statistical significance. Second, a density discontinuity test reveals an upward jump at the 5% threshold for phase III results by small industry sponsors. Third, we document a larger fraction of significant results in phase III compared to phase II. Linking trials across phases, we find that early favorable results increase the likelihood of continuing into the next phase. Once we take into account this selective continuation, we can explain almost completely the excess of significant results in phase III for trials conducted by large industry sponsors. For small industry sponsors, instead, part of the excess remains unexplained

P-hacking in clinical trials and how incentives shape the distribution of results across phases

Clinical research should conform to high standards of ethical and scientific integrity, given that human lives are at stake. However, economic incentives can generate conflicts of interest for investigators, who may be inclined to withhold unfavorable results or even tamper with data in order to achieve desired outcomes. To shed light on the integrity of clinical trial results, this paper systematically analyzes the distribution ofPvalues of primary outcomes for phase II and phase III drug trials reported to the ClinicalTrials.gov registry. First, we detect no bunching of results just above the classical 5% threshold for statistical significance. Second, a density-discontinuity test reveals an upward jump at the 5% threshold for phase III results by small industry sponsors. Third, we document a larger fraction of significant results in phase III compared to phase II. Linking trials across phases, we find that early favorable results increase the likelihood of continuing into the next phase. Once we take into account this selective continuation, we can explain almost completely the excess of significant results in phase III for trials conducted by large industry sponsors. For small industry sponsors, instead, part of the excess remains unexplained

Evaluierung von nachhaltiger Wirksamkeit in der wissenschaftlichen Weiterbildung: Erfahrungen und Empfehlungen für die Weiterbildungspraxis aus dem Projekt OTH mind

Evaluationen können einen wichtigen Beitrag für die professionelle Entwicklung der wissenschaftlichen Weiterbildung leisten. Voraussetzung hierfür ist die Berücksichtigung von nachhaltiger Wirksamkeit als Evaluationsziel und -gegenstand, denn daraus lassen sich wichtige Informationen für das professionelle Handeln der Beteiligten am Weiterbildungsgeschehen ableiten. Der Beitrag greift Erfahrungen aus der begleitenden Evaluations- und Wirksamkeitsforschung im Projekt OTH mind auf. Anhand der Evaluationsstandards der Deutschen Gesellschaft für Evaluation (DeGEval-Standards) werden das Vorgehen und die ergriffenen Maßnahmen in Hinblick auf die Qualität der Planung und Durchführung bewertet. Insgesamt werden fünf zentrale Empfehlungen für die Evaluationspraxis formuliert: für (1)die Einbindung von Beteiligten im Evaluationsprozess, (2) eine Nutzenevaluation auf verschiedenen Ebenen, (3) Ziele und Gegenstände einer professionalisierungsbezogenen Evaluation, (4) eine zielbezogene Messung sowie (5) die Nutzung/ Rückkopplung der Ergebnisse an Weiterbildungsverantwortliche. Weiterbildungspraktiker*innen an Hochschulen dienen die Empfehlungen als Impulse für eigene zukünftige Evaluationsanliegen

Complex matching of RDF datatype properties

Property mapping is a fundamental component of ontology matching, and yet there is little support that goes beyond the identification of single property matches. Real data often requires some degree of composition, trivially exemplified by the mapping of "first name" and "last name" to "full name" on one end, to complex matchings, such as parsing and pairing symbol/digit strings to SSN numbers, at the other end of the spectrum. In this paper, we propose a two-phase instance-based technique for complex datatype property matching. Phase 1 computes the Estimate Mutual Information matrix of the property values to (1) find simple, 1:1 matches, and (2) compute a list of possible complex matches. Phase 2 applies Genetic Programming to the much reduced search space of candidate matches to find complex matches. We conclude with experimental results that illustrate how the technique works. Furthermore, we show that the proposed technique greatly improves results over those obtained if the Estimate Mutual Information matrix or the Genetic Programming techniques were to be used independently. The final publication is available at Springer via http://dx.doi.org/10.1007/978-3-642-40285-2_18

Silica nanoparticles are less toxic to human lung cells when deposited at the air-liquid interface compared to conventional submerged exposure

Background: Investigations on adverse biological effects of nanoparticles (NPs) in the lung by in vitro studies are usually performed under submerged conditions where NPs are suspended in cell culture media. However, the behaviour of nanoparticles such as agglomeration and sedimentation in such complex suspensions is difficult to control and hence the deposited cellular dose often remains unknown. Moreover, the cellular responses to NPs under submerged culture conditions might differ from those observed at physiological settings at the air–liquid interface.Results: In order to avoid problems because of an altered behaviour of the nanoparticles in cell culture medium and to mimic a more realistic situation relevant for inhalation, human A549 lung epithelial cells were exposed to aerosols at the air–liquid interphase (ALI) by using the ALI deposition apparatus (ALIDA). The application of an electrostatic field allowed for particle deposition efficiencies that were higher by a factor of more than 20 compared to the unmodified VITROCELL deposition system. We studied two different amorphous silica nanoparticles (particles produced by flame synthesis and particles produced in suspension by the Stöber method). Aerosols with well-defined particle sizes and concentrations were generated by using a commercial electrospray generator or an atomizer. Only the electrospray method allowed for the generation of an aerosol containing monodisperse NPs. However, the deposited mass and surface dose of the particles was too low to induce cellular responses. Therefore, we generated the aerosol with an atomizer which supplied agglomerates and thus allowed a particle deposition with a three orders of magnitude higher mass and of surface doses on lung cells that induced significant biological effects. The deposited dose was estimated and independently validated by measurements using either transmission electron microscopy or, in case of labelled NPs, by fluorescence analyses. Surprisingly, cells exposed at the ALI were less sensitive to silica NPs as evidenced by reduced cytotoxicity and inflammatory responses.Conclusion: Amorphous silica NPs induced qualitatively similar cellular responses under submerged conditions and at the ALI. However, submerged exposure to NPs triggers stronger effects at much lower cellular doses. Hence, more studies are warranted to decipher whether cells at the ALI are in general less vulnerable to NPs or specific NPs show different activities dependent on the exposure method

Microstructural characterization of natural fractures and faults in the Opalinus Clay: insights from a deep drilling campaign across central northern Switzerland

Abstract The Middle-Jurassic Opalinus Clay is the foreseen host rock for radioactive waste disposal in central northern Switzerland. An extensive drilling campaign aiming to characterize the argillaceous formation resulted in a comprehensive drill core data set. The rheologically weak Opalinus Clay is only mildly deformed compared to the over- and underlying rock units but shows a variety of natural fractures. While these structures are hydraulically indistinguishable from macroscopically non-deformed Opalinus Clay today, their analysis allows for a better understanding of the deformation behaviour in the geological past. Here, we present an overview of the different fracture and fault types recorded in the Opalinus Clay and a detailed microstructural characterization of veins—natural dilational fractures healed by secondary calcite and celestite mineralizations. Macroscopic drill core analysis revealed five different natural fracture types that encompass tension gashes of various orientations with respect to bedding and small-scale faults with displacements typically not exceeding the drill core diameter. The occurrence of different fault types generally fits well with the local tectonic setting of the different drilling sites and with respect to the neighbouring regional fault zones. The microstructural investigations of the various vein types revealed their often polyphase character. Fibrous bedding-parallel veins of presumable early age were found to be overprinted by secondary slickenfibres. The polyphase nature of fibrous bedding parallel veins and slickenfibres is supported by differing elemental compositions, pointing towards repeated fracturing and mineralization events. Direct dating of vein calcites with U–Pb was unsuccessful. Nevertheless, age constraints can be inferred from structural orientations and fault slip kinematics. Accordingly, some of the veins already formed during sediment compaction in Mesozoic times, others possibly relate to Early Cenozoic foreland uplift. The youngest veins are most likely related to Late Cenozoic regional tectonic events, such as the Jura fold-and-thrust belt to the south and the Hegau-Lake Constance Graben to the northeast of the study area. During these latest tectonic events, previously formed veins acted as rheologically stiff discontinuities in the otherwise comparably weak Opalinus Clay along which deformation of the rock formation was re-localized

Air–Liquid Interface Exposure of Lung Epithelial Cells to Low Doses of Nanoparticles to Assess Pulmonary Adverse Effects

Reliable and predictive in vitro assays for hazard assessments of manufactured nanomaterials (MNMs) are still limited. Specifically, exposure systems which more realistically recapitulate the physiological conditions in the lung are needed to predict pulmonary toxicity. To this end, air-liquid interface (ALI) systems have been developed in recent years which might be better suited than conventional submerged exposure assays. However, there is still a need for rigorous side-by-side comparisons of the results obtained with the two different exposure methods considering numerous parameters, such as different MNMs, cell culture models and read outs. In this study, human A549 lung epithelial cells and differentiated THP-1 macrophages were exposed under submerged conditions to two abundant types of MNMs i.e., ceria and titania nanoparticles (NPs). Membrane integrity, metabolic activity as well as pro-inflammatory responses were recorded. For comparison, A549 monocultures were also exposed at the ALI to the same MNMs. In the case of titania NPs, genotoxicity was also investigated. In general, cells were more sensitive at the ALI compared to under classical submerged conditions. Whereas ceria NPs triggered only moderate effects, titania NPs clearly initiated cytotoxicity, pro-inflammatory gene expression and genotoxicity. Interestingly, low doses of NPs deposited at the ALI were sufficient to drive adverse outcomes, as also documented in rodent experiments. Therefore, further development of ALI systems seems promising to refine, reduce or even replace acute pulmonary toxicity studies in animals

Silica Nanoparticles Provoke Cell Death Independent of p53 and BAX in Human Colon Cancer Cells

Several in vitro studies have suggested that silica nanoparticles (NPs) might induce adverse effects in gut cells. Here, we used the human colon cancer epithelial cell line HCT116 to study the potential cytotoxic effects of ingested silica NPs in the presence or absence of serum. Furthermore, we evaluated different physico-chemical parameters important for the assessment of nanoparticle safety, including primary particle size (12, 70, 200, and 500 nm) and surface modification (–NH2 and –COOH). Silica NPs triggered cytotoxicity, as evidenced by reduced metabolism and enhanced membrane leakage. Automated microscopy revealed that the silica NPs promoted apoptosis and necrosis proportional to the administered specific surface area dose. Cytotoxicity of silica NPs was suppressed by increasing amount of serum and surface modification. Furthermore, inhibition of caspases partially prevented silica NP-induced cytotoxicity. In order to investigate the role of specific cell death pathways in more detail, we used isogenic derivatives of HCT116 cells which lack the pro-apoptotic proteins p53 or BAX. In contrast to the anticancer drug cisplatin, silica NPs induced cell death independent of the p53–BAX axis. In conclusion, silica NPs initiated cell death in colon cancer cells dependent on the specific surface area and presence of serum. Further studies in vivo are warranted to address potential cytotoxic actions in the gut epithelium. The unintended toxicity of silica NPs as observed here could also be beneficial. As loss of p53 in colon cancer cells contributes to resistance against anticancer drugs, and thus to reoccurrence of colon cancer, targeted delivery of silica NPs could be envisioned to also deplete p53 deficient tumor cells