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Background: H3B-6545, a novel Selective ERα Covalent Antagonist (SERCA), inactivates both mutant and wild-type ERα by targeting cysteine 530 and enforcing antagonist conformation. It demonstrated a manageable safety profile and single-agent antitumor activity in heavily pretreated ER+, HER2- mBC patients (pts) (Hamilton et al, ASCO, 2021). Methods: The study aims at determining the recommended phase II doses of the combination of H3B-6545 and palbociclib in pts with ER+, HER2- mBC. Other endpoints include safety, pharmacokinetics, and preliminary efficacy. The escalation phase enrolls pts with at least 2 prior therapies in the metastatic setting. Up to one prior chemotherapy and up to one prior CDK4/6 inhibitor are allowed. Each cohort enrolled 6 pts to ensure availability of sufficient PK data. During the first cycle, H3B-6545 was added to palbociclib on day 9. Dose-limiting toxicities (DLTs) were assessed during the first 28 days starting from the 1st day of adding H3B-6545 to palbociclib (cycle 1 day 9 to cycle 2 day 8). Both drugs were started on day 1 of each of the subsequent cycles. Results: As of June 15, 2021, 14 pts were enrolled: 7 in Cohort 1 (H3B-6545 300 mg QD and palbociclib 100 mg QD) and 7 in Cohort 2 (H3B-6545 300 mg QD and palbociclib 125 mg QD). Median age was 61 years (range: 28-75 years), ECOG performance status was 0 in 7 pts (50%) and 1 in 7 pts (50%) and 9 pts (64%) had lung and/or liver metastases. Median number of prior therapies in the metastatic setting was 3 (range: 1-6). Prior therapy in the metastatic setting included fulvestrant (93%), CDK4/6 inhibitors (79%), aromatase inhibitors (64%), and chemotherapy (29%). One pt in each Cohort was not evaluable for dose limiting toxicity (DLT) assessment and no DLTs were observed in the first 2 Cohorts. Seven pts discontinued study treatment because of progression and 1 pt discontinued due to diagnosis of a second primary cancer during the first cycle. Non-hematological grade 2 or higher adverse events (AE), irrespective of causality, reported in ≥2 pts were: nausea, vomiting, abdominal pain, and bone pain, each observed in 2 pts (14%). Gr. 1 and 2 sinus bradycardia were reported in 6 (43%) and 1 pts (7%), respectively. One pt (7%) had grade 1 QT prolongation. No grade 4 AEs or treatment-related deaths were reported. For hematology and chemistry laboratory abnormalities: gr. 3 and 4 neutropenia in 7 pts (50%) and 2 pts (14%), respectively, gr. 3 thrombocytopenia in 1 pt (7%), gr. 3 anemia in 2 pts (14%). Grade 2 decrease in estimated glomerular filtration rate was observed in 7 pts (50%), all reported irrespective of causality. Co-administration of palbociclib had no meaningful impact on H3B-6545 exposure (15% and 21% increase in geometric means of AUC and Cmax, respectively). Co-administration of H3B-6545 modestly increased palbociclib exposure (49% and 36% increase in geometric means of AUC and Cmax, respectively). Among 6 response-evaluable pts in Cohort 1, 2 pts (33%) had confirmed partial responses and 4 pts (67%) had stable disease. Both responding pts received prior therapy with a CDK4/6 inhibitor and fulvestrant. Cohort 2 efficacy data is not yet mature. Recruitment is currently ongoing in Cohort 3 (H3B-6545 450 mg QD and palbociclib 125 mg QD). Conclusions: The combination of H3B-6545 (up to 300 mg dose) and palbociclib (up to 125 mg dose) was well-tolerated and demonstrated preliminary anti-tumor activity in heavily pretreated pts with ER+, HER2- mBC. ClinicalTrials.gov Identifier: NCT04288089. Citation Format: Stephen Johnston, Timothy J Pluard, Judy S Wang, Erika P Hamilton, Dejan Juric, Catherine R Scholz, Elizabeth Hnitecki, Sara Dar, Lei Gao, Lisa Cantagallo, Manav Korpal, Jianjun Alan Xiao, Lihua Yu, Tarek Sahmoud, Antonio Gualberto. H3B-6545 in combination with palbociclib in women with metastatic estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 (HER2)-negative breast cancer, phase 1b study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-17-03.

According to a widely accepted conception, philosophy is essentially a second-order discipline raising second-order questions about the procedures and products of first-order reasonings (concepts; principles; theories etc.). While this conception has considerable prima facie plausibility and, carefully put, contains a grain of truth, it also invites serious misunderstandings that may be detrimental to an adequate understanding and public image of philosophy. To work out the grain of truth while avoiding the misunderstandings, I begin by asking: What is philosophical understanding? In answering this question, understanding in philosophy is compared and contrasted with everyday understanding, on the one hand, and scientific understanding, on the other hand. While philosophy itself is a scientific practice in a wide sense, in contrast to normal understanding within a special scientific discipline (physics; chemistry; biology; psychology; etc.) philosophical understanding is characterized by a particular critical attitude and particular principles of rational acceptability.

In total hip arthroplasty insufficient primary stability with excessive bone-implant micromotion is a major reason for aseptic loosening at the acetabular cup implant. In the literature, several methods were proposed for in vitro micromotion measurement, but none is capable of six degrees of freedom measurement at a large number of measuring points over the entire acetabular bone-implant interface, which was the aim of the current scientific work. A pin-sleeve sensor system was developed and an appropriate installing technique was incorporated. Micromotions were transmitted from the internal interface to the accessible periphery. Motion data of the sensors were optically tracked. A calculation algorithm was conceived, discretizing superimposed rotational and translational components. The method was tested and subsequently applied to a cementless revision cup implanted into an artificial hemipelvic bone featuring a typical bone defect. Using eighteen sensors in positions across the acetabular bone-implant interface, micromotion magnitudes from 59 µm ± 2 µm to 222 µm ± 5 µm were detected. Allocation of micromotion complied with case specific anticipations. The novel pin-sleeve sensors transmitted interface micromotion to the accessible periphery as desired. The measurement method enables instructive insights into three-dimensional bone-implant micromotion and may prospectively be used to evaluate different implant systems.

During the Mid-Miocene Climatic Optimum (MMCO, 14.7–17.3 Ma), global temperatures were warmer than present, and similar to predicted temperatures for the coming century. Limited paleoclimate data exist from the tropics during this period, despite its potential as an analog for future climate conditions. This study presents new subannual stable isotope data (δ18O and δ13C) from a large population of Miocene Turritella gastropods from the Jimol and Castilletes Formations of the Guajira Peninsula, Colombia. Turritellids are aragonitic marine mollusks that live in shallow coastal waters, and their rapid growth rates allow for high-resolution subannual records. We compare these fossils to modern Turritella gastropods from multiple tropical localities to reconstruct subannual climate conditions. The seasonal range in δ18O in the modern shells correlates with the seasonal variance of local precipitation, once temperature seasonality is accounted for. The Miocene fossils show larger (in some cases >2‰) seasonal variation in δ18O than modern Turritella from the same location, suggesting increased seasonality of precipitation in Miocene northern Colombia relative to today. We propose that this increased seasonality of precipitation was due to a more northerly position of the Intertropical Convergence Zone during the mid-Miocene. The resulting wet Miocene paleoenvironment is in stark contrast to semiarid conditions on the Guajira Peninsula today, indicating that this area of tropical South America has undergone a drastic environmental change since the Miocene.

We have determined the complex dielectric tensor of single crystalline 3,4,9,10-perylene tetracarboxylic dianhydride (𝛼-PTCDA) as a function of energy in the range between 1.4 and 5.0 eV. The results obtained reflect the monoclinic symmetry of the crystal: The principal axes of the real and the imaginary part of the tensor in general do not coincide and show chromatic dispersion. Monoclinic behavior allows rotation of the components 𝜀𝑋 and 𝜀𝑍 in the plane perpendicular to the unique symmetry axis 𝑌 . The experimental results indicate that the energies of the optical transitions observed in the weak 𝜀𝑋 component coincide with energies in which a resonance effect due to coupling with the stronger 𝜀𝑍 component occurs. These resonances appear at energies close to electronic excitations such as the optical gap, the transport gap and the highest occupied molecular orbital–lowest unoccupied molecular orbital (HOMO–LUMO) peak-to-peak gap and their assignments are discussed based on theoretical calculations, We dedicate this paper to the memory of Norbert Karl and Manuel Cardona who encouraged this work in its beginnings. MIA and MG acknowledge funding by the Spanish Ministerio de Ciencia e Innovación (MICINN) through grants PID2019-106860GB-I00 (highN) and CEX2019-000917-S (FUNFUTURE, in the framework of the Spanish Severo Ochoa Centre of Excellence program), as well as AGAUR, Spain for grant 2017-SGR-00488. FS and RS wish to acknowledge financial support from the DFG, Germany ., With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000917-S).

Paleotemperature reconstructions linked to Deccan traps volcanic greenhouse gas emissions and associated feedbacks in the lead-up to the end-Cretaceous meteorite impact and extinction document local and global climate trends during a key interval of geologic history. Here, we present a new clumped-isotope-based paleotemperature record derived from fossil bivalves from the Maastrichtian type region, in southeast Netherlands and northeast Belgium. Clumped isotope data documents a mean temperature of 19.2 ± 3.8 °C, consistent with other Maastrichtian temperature estimates, and an average seawater δ18O value of −0.3 ± 0.9 ‰ VSMOW for the region during the latest Cretaceous (67.1–66.0 Ma). A notable temperature increase at ~66.4 Ma is interpreted to be a regional manifestation of the globally-defined Late Maastrichtian Warming Event, linking Deccan Traps volcanic CO2 emissions prior to the end-Cretaceous extinction to climate change in the Maastricht region. Fluctuating seawater δ18O values coinciding with temperature changes suggest alternating influences of warm, salty southern-sourced waters and cooler, fresher northern-sourced waters from the Arctic Ocean. This new paleotemperature record contributes to the understanding of regional and global climate response to large-scale volcanism and ocean circulation changes leading up to a catastrophic mass extinction.

International audience; The seismometer deployed on the surface of Mars as part of the InSight mission (Interior Exploration using Seismic Investigations, Geodesy and Heat Transport) has recorded several hundreds of marsquakes in the first 478 sols after landing. The majority of these are classified as high-frequency (HF) events in the frequency range from approximately 1 to 10 Hz on Mars' surface. All the HF events excite a resonance around 2.4 Hz and show two distinct but broad arrivals of seismic energy that are separated by up to 450 s. Based on the frequency content and vertical-to-horizontal energy ratio, the HF event family has been subdivided into three event types, two of which we show to be identical and only appear separated due to the signal-to-noise ratio. We show here that the envelope shape of the HF events is explained by guided Pg and Sg phases in the Martian crust using simple layered models with scattering. Furthermore, the relative travel times between these two arrivals can be related to the epicentral distance, which shows distinct clustering. The rate at which HF events are observed varies by an order of magnitude over the course of one year and cannot be explained by changes of the background noise only. The HF content and the absence of additional seismic phases constrain crustal attenuation and layering, and the coda shape constrains the diffusivity in the uppermost shallow layers of Mars.

The self-determination literature is inconclusive about how basic need fulfillment affects job satisfaction and how needs-based models compare with models based on desires, i.e., organizational justice which forms the basis of popular employee engagement surveys. It is unclear also how individual performance is affected by job satisfaction that results either from basic needs or from organizational justice. Based on survey data, we compare needs-based and desire-based models. We assess how well such models explain and predict job satisfaction directly and indirectly predict individual performance through job satisfaction. This paper shows that, in lean management contexts, job satisfaction due to the fulfillment of basic human needs better predicts in-role performance than does job satisfaction due to organizational justice. We also find that (1) the need for relatedness is more important than previously theorized and (2) the effect of fulfilling basic needs depends on constraints that reflect how well other needs are satisfied. In general, basic human needs have much greater explanatory power with respect to job satisfaction than does organizational justice. Finally, our paper highlights the need to distinguish clearly between explanatory and predictive models, because our results show that a given model’s performance varies considerably as a function of the particular application.

Total Quality Management relies on the contributions of operational employees, but the process of motivating them to exhibit in-role and extra-role behaviors is unclear. Employees face trade-offs before adopting these behaviors based on preferred courses of action, which are seldom directly observed—and hence not well understood; moreover, it is often (yet unrealistically) assumed that workers have enough time to engage in all such behaviors. We examine the antecedents of that motivational process and then draw on self-determination theory to model the process leading to these behaviors. For these purposes, we employ a structural equation model, and the preferred behaviors in trade-off situations are elicited via a discrete choice experiment. We replicate results that have previously been reported only piecemeal. In answering calls for a broader exploration, we not only confirm “organizational justice” and “perceived strategic alignment" but also identify “quality philosophy” as critical antecedents of the motivational process. Furthermore, we establish that employees derive significantly higher utility from helping colleagues and improving operations quality than from merely focusing on their job; in fact, they seem willing to sacrifice performance and/or private time to engage in such voluntary behaviors. Hence, managers must realize that there is great potential in the employees that goes beyond the normal focus on in-role performance. Although front-line workers are often pushed by management to focus on short-term success, they are eager to devise strategies for achieving success in the long run.

Companies with high levels of bottom-up participation in operations strategy formation significantly outperform their peers in terms of productivity improvements. Unlike corporate strategy, operations strategy is influenced far more by operational employees through strategy-supportive behavior. The literature on bottom-up initiatives is vague about the antecedents of voluntary contributions to operations strategy formation; research on the possible antecedents of employee behavior more generally is inconclusive about its relation to bottom-up operations strategy formation. Survey data from 209 respondents is analyzed with structural equation modeling to test the hypothesized relationships. This paper develops the operations strategy opportunity-motivation-ability (OMA) framework. Leaders have to establish autonomy and structured idea management processes (O) top-down. Only then, employees can feel strategically aligned (A) and engage (M), and thus contribute to operations strategy bottom-up. In addition, we show that the indirect relations between top-down opportunities and behavior supporting bottom-up operations strategy formation are mediated by perceived strategic alignment and by employee engagement. Managers must first establish opportunities to behave strategy supportive. Only afterward do efforts to foster strategic alignment and employee engagement unlock the full potential of the contextual antecedents. Our findings enable operations managers to foster behavior supporting bottom-up operations strategy formation more effectively in their workforce.

In this contribution, a data-driven approach towards the prediction of maintenance for the critical component of an injection molding machine is presented. We present our path from exploring and cleaning the data towards the implementation of a prediction algorithm based on kernel density estimation. We give first analytical evidence of the algorithms potential. Moreover, we compare the approach described here with our previous work where we went a model-based approach and present advantages and disadvantages of the two approaches. We try to contribute to a non-comprehensive guide on the implementation of predictive maintenance systems for industrial mass production facilities.

ZusammenfassungKomplikationsmöglichkeiten sind jedweder Therapiemaßnahme immanent, insbesondere den operativen Behandlungsverfahren. Den allgemeinen Komplikationen, wie sie beispielsweise eine gestörte Hämostase oder Infektionen der Atemwege, des harnableitenden Systems oder andere Allgemeininfekte darstellen, stehen lokale Komplikationsmöglichkeiten am operativ behandelten rheumatischen Ellenbogengelenk gegenüber. Als wesentliche lokale Komplikationen sind am Ellenbogengelenk besonders Wundheilungsstörungen und Infektionen gefürchtet. Der immunsupprimierende Einfluss der Grund erkrankung einerseits sowie der medikamentösen Therapie andererseits kompliziert diese Problematik nicht selten. Darüber hinaus sind neurologische Komplikationen durch direkte oder häufiger durch indirekte Nervenschädigungen im Rahmen der Ellenbogenchirurgie öfter als an vielen anderen Regionen anzutreffen. Schließlich gilt das Ellenbogengelenk als ausgesprochen sensibel hinsichtlich postoperativer Bewegungseinschränkungen und im Extremfall der Ausbildung von Kontrakturen. Mechanische Komplikationen treten zum Beispiel im Rahmen endoprothetischer Versorgungen auf. So sind Luxationen, Endoprothesenlockerungen und auch periprothetische Frakturen möglich. Gerade letztere spielen im Falle von Endoprothesenwechseloperationen eine nicht zu unterschätzende Rolle. In den vergangenen Jahren sind erste Ansätze technischer Neuerungen für die Entwicklung modularer Systeme entstanden. Dennoch muss häufiger als an anderen Gelenken nach Versagen der Endoprothese auf individuell angefertigte Sonderimplantate zurückgegriffen werden. Arthrodesen oder Resektions-Interpositions-Arthroplastiken sind als Salvage-Procedure nur selten sinnvoll möglich und oft mit erheblichen funktionellen Einschränkungen verbunden. Sie stellen somit keine wirklichen Alternativen zur Revisionsalloarthroplastik dar. Nur im Zusammenspiel einer subtilen Indikationsstellung, der korrekten Operationsplanung und einer präzisen Operationstechnik sowie adäquaten Nachsorge lässt sich die vergleichsweise höhere Komplikationsrate der Eingriffe am rheumatischen Ellenbogengelenk minimieren.

How is metaphysics related to the empirical sciences? Should metaphysics in general be guided by the sources, methods and results of the sciences? And what about the special case of the metaphysics of the social world: should it likewise be guided by the sources, methods and results of the social sciences? In her paper “Social Science as a Guide to Social Metaphysics?”, K. Hawley raises the question: If we are sympathetic to the project of naturalising metaphysics, how should we approach the metaphysics of the social world? She proceeds by discussing three approaches to social metaphysics: (SM-1) inference to the best explanation (IBE) from current social science, (SM-2) descriptive conceptual analysis, and (SM-3) normative, especially ‘ameliorative’ projects. At the end of her discussion, she reaches a rather pessimistic conclusion, especially as regards the IBE approach: “a number of phenomena indicate that the prospects for securely basing social metaphysics via inference to the best explanation from social science are currently faint. […] We need to look elsewhere if we are to develop a metaphysics of the social world.” In my comments on her paper, I try to re-animate the program of an inductive metaphysics by defending the idea that the method of inference to the best explanation (IBE method) should be the central method of justification for metaphysics in general and for social metaphysics in particular.

In this contribution we present a model based approach towards predictive maintenance of the hydraulic pump of an injection-moulding machine for a system that remains in production. We present a methodology to iteratively gain a detailed understanding of a production facility. We describe our approach from problem evaluation, gathering of expert knowledge, data access, exploration of and knowledge mapping to the data, towards a first model. We discuss the advantages of the implementation of expert knowledge to define normal machine behaviour in terms of data-quality control and resource-friendly modelling. We present first results from a physical model of a subprocess and from a model based on vibration analysis and discuss their interplay and possible benefits from this different models.