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EuPd$_2$Si$_2$ is a valence-fluctuating system undergoing a temperature-induced valence crossover at $T'_V\approx160\,$K. We present the successful single crystal growth using the Czochralski method for the substitution series EuPd$_2$(Si$_{1-x}$Ge$_x$)$_2$, with substitution levels $x\leq 0.15$. A careful determination of the germanium content revealed that only half of the nominal concentration is build into the crystal structure. From thermodynamic measurements it is established that $T'_V$ is strongly suppressed for small substitution levels and antiferromagnetic order from stable divalent europium emerges for $x\gtrsim 0.10$. The valence transition is accompanied by a pronounced change of the lattice parameter $a$ of order 1.8%. In the antiferromagnetically ordered state below $T_N = 47$ K, we find sizeable magnetic anisotropy with an easy plane perpendicular to the crystallographic c direction. An entropy analysis revealed that no valence fluctuations are present for the magnetically ordered materials. Combining the obtained thermodynamic and structural data, we construct a concentration-temperature phase diagram demonstrating a rather abrupt change from a valence-fluctuating to a magnetically-ordered state in EuPd$_2$(Si$_{1-x}$Ge$_x$)$_2$.

Structural phase transitions accompanied with incommensurate and commensurate charge-density-waves (CDWs) modulations of unconventional nature have been reported in BaNi$_2$As$_2$, a non-magnetic cousin of the parent compound of Fe-based superconductors, BaFe$_2$As$_2$. The strong dependence of BaNi$_2$As$_2$ upon isoelectronic substitutions alongside original dynamical lattice effects suggest a strong tunability of the electronic phase of the system through structural effects. To gain further insights, we present a comprehensive synchrotron x-ray diffraction and first-principles calculation study of the evolution of the crystal structure and lattice instabilities of BaNi$_2$As$_2$ as function of temperature and hydrostatic pressures (up to 12 GPa). We report a cascade of pressure-induced structural phase transitions and electronic instabilities up to ca. 10 GPa, above which all CDW superstructures disappear. We reveal that the stable high-pressure phase consists of planar Ni zigzag chains, from which the surrounding As have been pushed away. This yields a strong reduction of the interlayer As-As distance (along the original $c$ axis), akin to what is observed in the collapsed tetragonal structure of other pnictides, albeit here with a monoclinic structure. The discovery of new polymorphs in the pressure-temperature phase diagram of BaNi$_2$As$_2$ emphasizes the importance of the relative Ni-Ni and Ni-As bond lengths in controlling the electronic ground state of this compound and replenish our understanding of viable electronic phases under extreme conditions., Comment: 10 pages, 5 figures, 1 table

Ta$_2$NiSe$_5$ is an excitonic insulator candidate showing the semiconductor/semimetal-to-insulator (SI) transition below $T_{\text{c}}$ = 326 K. However, since a structural transition accompanies the SI transition, deciphering the role of electronic and lattice degrees of freedom in driving the SI transition has remained controversial. Here, we investigate the photoexcited nonequilibrium state in Ta$_2$NiSe$_5$ using pump-probe Raman and photoluminescence (PL) spectroscopies. The combined nonequilibrium spectroscopic measurements of the lattice and electronic states reveal the presence of a photoexcited metastable state where the insulating gap is suppressed, but the low-temperature structural distortion is preserved. We conclude that electron correlations play a vital role in the SI transition of Ta$_2$NiSe$_5$., 13 pages, 10 figures

We study the valence crossover and strong electron-phonon coupling of EuPd$_2$Si$_2$ by polarization-resolved Raman spectroscopy. The fully-symmetric phonon mode shows strongly asymmetric lineshape at low temperature, indicating Fano-type interaction between this mode and a continuum of electron-hole excitations. Moreover, the frequency and linewidth of the phonon modes exhibit anomalies across the valence-crossover temperature, suggesting the coupling between valence fluctuations and lattice vibration. In particular, two phonon modes show significantly enhanced Gr\"uneisen parameter, possibly related to a nearby critical elastic regime. The relative contribution of the structural change and valence change to the phonon anomalies is evaluated by density functional theory calculations.

A detailed investigation of BaNi2(As,P)2 single crystals using high-resolution thermal-expansion, heat-capacity,Young-modulus and resistivity measurements is presented. The experimental data are complemented by density-functional calculations. The phase diagram of BaNi2(As,P)2 is shown to be much richer than suggested by the original data of Kudo et al. [Phys. Rev. Lett. 109, 097002 (2012)]. The transition to the commensurate charge-density-wave (C-CDW) is always preceded by a four-fold symmetry-breaking transition associated with the long-range ordering of a strongly fluctuating unidirectional incommensurate charge-density wave (I-CDW). Significant precursors above the I-CDW and C-CDW transitions are seen in the thermal expansion and resistivity and are particularly evident in the temperature dependence of the $c/a$ ratio of the lattice parameters. Heat-capacity measurements of the crystals with a higher P content and a higher critical temperature of 3.2 K uncover a Debye-like behavior of a soft-phonon mode with a very low Debye temperature of roughly 15 K. Associated with this soft phonon are unusually large thermal-expansion anomalies, resulting in logarithmically diverging uniaxial phonon Grueneisen parameters. Young-modulus data of these higher-Tc crystals exhibit a significant softening in both B1g and B2g channels, which is argued to be incompatible with nematic criticality and is rather associated with a broad phase transition to an hitherto unknown structure. Possible origins of the increase in the superconducting critical temperature with P-substitution are discussed., 9 pages, 9 figures

Understanding the organizing principles of interacting electrons and the emergence of novel electronic phases is a central endeavor of condensed matter physics. Electronic nematicity, in which the discrete rotational symmetry in the electron fluid is broken while the translational one remains unaffected, is a prominent example of such a phase. It has proven ubiquitous in correlated electron systems, and is of prime importance to understand Fe-based superconductors. Here, we find that fluctuations of such broken symmetry are exceptionally strong over an extended temperature range above phase transitions in \bnap, the nickel homologue to the Fe-based systems. This provides evidence for a type of electronic nematicity, dynamical in nature, which exhibits an unprecedented coupling to the underlying crystal lattice. Fluctuations between degenerate nematic configurations cause a splitting of phonon lines, without lifting degeneracies nor breaking symmetries, akin to spin liquids in magnetic systems., Comment: Originally submitted version (references have been updated). The version to be published has been significantly revised and is available upon request to MLT

Bond formation and breakage is crucial upon energy storage in lithium transition metal oxides (LiMeO$_{2}$, Me = Ni, Co, Mn), i.e., the conventional cathode materials in Li ion batteries. Near-edge X-ray absorption finestructure spectroscopy (NEXAFS) of the Me L and O K edge performed upon the first discharge of LiNi$_{x}$Co$_{(1-x)/2}$Mn$_{(1-x)/2}$O$_{2}$ (x = 0.33: NCM111, x = 0.6: NCM622, x = 0.8: NCM811) in combination with charge transfer multiplet (CTM) calculations provide unambiguous evidence that redox reactions in NCMs proceed via a reversible oxidation of Ni associated with the formation of covalent bonds to O neighbors, and not, as widely assumed, via pure cationic or more recently discussed, pure anionic redox processes. Correlating these electronic changes with crystallographic data using operando synchrotron X-ray powder diffraction (SXPD) shows that the amount of ionic Ni limits the reversible capacity— at states of charge where all ionic Ni is oxidized (above 155 mAh g$^{-1}$), the lattice parameters collapse, and irreversible reactions are observed. Yet the covalence of the Ni–O bonds also triggers the electronic structure and thus the operation potential of the cathodes.

Doping of silicon nanostructures is crucial to understand their properties and to enhance their potential in various fields of application. Herein, SiO2-embedded Si nanocrystals (quantum dots) ≈3–6 nm in diameter are used as a model system to study the incorporation of B dopants by X-ray absorption near-edge spectroscopy (XANES). Such samples represent a model system for ultimately scaled, 3D-confined Si nanovolumes. The analysis is complemented by real-space density functional theory to calculate the 1s (K shell) electron binding energies of B in 11 different, thermodynamically stable configurations of the Si/SiOx/SiO2 system. Although no indications for a substitutional B-acceptor configuration are found, the predominant O coordination of B indicates the preferred B incorporation into the SiO2 matrix and near the Si-nanocrystal/SiO2 interface, which is inherently incompatible with charge carrier generation by dopants. It is concluded that B doping of ultrasmall Si nanostructures fails due to a lack of B incorporation onto Si lattice sites that cannot be overcome by increasing the B concentration. The inability to efficiently insert B into Si nanovolumes appears to be a boron-specific fundamental obstacle for electronic doping (e.g., not observed for phosphorus) that adds to the established nanosize effects, namely, increased dopant activation and ionization energies.

A main difficulty in actuarial claim size modeling is that there is no simple off-the-shelf distribution that simultaneously provides a good distributional model for the main body and the tail of the data. In particular, covariates may have different effects for small and for large claim sizes. To cope with this problem, we introduce a deep composite regression model whose splicing point is given in terms of a quantile of the conditional claim size distribution rather than a constant. To facilitate M-estimation for such models, we introduce and characterize the class of strictly consistent scoring functions for the triplet consisting a quantile, as well as the lower and upper expected shortfall beyond that quantile. In a second step, this elicitability result is applied to fit deep neural network regression models. We demonstrate the applicability of our approach and its superiority over classical approaches on a real accident insurance data set., Comment: 32 pages, 6 figures

The CaK(Fe$_{1-x}$Ni$_{x}$)$_{4}$As$_{4}$ superconductors resemble the archetypal 122-type iron-based materials but have a crystal structure with distinctly lower symmetry. This family hosts one of the few examples of the so-called spin-vortex crystal magnetic order, a non-collinear magnetic configuration that preserves tetragonal symmetry, in contrast to the orthorhombic collinear stripe-type magnetic configuration common to the 122-type systems. Thus, nematic order is completely absent from its phase diagram. To investigate the evolution of nematic fluctuations in such a case, we present elastoresistance and elastic modulus measurements in CaK(Fe$_{1-x}$Ni$_{x}$)$_{4}$As$_{4}$ ($x = 0-0.05$) combined with phenomenological modeling and density functional theory. We find clear experimental signatures of considerable nematic fluctuations, including softening of the Young's modulus $Y_{[110]}$ and a Curie-Weiss type divergence of the B2g elastoresistance coefficient in CaK(Fe$_{0.951}$Ni$_{0.049}$)$_4$As$_4$. Overall, nematic fluctuations within this series bear strong similarities to the hole-doped Ba$_{1-x}$K$_x$Fe$_2$As$_2$ series, including a substitution-induced sign change. Our theoretical analysis addresses the effect of the specific crystal symmetry of the 1144-type structure in determining its magnetic ground state and on the nematic fluctuations.

Energy density limitations of layered oxides with different Ni contents, i.e., of the conventional cathode materials in Li-ion batteries, are investigated across the first discharge cycle using advanced spectroscopy and state-of-the-art diffraction. For the first time unambiguous experimental evidence is provided, that redox reactions in NCMs proceed via a reversible oxidation of Ni and a hybridization with O, and not, as widely assumed, via pure cationic or more recently discussed, pure anionic redox processes. Once Ni-O hybrid states are formed, the sites cannot be further oxidized. Instead, irreversible reactions set in which lead to a structural collapse and thus, the lack of ionic Ni limits the reversible capacity. Moreover, the degree of hybridization, which varies with the Ni content, triggers the electronic structure and the operation potential of the cathodes. With an increasing amount of Ni, the covalent character of the materials increases and the potential decreases.

Funding: The Leverhulme Trust and The Royal Society. We present a combined study from angle-resolved photoemission and density-functional-theory calculations of the temperature-dependent electronic structure in the excitonic insulator candidate Ta2NiSe5. Our experimental measurements unambiguously establish the normal state as a semimetal with a significant band overlap of >100 meV. Our temperature-dependent measurements indicate how these low-energy states hybridize when cooling through the well-known 327 K phase transition in this system. From our calculations and polarization-dependent photoemission measurements, we demonstrate the importance of a loss of mirror symmetry in enabling the band hybridization, driven by a shearlike structural distortion which reduces the crystal symmetry from orthorhombic to monoclinic. Our results thus point to the key role of the lattice distortion in enabling the phase transition of Ta2NiSe5. Publisher PDF

The Li−Ni−O phase diagram contains a variety of compounds, most of which are electrochemically active in Li-ion batteries. Other than the well-known LiNiO2, here we report a facile solid-state method to prepare Li2NiO3 and other Li-rich Ni oxides of composition Li1+xNi1−xO2 (0 ≤ x ≤ 0.33). We characterize their crystal and electronic structure, exhibiting a highly oxidized Ni state and defects of various nature (Li−Ni disorder, stacking faults, oxygen vacancies). We then investigate the use of Li2NiO3 as a cathode active material and show its remarkably high specific capacity, which however fades quickly. While we demonstrate that the initial capacity is due to irreversible O2 release, such process stops quickly in favor of more classical reversible redox mechanisms that allow cycling the material for >100 cycles. After the severe oxygen loss (∼15−20%) and prolonged cycling, the Bragg reflections of Li2NiO3 disappear. Analysis of the diffracted intensities suggests the resulting phase is a disordered rock salt-type material with high Li content, close to Li0.5Ni0.5O, never reported to date and capable of Li diffusion. Our findings demonstrate that the Li−Ni−O phase diagram has not been fully investigated yet, especially concerning the preparation of new promising materials by out-of-equilibrium methods.

Nematic phase transitions in high-temperature superconductors have a strong impact on the electronic properties of these systems. BaFe$_2$As$_2$,\@ with an established nematic transition around 137 K induced by magnetic fluctuations, and BaNi$_2$As$_2$,\@ a non-magnetic analog of BaFe$_2$As$_2$ with a structural transition in the same temperature range,\@ share a common tetragonal aristotype crystal structure with space-group type $I4/mmm$.\@ In contrast to BaFe$_2$As$_2$ where collinear stripe magnetic order is found for the orthorhombic low-$T$ phase, a unidirectional charge density wave together with (distorted) zig-zag chains are observed for the triclinic low-$T$ phase of BaNi$_2$As$_2$.\@ Here we show that between the high- and low-$T$ phases of Ba(Ni,Co)$_2$(As,P)$_2$ an additional phase with broken fourfold symmetry and $d_{xz}$ orbital order exists which is a promising candidate for charge/orbital-fluctuation-induced nematicity. Moreover, our data suggest that the enhanced $T_{\rm c}$ found for Ba(Ni,Co)$_2$(As,P)$_2$ for higher Co or P substitution levels might result from suppression of the (distorted) zig-zag chains by reducing the contribution of the $d_{xy}$ orbitals., Comment: 17 pages, 20 figures, submitted

Since 2000, the intensive effort in materials research to develop a diluted magnetic semiconductor exhibiting high-temperature (HT) ferromagnetism above room temperature was not successful. Here, the possible first bulk diluted HT-ferromagnetic non-metallic materials, based on the perovskite-type oxynitrides LaTa1-xCox(O,N)3-d (x = 0.01, 0.03, 0.05) are realized. The Curie temperature of the synthesized powders exceeds 600 K and the sample magnetizations are large enough to be directly attracted by permanent magnets. Cobalt clusters as a possible source for the observed HT-ferromagnetism can be excluded, since all applied characterization methods verify phase purity. Applied conventional and element-specific magnetometry imply ferromagnetic intermediate spin (IS) Co3+ which is included in a ferromagnetic host matrix. This indicates a complex magnetic interplay between the existing crystal structure, the observed anionic vacancies, and the introduced cobalt ions. These results lay the foundation for the experimental investigation and design of further diluted HT-ferromagnetic semiconductors., Comment: submitted to journal

We present a combined study from angle-resolved photoemission and density-functional theory calculations of the temperature-dependent electronic structure in the excitonic insulator candidate Ta$_2$NiSe$_5$. Our experimental measurements unambiguously establish the normal state as a semimetal with a significant band overlap of $>$100~meV. Our temperature-dependent measurements indicate how these low-energy states hybridise when cooling through the well-known 327~K phase transition in this system. From our calculations and polarisation-dependent photoemission measurements, we demonstrate the importance of a loss of mirror symmetry in enabling the band hybridisation, driven by a shear-like structural distortion which reduces the crystal symmetry from orthorhombic to monoclinic. Our results thus point to the key role of the lattice distortion in enabling the phase transition of Ta$_2$NiSe$_5$., 6 pages, 4 figures

In this contribution, we demonstrate the presence of high-spin Fe3+ in Fe-substituted ZrO2 (FexZr1−xO2−δ), as deduced from X-ray photoelectron spectroscopy (XPS), near-edge X-ray absorption fine structure (NEXAFS), and 57Fe Mössbauer spectroscopy measurements. The activity of this carbon-supported FexZr1−xO2−δ catalyst towards the oxygen reduction reaction (ORR) was examined by both the rotating (ring) disk electrode (R(R)DE) method and in single-cell proton exchange membrane fuel cells (PEMFCs). DFT calculations suggest that the much higher ORR mass activity of FexZr1−xO2−δ compared to Fe-free ZrO2 is due to the enhanced formation of oxygen vacancies: their formation is favored after Zr4+ substitution with Fe3+ and the oxygen vacancies create potential adsorption sites, which act as active centers for the ORR. H2O and/or H2O2 production observed in RRDE measurements for the Fe0.07Zr0.93O1.97 is also in agreement with the most likely reaction paths from DFT calculations. In addition, Tafel and Arrhenius analyses are performed on Fe0.07Zr0.93O1.97 using both RRDE and PEMFC data at various temperatures.

Findings - The results provide (longitudinal) support for the proposed evaluative approach. They reveal new evidence that building brand equity is a means to mitigate negative effects, and indicate that negative spillover effects within a high-equity brand portfolio are unlikely. Finally, this research identifies situations in which developing a new brand might be more beneficial than leveraging an existing brand. Practical implications - This research has significant implications for firms with high-equity brands that might be affected by a scandal. The findings support managers to navigate their brands through a crisis.

Superconductivity in FeSe has recently attracted a great deal of attention because it emerges out of an electronic nematic state of elusive character. Here we study both the electronic normal state and the superconducting gap structure using heat-capacity measurements on high-quality single crystals. The specific-heat curve, from 0.4 K to Tc = 9.1 K, is found to be consistent with a recent gap determination using Bogoliubov quasiparticle interference [P. O. Sprau et al., Science 357, 75 (2017)], however only if nodes are introduced on either the electron or the hole Fermi-surface sheets. Our analysis, which is consistent with quantum-oscillation measurements, relies on the presence of only two bands, and thus the fate of the theoretically predicted second electron pocket remains mysterious., 6 pages, 4 figures

The nematic susceptibility of Ba$_{1-x}$Na$_{x}$Fe$_{2}$As$_{2}$ single crystals is studied by measuring the Young's modulus using a three-point-bending setup in a capacitance dilatometer over a wide doping range. Particular emphasis is placed on the behavior within the double-Q antiferromagnetic $C_{4}$ re-entrant phase. Here, we surprisingly still observe a sizable nematic susceptibility in spite of the well-developed magnetic order, consistent with recent theoretical calculations. Outside the $C_{4}$ re-entrant region, the behavior is very similar to that of K-doped BaFe$_{2}$As$_{2}$. A significant coupling of superconductivity to the shear modulus is observed and is discussed in terms of strong competition between the superconducting and magnetic phases., Comment: 5 pages, 5 figures

The somatostatin analog octreotide can lead to hyperbilirubinemia without evidence of liver injury. Here we investigate whether octreotide inhibits the main sinusoidal/canalicular bilirubin carriers and whether it is a transport substrate. Octreotide showed the most potent inhibitory effect toward OATP1B1 mediated transport and weaker inhibition for OATP1B3 and MRP2 mediated transport. Octreotide had no effect on OATP2B1 mediated transport. Octreotide inhibited [(3)H]estradiol 17 ß glucuronide (E17ßG) influx mediated by OATP1B1 1B3 and multidrug resistance associated protein 2 (MRP2) in a concentration dependent manner and the IC50 values were computed to be 23 µM (95 confidence interval [CI] 18 29) 68 µM (95 CI 50 91) and 116.6 µM (95 CI 74.5 182.4) respectively. The interaction between octreotide and OATP1B1 was further studied. Inhibition of [(3)H]E17ßG OATP1B1 mediated transport was purely competitive with no changes in maximum transport capacity (Vmax) and a twofold Km increase when the influx kinetics of [(3)H]E17ßG were measured in the presence of octreotide (8.8 ± 3.1 versus 4.4 ± 1.2 µM P = 0.03). The inhibition constant (Ki) of octreotide for the transport of [(3)H]E17ßG was calculated at 33.5 ± 5.5 µM. Uptake of radiolabeled octreotide by OATP1B1 CHO cells was higher than in wild type CHO cells and nonlabeled octreotide at the extracellular compartment was able to trans stimulate the OATP1B1 mediated efflux of intracellular [(3)H]E17ßG suggesting that octreotide is a substrate of OATP1B1. In summary this study shows interaction of octreotide on the human hepatocellular bilirubin transporters OATP1B1 OATP1B3 and MRP2 notably OATP1B1. These findings are in line with the clinical observation that a fraction of patients under treatment with octreotide exhibit hyperbilirubinemia.

Superconductors close to quantum phase transitions often exhibit a simultaneous increase of electronic correlations and superconducting transition temperatures. Typical examples are given by the recently discovered iron-based superconductors. We investigated the band-specific quasiparticle masses of AFe2As2 single crystals with A = K, Rb, and Cs and determined their pressure dependence. The evolution of electronic correlations could be tracked as a function of volume and hole doping. The results indicate that with increasing alkali-metal ion radius a quantum critical point is approached. The critical fluctuations responsible for the enhancement of the quasiparticle masses appear to suppress the superconductivity., main text: 5 pages, 4 figures; supplemental material: 6 pages, 6 figures, 3 tables

Journal Article; A workshop was convened to discuss best practices for the assessment of drug-induced liver injury (DILI) in clinical trials. In a breakout session, workshop attendees discussed necessary data elements and standards for the accurate measurement of DILI risk associated with new therapeutic agents in clinical trials. There was agreement that in order to achieve this goal the systematic acquisition of protocol-specified clinical measures and lab specimens from all study subjects is crucial. In addition, standard DILI terms that address the diverse clinical and pathologic signatures of DILI were considered essential. There was a strong consensus that clinical and lab analyses necessary for the evaluation of cases of acute liver injury should be consistent with the US Food and Drug Administration (FDA) guidance on pre-marketing risk assessment of DILI in clinical trials issued in 2009. A recommendation that liver injury case review and management be guided by clinicians with hepatologic expertise was made. Of note, there was agreement that emerging DILI signals should prompt the systematic collection of candidate pharmacogenomic, proteomic and/or metabonomic biomarkers from all study subjects. The use of emerging standardized clinical terminology, CRFs and graphic tools for data review to enable harmonization across clinical trials was strongly encouraged. Many of the recommendations made in the breakout session are in alignment with those made in the other parallel sessions on methodology to assess clinical liver safety data, causality assessment for suspected DILI, and liver safety assessment in special populations (hepatitis B, C, and oncology trials). Nonetheless, a few outstanding issues remain for future consideration. Yes

ASTIN Bulletin, 42 (1), ISSN:0515-0361, ISSN:1783-1350

It is well known that credibility theory in discrete time is closely related to the discrete technique of Kalman filtering. In this paper we show the close relationship between credibility theory and filter theory in discrete and continuous time as well as between credibility theory in a discrete and continuous time setting.

It is well known that credibility theory in discrete time is closely related to the discrete technique of Kalman filtering. In this paper we show the close relationship between credibility theory and filter theory in discrete and continuous time as well as between credibility theory in a discrete and continuous time setting.

In Buchwalder et al. (2006) we revisited Mack's (1993) and Murphy's (1994) estimates for the mean square error of prediction (MSEP) of the chain ladder claims reserving method. This was done using a time series model for the chain ladder method. In this paper we extend the time series model to determine an estimate for the MSEP of a portfolio of N correlated run-off triangles. This estimate differs in the special case N = 2 from the estimate given by Braun (2004). We discuss the differences between the estimates., Annals of Actuarial Science, 2 (1), ISSN:1748-5002, ISSN:1748-4995

EINLEITUNG: In zahlreichen Studien wurde eine positive Familienanamnese als einer der größten Risikofaktoren für die Entwicklung eines Prostatakarzinoms (PCA) dokumentiert. In einer US-Population wurde gezeigt, dass ein frühes Erkrankungsalter bei familiären PCA-Patienten mit einem besser differenzierten Tumor assoziiert ist. Das Ziel dieser Studie war der Vergleich klinischer Parameter zwischen sporadischen und familiären bzw. hereditären Patienten mit einem Erkrankungsalter kleiner / gleich 55 Jahren. MATERIAL UND METHODIK: Von PCA-Patienten mit einem Diagnosealter = 55 Jahren, welche im Zeitraum von Juli 1999 bis Juli 2004 in die Datenbank "familiäres Prostatakarzinom" aufgenommen wurden, wurden die klinischen Daten ausgewertet. Folgende Daten wurden für alle Patienten erhoben: PSA-Wert bei Diagnose, histologisches Stadium, Grading, Gleason-Score und progressfreie Überlebenszeit. ERGEBNISSE: Von 685 Patienten konnten die klinischen Daten komplettiert werden. 222 (32,4 %) dieser Patienten gaben an, einen erstgradigen Familienangehörigen mit einem PCA zu haben, davon waren 48 (7,0 %) hereditär betroffen; 463 (67,6 %) waren sporadisch betroffen. Das mittlere Erkrankungsalter lag bei den hereditären Patienten bei 51,6 (41 - 55) Jahren, den familiären Patienten bei 51,1 (35 - 55) Jahren und den sporadischen Patienten bei 52,0 (38 - 55) Jahren. Das Follow-up betrug im Median bei den hereditären Patienten 24 Monate, den familiären Patienten 36 Monate und den sporadischen Patienten 35 Monate. Ein kurativer Therapieansatz mittels RPX bzw. Radiatio/ Brachytherapie war bei 657/685 (95,9 %) der Patienten initial geplant. Der PSA-Wert bei Diagnose, die postoperativen klinischen Parameter (Organbegrenzung, Lymphknotenbeteiligung, Gleason-Score, Grading) und das progressfreie Überleben unterschieden sich nicht deutlich zwischen sporadischen und familiären bzw. hereditären Fällen. ZUSAMMENFASSUNG: Patienten mit einem Diagnosealter kleiner / gleich 55 Jahren weisen häufiger eine positive Familienanamnese auf als das Gesamtkollektiv aller PCA-Patienten in Deutschland. Es konnte kein Zusammenhang zwischen histologischem Stadium bzw. klinischem Verlauf und der Familienanamnese bei Patienten mit einem Diagnosealter kleiner / gleich 55 Jahren gezeigt werden.

Diakonia, Bd. 11 Nr. 2 (1980): Diakonia, Band 11, Heft 2

The FDA guidance for industry in the premarketing clinical evaluation of drug-induced liver injury (DILI) is the most specific regulatory guidance currently available and has been useful in setting standards for the great majority of clinical indications involving subjects with a low risk of liver disorders. However, liver safety assessment faces challenges in populations with underlying liver disease, such as viral hepatitis or metastatic cancer. This is an important issue because there are currently many promising anti-viral and oncologic therapies in clinical development, with a trend toward oral therapies with reduced side effects. Without clearer guidelines, questions regarding liver safety may become a major factor in regulatory approval and ultimately physician uptake of the new treatments. The lack of consensus in defining stopping rules based on serum alanine aminotransferase (ALT) levels underscores the need for precompetitive data sharing to improve our understanding of DILI in these populations and to allow evidence-based rather than empirical definition of stopping rules. A workshop was convened to discuss best practices for the assessment of drug-induced liver injury (DILI) in clinical trials.

Analysis of liver safety data has to be multivariate by nature and needs to take into account time dependency of observations. Current standard tools for liver safety assessment such as summary tables, individual data listings, and narratives address these requirements to a limited extent only. Using graphics in the context of a systematic workflow including predefined graph templates is a valuable addition to standard instruments, helping to ensure completeness of evaluation, and supporting both hypothesis generation and testing. Employing graphical workflows interactively allows analysis in a team-based setting and facilitates identification of the most suitable graphics for publishing and regulatory reporting. Another important tool is statistical outlier detection, accounting for the fact that for assessment of Drug-Induced Liver Injury, identification and thorough evaluation of extreme values has much more relevance than measures of central tendency in the data. Taken together, systematical graphical data exploration and statistical outlier detection may have the potential to significantly improve assessment and interpretation of clinical liver safety data. A workshop was convened to discuss best practices for the assessment of drug-induced liver injury (DILI) in clinical trials.