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Immune checkpoint inhibitors have revolutionised cancer treatment by offering durable responses to many patients with solid and haematological cancers. The high prices and increasing use of immune checkpoint inhibitors put considerable strain on health-care budgets globally. This financial strain could jeopardise patients' access to these anti-cancer therapies. However, substantial evidence suggests that immune checkpoint inhibitors are being administered at doses that exceed the minimum dose required for maximum anti-tumour efficacy. Therefore, investigating and implementing the most cost-effective dosing strategies for immune checkpoint inhibitors are urgently necessary. This Personal View provides an overview of existing data on immune checkpoint inhibitor pharmacology and (novel) dosing strategies for anti-PD-1 therapy with nivolumab and pembrolizumab, with a special focus on cost-effectiveness and saving potential. Furthermore, specific recommendations to guide health-care professionals are provided, through the process of prescribing, rounding, preparing, and administering nivolumab and pembrolizumab in the most practical and cost-effective way possible.

We present the first constraints on the prevalence of z>10 galaxies in the Hubble Ultra Deep Field (HUDF) leveraging new NIRCam observations from JEMS (JWST Extragalactic Medium-band Survey). These NIRCam observations probe redward of 1.6$μ$m, beyond the wavelength limit of HST, allowing us to search for galaxies to z>10. These observations indicate that the highest redshift candidate identified in the HUDF09 data with HST, UDFj-39546284, has a redshift of z>11.5, as had been suggested in analyses of the HUDF12/XDF data. This has now been confirmed with JWST NIRSpec. This source is thus the most distant galaxy discovered by HST in its >30 years of operation. Additionally, we identify nine other z~8-13 candidate galaxies over the HUDF, two of which are new discoveries that appear to lie at z~11-12. We use these results to characterize the evolution of the UV luminosity function (LF) from z~15 to z~8.7. While our LF results at z~8.7 and z~10.5 are consistent with previous findings over the HUDF, our new LF estimates at z~12.6 are higher than other results in the literature, potentially pointing to a milder evolution in the UV luminosity density from z~12.6. We emphasize that our LF results are uncertain given the small number of z~12.6 sources and limited volume probed. The new NIRCam data also indicate that the faint z~8-13 galaxies in the HUDF/XDF show blue UV-continuum slopes beta~-2.7, high specific star formation rates ~24.5 Gyr**-1, and high EW (~1300A) [OIII]+H$β$ emission, with two z~8.5 sources showing [OIII]+H$β$ EWs of ~2300 A., 21 pages, 14 figures, 7 tables, resubmitted to MNRAS, after replying to the referee report

Background: Ranitidine, a histamine 2 blocker, is the standard of care to prevent hypersensitivity reactions (HSRs) caused by paclitaxel infusion. However, the added value of ranitidine in this premedication regimen is controversial. Therefore, we compared the incidence of HSRs during paclitaxel treatment between a standard regimen including ranitidine and a regimen without ranitidine. Methods: This prospective, pre–post interventional, non-inferiority study compared the standard premedication regimen (N = 183) with dexamethasone, clemastine and ranitidine with a premedication regimen without ranitidine (N = 183). The primary outcome was the incidence of HSR grade ≥3. Non-inferiority was determined by checking whether the upper bound of the two-sided 90% confidence interval (CI) for the difference in HSR rates excluded the +6% non-inferiority margin. Results: In both the pre-intervention (with ranitidine) and post-intervention (without ranitidine) group 183 patients were included. The incidence of HSR grade ≥3 was 4.4% (N = 8) in the pre-intervention group and 1.6% (N = 3) in the post-intervention group: difference −2.7% (90% CI: −6.2 to 0.1). Conclusions: As the upper boundary of the 90% CI does not exceed the predefined non-inferiority margin of +6%, it can be concluded that a premedication regimen without ranitidine is non-inferior to a premedication regimen with ranitidine. Clinical Trial Registration: www.trialregister.nl; NL8173.

Aims. We produce a clean and well-characterised catalogue of objects within 100 pc of the Sun from the Gaia Early Data Release 3. We characterise the catalogue through comparisons to the full data release, external catalogues, and simulations. We carry out a first analysis of the science that is possible with this sample to demonstrate its potential and best practices for its use., Methods. Theselection of objects within 100 pc from the full catalogue used selected training sets, machine-learning procedures, astrometric quantities, and solution quality indicators to determine a probability that the astrometric solution is reliable. The training set construction exploited the astrometric data, quality flags, and external photometry. For all candidates we calculated distance posterior probability densities using Bayesian procedures and mock catalogues to define priors. Any object with reliable astrometry and a non-zero probability of being within 100 pc is included in the catalogue., Results. We have produced a catalogue of 331 312 objects that we estimate contains at least 92% of stars of stellar type M9 within 100 pc of the Sun. We estimate that 9% of the stars in this catalogue probably lie outside 100 pc, but when the distance probability function is used, a correct treatment of this contamination is possible. We produced luminosity functions with a high signal-to-noise ratio for the main-sequence stars, giants, and white dwarfs. We examined in detail the Hyades cluster, the white dwarf population, and wide-binary systems and produced candidate lists for all three samples. We detected local manifestations of several streams, superclusters, and halo objects, in which we identified 12 members of Gaia Enceladus. We present the first direct parallaxes of five objects in multiple systems within 10 pc of the Sun., Conclusions. We provide the community with a large, well-characterised catalogue of objects in the solar neighbourhood. This is a primary benchmark for measuring and understanding fundamental parameters and descriptive functions in astronomy.

Theories link threat with right-wing political beliefs. We use the World Values Survey (60,378 participants) to explore how six types of threat (e.g., economic, violence, and surveillance) are associated with multiple political beliefs (e.g., cultural, economic, and ideological identification) in 56 countries/territories. Multilevel models with individuals nested in countries revealed that the threat-political belief association depends on the type of threat, the type of political beliefs, and the country. Economic-related threats tended to be associated with more left-wing economic political beliefs and violence-related threats tended to be associated with more cultural right-wing beliefs, but there were exceptions to this pattern. Additional analyses revealed that the associations between threat and political beliefs were different across countries. However, our analyses identified few country characteristics that could account for these cross-country differences. Our findings revealed that political beliefs and perceptions of threat are linked, but that the relationship is not simple. Keywords: Ideology, Belief Systems, Threat, Culture

Introduction: Erlotinib’s gastrointestinal solubility and absorption are decreased by proton pump inhibitors (PPIs). Since erlotinib is a lipophilic drug, we hypothesized that concomitant intake with the fatty beverage milk may be a feasible way to increase erlotinib uptake. We performed a two-period, randomized, crossover study to investigate the influence of cow’s milk with 3.9% fat on the exposure of erlotinib with and without the PPI esomeprazole in patients with non-small cell lung cancer (NSCLC). The effect of esomeprazole was studied in an additional intrapatient comparison. Method: Pharmacokinetic sampling was performed on days 7 and 14 during 24 consecutive hours. During the 7 days prior to pharmacokinetic sampling, erlotinib was taken daily with 250 mL of either water or milk. In the PPI arm, esomeprazole (40 mg once daily 3 h prior to erlotinib) was taken for 3 days. Results: Erlotinib area under the curve from time zero to 24 h (AUC24) did not significantly change when administered with milk, compared with water, in both non-PPI users (n = 14; − 3%; 95% confidence interval [CI] − 12 to 8%; p = 0.57) and patients who used esomeprazole (n = 15; 0%; 95% CI − 15 to 17%; p = 0.95). Esomeprazole decreased erlotinib AUC24 by 47% (n = 9; 95% CI − 57 to − 34%; p < 0.001) and Cmax by 56% (95% CI − 64 to − 46%; p < 0.001). No differences in toxicities were observed between milk and water. Conclusion: Milk with 3.9% fat has no effect on the exposure to erlotinib in NSCLC patients, independent of PPI use. The combination with milk is safe and well tolerated. Concomitant esomeprazole treatment strongly decreased both erlotinib AUC24 and Cmax and should be avoided if possible.

During the past two decades, small-molecule kinase inhibitors have proven to be valuable in the treatment of solid and haematological tumours. However, because of their oral administration, the intrapatient and interpatient exposure to small-molecule kinase inhibitors (SMKIs) is highly variable and is affected by many factors, such as concomitant use of food and herbs. Food–drug interactions are capable of altering the systemic bioavailability and pharmacokinetics of these drugs. The most important mechanisms underlying food–drug interactions are gastrointestinal drug absorption and hepatic metabolism through cytochrome P450 isoenzymes. As food–drug interactions can lead to therapy failure or severe toxicity, knowledge of these interactions is essential. This Review provides a comprehensive overview of published studies involving food–drug interactions and herb–drug interactions for all registered SMKIs up to Oct 1, 2019. We critically discuss US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines concerning food-drug interactions and offer clear recommendations for their management in clinical practice.

Background: Approximately 5% of patients experience recurrent symptoms after carpal tunnel release (CTR) and need revision surgery. Several surgical techniques have been described for recurrent carpal tunnel syndrome (CTS) and the abductor digiti minimi (ADM) flap is one of them. Literature concerning clinical results of the ADM flap for recurrent CTS is lacking. The aim of this study is to evaluate the outcomes of the ADM flap for recurrent CTS. Methods: We treated seven patients with the ADM flap (eight hands) between July 2016 and February 2019. Patient characteristics were assessed, and patients were asked about their symptoms (pain, sensation and paresthesia) before and after surgery. Postoperatively, we administered CTS symptoms, satisfaction with the surgery, patient-reported outcome measurements (BCTQ and QuickDASH) and whether they would undergo the same surgery again. Complications were also recorded Results: The median follow-up was 14 months. The success rate measured by CTS symptoms was 88%. Seven out of eight patients were satisfied with the results and two patients would not elect to undergo the same procedure again. Two patients reported having a weaker grip at the donor site. The median BCTQ symptom and function scores were 2.9 (1.7–3.5) and 2.6 (1.8–3.0) respectively. The median QuickDASH score was 41 (IQR 22–52). Complications reported were wound dehiscence (n = 1) and hypertrophic scar (n = 1). Conclusions: The outcomes of the ADM flap in patients with recurrent CTS were like other commonly used procedures in recurrent CTS. Level of Evidence: Level IV (Therapeutic)

Background: Total wrist arthroplasty (TWA) is a treatment option for many debilitating wrist conditions. With recent improvements in implant design, indications for TWA have broadened. However, despite these improvements, there are still complications associated with TWA, such as unplanned reoperation and eventual implant removal. The goal of this study was to identify risk factors for an unplanned reoperation or implant revision after a TWA at 2 academic medical centers between 2002 and 2015. Methods: In this retrospective study, 24 consecutive TWAs were identified using CPT codes. Medical records were manually reviewed to identify demographic, patient- or disease-related, and surgery-related risk factors for reoperation and implant removal after a primary TWA. Results: Forty-six percent of wrists (11 of 24 TWAs performed) had a reoperation after a median of 3.4 years, while 29% (7 of 24) underwent implant revision after a median of 5 years. Two patients had wrist surgery prior to their TWA, both eventually had their implant removed ( P = .08). There were no risk factors associated with reoperation or implant removal. Conclusion: Unplanned reoperation and implant removal after a primary TWA are common. Approximately 1 in 3 wrists are likely to undergo revision surgery. We found no factors associated with reoperation or implant removal; however, prior wrist surgery showed a trend toward risk of implant removal after TWA.

Objective To analyze the reproducibility, reliability, and demographics of a simplified anatomical scaphoid fracture classification based on posteroanterior radiographs using a large database of scaphoid fractures. Methods The study consisted of a retrospective review of electronic medical records of 871 consecutive patients. All patients presented between 2003 and 2014 at two centers. Patient- and surgeon-related factors were analyzed. Additionally, interobserver reliability of the Herbert and simplified scaphoid fracture classifications were tested. Results Proximal pole fractures were defined as fractures in which the center of the fracture line was proximal to the distal scapholunate interval (n = 30), waist fractures (n = 802) were defined as fractures involving the scaphocapitate interval, and distal tubercle fractures (n = 39) were defined as fractures involving the scaphotrapeziotrapezoid (STT) interval. The interobserver reliability of the simplified classification was fair (κ = 0.37) as for the Herbert classification (κ = 0.31). The average doubt of the answers of the observers was 2.1 on a scale from 0 to 10 for the simplified classification and 3.6 for the Herbert classification (P Conclusions All complete fractures across the entire scaphoid distal to the scapholunate articulation and proximal to the STT joint can be classified as waist fractures; nonwaist scaphoid fractures are uncommon (6%) and have somewhat different presentations compared to waist fractures. Simplifying the fracture classification slightly improves interobserver reliability, although remaining fair, and significantly reduces doubt. Level of Evidence This is a Level III, prognostic study.

Context. The full third Gaia data release will provide, for the first time, the calibrated spectra obtained with the blue and red Gaia slitless spectrophotometers (BP and RP, respectively). Gaia is a very complex mission and cannot be considered as a single instrument, but rather as many instruments. The two lines of sight with wide fields of view introduce strong variations of the observations across the large focal plane with more than one hundred different detectors. The main challenge when facing Gaia spectral calibration is that no lamp spectra or flat fields are available during the mission. Also, the significant size of the line spread function with respect to the dispersion of the prisms produces alien photons contaminating neighbouring positions of the spectra. This makes the calibration special and different from standard approaches. Aims. This work gives a detailed description of the internal calibration model for the spectrophotometric data used to obtain the content of the Gaia catalogue. The main purpose of the internal calibration is to bring all the epoch spectra onto a common flux and pixel (pseudo-wavelength) scale, taking into account variations over the focal plane and with time, producing a mean spectrum from all the observations of the same source. Methods. In order to describe all observations on a common mean flux and pseudo-wavelength scale, we constructed a suitable representation of the internally calibrated mean spectra via basis functions, and we described the transformation between non-calibrated epoch spectra and calibrated mean spectra via a discrete convolution, parametrising the convolution kernel to recover the relevant coefficients. Results. The model proposed here for the internal calibration of the Gaia spectrophotometric observations is able to combine all observations into a mean instrument to allow the comparison of different sources and observations obtained with different instrumental conditions along the mission and the generation of mean spectra from a number of observations of the same source. We derived a calibration model that can handle the self-calibrating nature of the problem. The output of this model provides the internal mean spectra, not as a sampled function (flux and wavelength), but as a linear combination of basis functions, although sampled spectra can easily be derived from them., Authors at the ICCUB were supported by the Spanish Ministry of Science, Innovation and University (MICIU/FEDER, UE) through grant RTI2018-095076-B-C21, and the Institute of Cosmos Sciences University of Barcelona (ICCUB, Unidad de Excelencia “María de Maeztu”) through grant CEX2019-000918-M. Authors at the Institute of Astronomy of the University of Cambridge were supported by the United Kingdom Science and Technology Facilities Council (STFC) and the United Kingdom Space Agency (UKSA) through the following grants to the University of Cambridge: ST/K000756/1, ST/N000641/1 and ST/S000089/1. Authors at INAF were supported by the Agenzia Spaziale Italiana (ASI) through contracts I/037/08/0, I/058/10/0, 2014-025-R.0, 2014-025-R.1.2015 and 2018-24-HH.0 to the Italian Istituto Nazionale di Astrofisica (INAF), and INAF.

Rowell, N., et al., [Context] The unprecedented astrometric precision of the Gaia mission relies on accurate estimates of the locations of sources in the Gaia data stream. This is ultimately performed by point spread function (PSF) fitting, which in turn requires an accurate reconstruction of the PSF, including calibrations of all the major dependences. These include a strong colour dependence due to Gaia's broad G band and a strong time dependence due to the evolving contamination levels and instrument focus. Accurate PSF reconstruction is also important for photometry. Gaia Early Data Release 3 (EDR3) will, for the first time, use a PSF calibration that models several of the strongest dependences, leading to signficantly reduced systematic errors. [Aims] We describe the PSF model and calibration pipeline implemented for Gaia EDR3, including an analysis of the calibration results over the 34 months of data. We include a discussion of the limitations of the current pipeline and directions for future releases. This will be of use both to users of Gaia data and as a reference for other precision astrometry missions. [Methods] We develop models of the 1D line spread function (LSF) and 2D PSF profiles based on a linear combination of basis components. These are designed for flexibility and performance, as well as to meet several mathematical criteria such as normalisation. We fit the models to selected primary sources in independent time ranges, using simple parameterisations for the colour and other dependences. Variation in time is smoothed by merging the independent calibrations in a square root information filter, with resets at certain mission events that induce a discontinuous change in the PSF. [Results] The PSF calibration shows strong time and colour dependences that accurately reproduce the varying state of the Gaia astrometric instrument. Analysis of the residuals reveals both the performance and the limitations of the current models and calibration pipeline, and indicates the directions for future development. [Conclusions] The PSF modelling and calibration carried out for Gaia EDR3 represents a major step forwards in the data processing and will lead to reduced systematic errors in the core mission data products. Further significant improvements are expected in the future data releases., The work described in this paper has been financially supported by the United Kingdom Particle Physics and Astronomy Research Council (PPARC), the United Kingdom Science and Technology Facilities Council (STFC), and the United Kingdom Space Agency (UKSA) through the following grants to the University of Bristol, the University of Cambridge, the University of Edinburgh, the University of Leicester, the Mullard Space Sciences Laboratory of University College London, and the United Kingdom Rutherford Appleton Laboratory (RAL): PP/D006511/1, PP/D006546/1, PP/D006570/1, ST/I000852/1, ST/J005045/1, ST/K00056X/1, ST/K000209/1, ST/K000756/1, ST/L006561/1, ST/N000595/1, ST/N000641/1, ST/N000978/1, ST/N001117/1, ST/S000089/1, ST/S000976/1, ST/S001123/1, ST/S001948/1, ST/S002103/1, and ST/V000969/1; the Spanish Ministry of Economy (MINECO/FEDER, UE) through grants ESP2016-80079-C2-1-R, RTI2018-095076-B-C21 and the Institute of Cosmos Sciences University of Barcelona (ICCUB, Unidad de Excelencia “María de Maeztu”) through grants MDM-2014-0369 and CEX2019-000918-M; the German Aerospace Agency (Deutsches Zentrum für Luft- und Raumfahrt e.V., DLR) through grants 50QG0501, 50QG0601, 50QG0602, 50QG0701, 50QG0901, 50QG1001, 50QG1101, 50QG1401, 50QG1402, 50QG1403, and 50QG1404 and the Centre for Information Services and High Performance Computing (ZIH) at the Technische Universität (TU) Dresden for generous allocations of computer time; the Agenzia Spaziale Italiana (ASI) through contracts I/037/08/0, I/058/10/0, 2014-025-R.0, 2014-025-R.1.2015 and 2018-24-HH.0 to the Italian Istituto Nazionale di Astrofisica; and the Swedish National Space Board (SNSB/Rymdstyrelsen). A.B. additionally acknowledges financial support from the Netherlands Research School for Astronomy (NOVA).

Full list of authors: Hodgkin, S. T.; Harrison, D. L.; Breedt, E.; Wevers, T.; Rixon, G.; Delgado, A.; Yoldas, A.; Kostrzewa-Rutkowska, Z.; Wyrzykowski, Ł.; van Leeuwen, M.; Blagorodnova, N.; Campbell, H.; Eappachen, D.; Fraser, M.; Ihanec, N.; Koposov, S. E.; Kruszyńska, K.; Marton, G.; Rybicki, K. A.; Brown, A. G. A.; Burgess, P. W.; Busso, G.; Cowell, S.; De Angeli, F.; Diener, C.; Evans, D. W.; Gilmore, G.; Holland, G.; Jonker, P. G.; van Leeuwen, F.; Mignard, F.; Osborne, P. J.; Portell, J.; Prusti, T.; Richards, P. J.; Riello, M.; Seabroke, G. M.; Walton, N. A.; Ábrahám, P.; Altavilla, G.; Baker, S. G.; Bastian, U.; O'Brien, P.; de Bruijne, J.; Butterley, T.; Carrasco, J. M.; Castañeda, J.; Clark, J. S.; Clementini, G.; Copperwheat, C. M.; Cropper, M.; Damljanovic, G.; Davidson, M.; Davis, C. J.; Dennefeld, M.; Dhillon, V. S.; Dolding, C.; Dominik, M.; Esquej, P.; Eyer, L.; Fabricius, C.; Fridman, M.; Froebrich, D.; Garralda, N.; Gomboc, A.; González-Vidal, J. J.; Guerra, R.; Hambly, N. C.; Hardy, L. K.; Holl, B.; Hourihane, A.; Japelj, J.; Kann, D. A.; Kiss, C.; Knigge, C.; Kolb, U.; Komossa, S.; Kóspál, Á.; Kovács, G.; Kun, M.; Leto, G.; Lewis, F.; Littlefair, S. P.; Mahabal, A. A.; Mundell, C. G.; Nagy, Z.; Padeletti, D.; Palaversa, L.; Pigulski, A.; Pretorius, M. L.; van Reeven, W.; Ribeiro, V. A. R. M.; Roelens, M.; Rowell, N.; Schartel, N.; Scholz, A.; Schwope, A.; Sipőcz, B. M.; Smartt, S. J.; Smith, M. D.; Serraller, I.; Steeghs, D.; Sullivan, M.; Szabados, L.; Szegedi-Elek, E.; Tisserand, P.; Tomasella, L.; van Velzen, S.; Whitelock, P. A.; Wilson, R. W.; Young, D. R.-- This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited., Context. Since July 2014, the Gaia mission has been engaged in a high-spatial-resolution, time-resolved, precise, accurate astrometric, and photometric survey of the entire sky. Aims. We present the Gaia Science Alerts project, which has been in operation since 1 June 2016. We describe the system which has been developed to enable the discovery and publication of transient photometric events as seen by Gaia. Methods. We outline the data handling, timings, and performances, and we describe the transient detection algorithms and filtering procedures needed to manage the high false alarm rate. We identify two classes of events: (1) sources which are new to Gaia and (2) Gaia sources which have undergone a significant brightening or fading. Validation of the Gaia transit astrometry and photometry was performed, followed by testing of the source environment to minimise contamination from Solar System objects, bright stars, and fainter near-neighbours. Results. We show that the Gaia Science Alerts project suffers from very low contamination, that is there are very few false-positives. We find that the external completeness for supernovae, CE = 0.46, is dominated by the Gaia scanning law and the requirement of detections from both fields-of-view. Where we have two or more scans the internal completeness is CI = 0.79 at 3 arcsec or larger from the centres of galaxies, but it drops closer in, especially within 1 arcsec. Conclusions. The per-Transit photometry for Gaia transients is precise to 1% at G = 13, and 3% at G = 19. The per-Transit astrometry is accurate to 55 mas when compared to Gaia DR2. The Gaia Science Alerts project is one of the most homogeneous and productive transient surveys in operation, and it is the only survey which covers the whole sky at high spatial resolution (subarcsecond), including the Galactic plane and bulge. © S. T. Hodgkin et al. 2021., This work has made use of data from the European Space Agency (ESA) mission Gaia (https://www.cosmos.esa.int/gaia), processed by the Gaia Data Processing and Analysis Consortium (DPAC, https://www.cosmos.esa.int/web/gaia/dpac/consortium). Funding for the DPAC has been provided by national institutions, in particular the institutions participating in the Gaia Multilateral Agreement. Further details of funding authorities and individuals contributing to the success of the mission is shown at https://gea.esac.esa.int/archive/documentation/GEDR3/Miscellaneous/sec_acknowl/. We thank the United Kingdom Particle Physics and Astronomy Research Council (PPARC), the United Kingdom Science and Technology Facilities Council (STFC), and the United Kingdom Space Agency (UKSA) through the following grants to the University of Bristol, the University of Cambridge, the University of Edinburgh, the University of Leicester, the Mullard Space Sciences Laboratory of University College London, and the United Kingdom Rutherford Appleton Laboratory (RAL): PP/D006511/1, PP/D006546/1, PP/D006570/1, ST/I000852/1, ST/J005045/1, ST/K00056X/1, ST/K000209/1, ST/K000756/1, ST/L006561/1, ST/N000595/1, ST/S000623/1, ST/N000641/1, ST/N000978/1, ST/N001117/1, ST/S000089/1, ST/S000976/1, ST/S001123/1, ST/S001948/1, ST/S002103/1, and ST/V000969/1. This paper made use of the Whole Sky Database (WSDB) created by Sergey Koposov and maintained at the Institute of Astronomy, Cambridge with financial support from the Science and Technology Facilities Council (STFC) and the European Research Council (ERC). We thank the William Herschel and Isaac Newton Telescopes on the Roque de los Muchachos Observatory, La Palma, Spain, as well as the Optical Infrared Coordination Network for Astronomy (OPTICON) for their support of this project through telescope time, especially during the commissioning and verification phases. We thank the Copernico 1.82 m telescope (Mt. Ekar, Asiago Italy) operated by INAF Padova for supporting the project through telescope time (under the Large Programme Tomasella-SNe) during the verification phases. We acknowledge observations taken as part of the PESSTO project collected at the European Organisation for Astronomical Research in the Southern Hemisphere under ESO programme 199.D-0143. Authors at the ICCUB were supported by the Spanish Ministry of Science, Innovation and University (MICIU/FEDER, UE) through grant RTI2018-095076-B-C21, and the Institute of Cosmos Sciences University of Barcelona (ICCUB, Unidad de Excelencia ’María de Maeztu’) through grant CEX2019-000918-M. This work is supported by Polish NCN grants: Daina No. 2017/27/L/ST9/03221, Harmonia No. 2018/30/M/ST9/00311, Preludium No. 2017/25/N/ST9/01253 and MNiSW grant DIR/WK/2018/12 as well as the European Commission’s Horizon2020 OPTICON grant No. 730890. The Authors would like to thank the Warsaw University OGLE project for their continuous support in this work. AB acknowledges financial support from the Netherlands Research School for Astronomy (NOVA). AG acknowledges the financial support from the Slovenian Research Agency (grants P1-0031, I0-0033, J1-8136, J1-2460). AH was funded in part by the Leverhulme Trust through grant RPG-2012-541 and by the European Research Council grant 320360. AP acknowledges support from the NCN grant no. 2016/21/B/ST9/01126. CM acknowledges support from Jim and Hiroko Sherwin. DAK acknowledges support from the Spanish research projects AYA 2014-58381-P, AYA2017-89384-P, from Juan de la Cierva Incorporación fellowship IJCI-2015-26153, and from Spanish National Research Project RTI2018-098104-J-I00 (GRBPhot). EB and STH are funded by the Science and Technology Facilities Council grant ST/S000623/1. TW was funded in part by European Research Council grant 320360 and by European Commission grant 730980. GC acknowledges the Agenzia Spaziale Italiana (ASI) for its continuing support through contract 2018-24-HH.0 to the Italian Istituto Nazionale di Astrofisica (INAF). GD acknowledges the observing grant support from the Institute of Astronomy and Rozhen NAO BAS through the bilateral joint research project “Gaia Celestial Reference Frame (CRF) and fast variable astronomical objects” (during 2020-2022, leader is G. Damljanovic), and support by the Ministry of Education, Science and Technological Development of the Republic of Serbia (contract no. 451-03-68/2020-14/200002). G. Marton acknowledges support from the EC Horizon 2020 project OPTICON (730890) and the ESA PRODEX contract no. 4000129910. MF is supported by a Royal Society - Science Foundation Ireland University Research Fellowship NB acknowledges support from the research programme VENI, with project number 016.192.277, which is (partly) financed by the Netherlands Organisation for Scientific Research (NWO). NI is partially supported by Polish NCN DAINA grant no. 2017/27/L/ST9/03221. PAW acknowledges research funding from the South African National Research Foundation. RWW was funded by the Science and Technology Facilities Council grant ST/P000541/1. V.A.R.M.R. acknowledges financial support from Radboud Excellence Initiative, the Fundação para a Ciência e a Tecnologia (FCT) in the form of an exploratory project of reference IF/00498/2015/CP1302/CT0001, FCT and the Ministério da Ciência, Tecnologia e Ensino Superior (MCTES) through national funds and when applicable co-funded EU funds under the project UIDB/EEA/50008/2020, and supported by Enabling Green E-science for the Square Kilometre Array Research Infrastructure (ENGAGE-SKA), POCI-01-0145-FEDER-022217, and PHOBOS, POCI-01-0145-FEDER-029932, funded by Programa Operacional Competitividade e Internacionalização (COMPETE 2020) and FCT, Portugal. ZKR acknowledges funding from the Netherlands Research School for Astronomy (NOVA). ZN acknowledges support from the ESA PRODEX contract nr. 4000129910., With funding from the Spanish government through the Severo Ochoa Centre of Excellence accreditation SEV-2017-0709.

Aims. We aim to demonstrate the scientific potential of the Gaia Early Data Release 3 (EDR3) for the study of different aspects of the Milky Way structure and evolution and we provide, at the same time, a description of several practical aspects of the data and examples of their usage., Methods. We used astrometric positions, proper motions, parallaxes, and photometry from EDR3 to select different populations and components and to calculate the distances and velocities in the direction of the anticentre. In this direction, the Gaia astrometric data alone enable the calculation of the vertical and azimuthal velocities; also, the extinction is relatively low compared to other directions in the Galactic plane. We then explore the disturbances of the current disc, the spatial and kinematical distributions of early accreted versus in situ stars, the structures in the outer parts of the disc, and the orbits of open clusters Berkeley 29 and Saurer 1., Results. With the improved astrometry and photometry of EDR3, we find that: (i) the dynamics of the Galactic disc are very complex with oscillations in the median rotation and vertical velocities as a function of radius, vertical asymmetries, and new correlations, including a bimodality with disc stars with large angular momentum moving vertically upwards from below the plane, and disc stars with slightly lower angular momentum moving preferentially downwards; (ii) we resolve the kinematic substructure (diagonal ridges) in the outer parts of the disc for the first time; (iii) the red sequence that has been associated with the proto-Galactic disc that was present at the time of the merger with Gaia-Enceladus-Sausage is currently radially concentrated up to around 14 kpc, while the blue sequence that has been associated with debris of the satellite extends beyond that; (iv) there are density structures in the outer disc, both above and below the plane, most probably related to Monoceros, the Anticentre Stream, and TriAnd, for which the Gaia data allow an exhaustive selection of candidate member stars and dynamical study; and (v) the open clusters Berkeley 29 and Saurer 1, despite being located at large distances from the Galactic centre, are on nearly circular disc-like orbits., Conclusions. Even with our simple preliminary exploration of the Gaia EDR3, we demonstrate how, once again, these data from the European Space Agency are crucial for our understanding of the different pieces of our Galaxy and their connection to its global structure and history.

We present the early installment of the third Gaia data release, Gaia EDR3, consisting of astrometry and photometry for 1.8 billion sources brighter than magnitude 21, complemented with the list of radial velocities from Gaia DR2. Gaia EDR3 contains celestial positions and the apparent brightness in G for approximately 1.8 billion sources. For 1.5 billion of those sources, parallaxes, proper motions, and the (G_BP-G_RP) colour are also available. The passbands for G, G_BP, and G_RP are provided as part of the release. For ease of use, the 7 million radial velocities from Gaia DR2 are included in this release, after the removal of a small number of spurious values. New radial velocities will appear as part of Gaia DR3. Finally, Gaia EDR3 represents an updated materialisation of the celestial reference frame (CRF) in the optical, the Gaia-CRF3, which is based solely on extragalactic sources. The creation of the source list for Gaia EDR3 includes enhancements that make it more robust with respect to high proper motion stars, and the disturbing effects of spurious and partially resolved sources. The source list is largely the same as that for Gaia DR2, but it does feature new sources and there are some notable changes. The source list will not change for Gaia DR3. Gaia EDR3 represents a significant advance over Gaia DR2, with parallax precisions increased by 30 percent, proper motion precisions increased by a factor of 2, and the systematic errors in the astrometry suppressed by 30--40 percent for the parallaxes and by a factor ~2.5 for the proper motions. The photometry also features increased precision, but above all much better homogeneity across colour, magnitude, and celestial position. A single passband for G, G_BP, and G_RP is valid over the entire magnitude and colour range, with no systematics above the 1 percent level.

Objective To determine the rate of salvage procedures and any other unplanned reoperations in patients with symptomatic Kienböck's disease who were treated with radial shortening osteotomy. In addition, we studied patient-reported outcome in the long term using Patient-Reported Outcome Measure Information System (PROMIS) instruments.Patients and Methods We performed a retrospective review of all patients who underwent radial shortening osteotomy for stage 2 and 3A Kienböck's disease. Patients who had concomitant revascularization were grouped separately. We collected demographic data, data regarding type of surgery and reoperations, and radiographic data. Patient-reported outcome measures were the PROMIS Upper Extremity Computer Adaptive Testing (CAT) and Pain Interference instruments, the abbreviated Disabilities of Arm, Shoulder, and Hand (QuickDASH), and the 0 to 10 numeric rating scale for pain and satisfaction.Results We included 48 patients who had radial shortening osteotomy alone, and 17 patients who had a combined procedure of radial shortening and direct revascularization. The rate of unplanned reoperations was 33% (16 of 48) in those who had radial shortening osteotomy and 24% (4 of 17) in those who had a combined procedure. Six (13%) of 48 patients underwent proximal row carpectomy due to failed radial shortening osteotomy. No salvage procedures were performed after combined radial shortening/revascularization. Median PROMIS Physical Function CAT scores were 56 (interquartile range [IQR]: 44–56) and 56 (IQR: 41–56), respectively. Median PROMIS Pain Interference scores were 39 (IQR: 39–52) and 39 (IQR: 39–49), respectively. Median QuickDASH scores were 2.3 (IQR: 0–23) and 4.5 (IQR: 2.3–14), respectively.Conclusion Radial shortening osteotomy for symptomatic Kienböck's disease yields reasonable long-term function. We observed that approximately one in eight patients underwent salvage surgery after radial shortening, and this should be taken into account when making the initial decision to treat Kienböck's disease surgically. There appeared to be no benefit of direct revascularization in addition to radial shortening in terms of patient-reported outcome in the long term.Level of Evidence This is a Level IV, therapeutic study.

Ranitidine, a histamine 2 blocker, is the standard of care to prevent hypersensitivity reactions (HSRs) caused by paclitaxel infusion. However, the added value of ranitidine in this premedication regimen is controversial. Therefore, we compared the incidence of HSRs during paclitaxel treatment between a standard regimen including ranitidine and a regimen without ranitidine.This prospective, pre-post interventional, non-inferiority study compared the standard premedication regimen (N = 183) with dexamethasone, clemastine and ranitidine with a premedication regimen without ranitidine (N = 183). The primary outcome was the incidence of HSR grade ≥3. Non-inferiority was determined by checking whether the upper bound of the two-sided 90% confidence interval (CI) for the difference in HSR rates excluded the +6% non-inferiority margin.In both the pre-intervention (with ranitidine) and post-intervention (without ranitidine) group 183 patients were included. The incidence of HSR grade ≥3 was 4.4% (N = 8) in the pre-intervention group and 1.6% (N = 3) in the post-intervention group: difference -2.7% (90% CI: -6.2 to 0.1).As the upper boundary of the 90% CI does not exceed the predefined non-inferiority margin of +6%, it can be concluded that a premedication regimen without ranitidine is non-inferior to a premedication regimen with ranitidine.www.trialregister.nl ; NL8173.

Background Many cancer patients use additional herbs or supplements in combination with their anti-cancer therapy. Green tea—active ingredient epigallocatechin-3-gallate (EGCG)—is one of the most commonly used dietary supplements among breast cancer patients. EGCG may alter the metabolism of tamoxifen. Therefore, the aim of this study was to investigate the influence of green tea supplements on the pharmacokinetics of endoxifen; the most relevant active metabolite of tamoxifen. Methods In this single-center, randomized cross-over trial, effects of green tea capsules on endoxifen levels were evaluated. Patients treated with tamoxifen for at least 3 months were eligible for this study. After inclusion, patients were consecutively treated with tamoxifen monotherapy for 28 days and in combination with green tea supplements (1 g twice daily; containing 300 mg EGCG) for 14 days (or vice versa). Blood samples were collected on the last day of monotherapy or combination therapy. Area under the curve (AUC0–24h), maximum concentration (Cmax) and minimum concentration (Ctrough) were obtained from individual plasma concentration–time curves. Results No difference was found in geometric mean endoxifen AUC0–24h in the period with green tea versus tamoxifen monotherapy (− 0.4%; 95% CI − 8.6 to 8.5%; p = 0.92). Furthermore, no differences in Cmax (− 2.8%; − 10.6 to 5.6%; p = 0.47) nor Ctrough (1.2%; − 7.3 to 10.5%; p = 0.77) were found. Moreover, no severe toxicity was reported during the whole study period. Conclusions This study demonstrated the absence of a pharmacokinetic interaction between green tea supplements and tamoxifen. Therefore, the use of green tea by patients with tamoxifen does not have to be discouraged.

Prior studies have demonstrated an organic anion transporter 6 (OAT6)-mediated accumulation of sorafenib in keratinocytes. The OAT6 inhibitor probenecid decreases sorafenib uptake in skin and might, therefore, decrease sorafenib-induced cutaneous adverse events. Here, the influence of probenecid on sorafenib pharmacokinetics and toxicity was investigated. Pharmacokinetic sampling was performed in 16 patients on steady-state sorafenib treatment at days 1 and 15 of the study. Patients received sorafenib (200&ndash, 800 mg daily) in combination with probenecid (500 mg two times daily (b.i.d.)) on days 2&ndash, 15. This study was designed to determine bioequivalence with geometric mean Area under the curve from zero to twelve hours (AUC0&ndash, 12 h) as primary endpoint. During concomitant probenecid, sorafenib plasma AUC0&ndash, 12 h decreased by 27% (90% CI: &minus, 38% to &minus, 14%, P &lt, 0.01). Furthermore, peak and trough levels of sorafenib, as well as sorafenib concentrations in skin, decreased to a similar extent in the presence of probenecid. The metabolic ratio of sorafenib-glucuronide to parent drug increased (+29%) in the presence of probenecid. A decrease in systemic sorafenib concentrations during probenecid administration seems to have influenced cutaneous concentrations. Since sorafenib-glucuronide concentrations increased compared with sorafenib and sorafenib-N-oxide, probenecid may have interrupted enterohepatic circulation of sorafenib by inhibition of the organic anion transporting polypeptides 1B1 (OATP1B1). Sorafenib treatment with probenecid is, therefore, not bioequivalent to sorafenib monotherapy. A clear effect of probenecid on sorafenib toxicity could not be identified in this study.

Aims: Survival after cancer diagnosed during childhood or adolescence continues to improve with new treatments and supportive therapies. Optimal long-term care requires that risks to vulnerable organs are clearly defined and translated into guidelines that are implemented into practice. PanCareLIFE is a pan-European consortium that addresses survivorship issues comprising fertility, hearing impairment and quality of life. This article describes the scientific basis of PanCareLIFE's studies.Methods: PanCareLIFE involves 17 partner institutions from eight European countries, with additional 11 data providers from five other countries. Study designs and methods include molecular genetic, cohort and case-control studies, a longitudinal study and an intervention study. Ethics and data protection issues have been taken into account from the beginning.Results: PanCareLIFE will investigate the way that treatment impairs female fertility, by evaluating anti-Mullerian hormone levels and the underlying genetic susceptibility to loss of fertility. For our fertility studies, more than 6000 survivors have completed questionnaires, more than 1500 provided serum samples and more than 400 case-control triads have been identified. Fertility preservation guidelines for boys and girls will be developed. More than 2000 survivors have contributed audiograms for the ototoxicity study. Almost 1000 samples were sent for genetic analysis related to ototoxicity and gonadal reserve. The SF-36 questionnaire will measure quality of life in more than 10,000 survivors.Conclusions: The large number of subjects enrolled in PanCareLIFE and the detailed information accumulated will allow in-depth evaluation of important outcomes. Fertility preservation guidelines will help patients and their families make informed decisions and contribute to their long-term well-being. (C) 2018 Elsevier Ltd. All rights reserved.

Objective Outcomes after repair of ruptured abdominal aortic aneurysm (RAAA) have improved in the last decade. It is unknown whether this has resulted in a reduction of postoperative bowel ischemia (BI). The primary objective was to determine BI prevalence after RAAA repair. Secondary objectives were to determine its major sequelae and differences between open repair (OR) and endovascular aneurysm repair (EVAR). Methods This systematic review (PROSPERO CRD42017055920) followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. MEDLINE and Embase were searched for studies published from 2005 until 2018. The methodologic quality of observational studies was assessed with the Methodological Index for Non-Randomized Studies (MINORS) tool. The quality of the randomized controlled trials (RCTs) was assessed with the Cochrane Collaboration's tool for assessing risk of bias. BI prevalence and rates of BI as cause of death, reoperation, and bowel resection were estimated with meta-analyses with a random-effects model. Differences between OR and EVAR were estimated with pooled risk ratios with 95% confidence intervals (CIs). Changes over time were assessed with Spearman rank test (ρ). Publication bias was assessed with a funnel plot analysis. Results A total of 101 studies with 52,670 patients were included; 72 studies were retrospective cohort studies, 14 studies were prospective cohort studies, 12 studies were retrospective administrative database studies, and 3 studies were RCTs. The overall methodologic quality of the RCTs was high, but that of observational studies was low. The pooled prevalence of BI ranged from of 0.08 (95% CI, 0.07-0.09) in database studies to 0.10 (95% CI, 0.08-0.12) in cohort studies. The risk of BI was higher after OR than after EVAR (risk ratio, 1.79; 95% CI, 1.25-2.57). The pooled rate of BI as cause of death was 0.04 (95% CI, 0.03-0.05), and that of BI as cause of reoperation and bowel resection ranged between 0.05 and 0.07. BI prevalence did not change over time (ρ, −0.01; P = .93). The funnel plot analysis was highly suggestive of publication bias. Conclusions The prevalence of clinically relevant BI after RAAA repair is approximately 10%. Approximately 5% of patients undergoing RAAA repair suffer from severe consequences of BI. BI is less prevalent after EVAR than after OR.

Background: The purpose of this study was to identify factors associated with unplanned reoperation after surgery for scapholunate interosseous ligament (SLIL) insufficiency. Methods: Using Current Procedural Terminology (CPT) codes from 3 hand surgery centers across 2 metropolitan areas, we identified 316 patients undergoing surgery for SLIL insufficiency from 2000 to 2014. Medical records were manually reviewed to collect data on factors that might be associated with unplanned reoperation, including age, sex, tobacco use, occupation, acuity of treatment, and reconstruction method. Results: Thirty-eight patients (12%) had an unplanned reoperation; most of them (65%) were a secondary reconstruction or salvage procedure (eg, 6 proximal row carpectomies, 9 revision reconstruction, and 10 partial carpal arthrodeses), while 5 (13%) were for unplanned screw removal. The median time between the index and second surgery was 16 months (range, 2-97 months). The type of index procedure was not associated with reoperation. The only factor associated with reoperation was cigarette smoking, and this association persisted when looking specifically at reoperations for revision or salvage. Conclusions: Patients should be counseled that smoking is associated with reoperation after SLIL surgery. Smoking cessation or decreasing nicotine usage may be beneficial prior to surgery. With the numbers available, there was no association between surgical technique and reoperation.

Purpose: In ongoing clinical research on metastatic castration-resistant prostate cancer (mCRPC) treatment, the potential enhanced efficacy of the combination of taxanes with AR-targeted agents, that is, enzalutamide and abiraterone, is currently being explored. Because enzalutamide induces the CYP3A4 enzyme and taxanes are metabolized by this enzyme, a potential drug–drug interaction needs to be investigated. Experimental Design: Therefore, we performed a pharmacokinetic cross-over study in mCRPC patients who were scheduled for treatment with cabazitaxel Q3W (25 mg/m2). Patients were studied for three consecutive cabazitaxel cycles. Enzalutamide (160 mg once daily) was administered concomitantly after the first cabazitaxel cycle, during 6 weeks. Primary endpoint was the difference in mean area under the curve (AUC) between the first (cabazitaxel monotherapy) and third cabazitaxel cycle, when enzalutamide was added. Results: A potential clinically relevant 22% (95% CI, 9%–34%; P = 0.005) reduction in cabazitaxel exposure was found with concomitant enzalutamide use. The geometric mean AUC0–24h of cabazitaxel was 181 ng*h/mL (95% CI, 150–219 ng*h/mL) in cycle 3 and 234 ng*h/mL (95% CI, 209–261 ng*h/mL) in cycle 1. This combination did not result in excessive toxicity, whereas PSA response was promising. Conclusions: We found a significant decrease in cabazitaxel exposure when combined with enzalutamide. In an era of clinical trials on combination strategies for mCRPC, it is important to be aware of clinically relevant drug–drug interactions. Because recent study results support the use of a lower standard cabazitaxel dose of 20 mg/m2, the clinical relevance of this interaction may be substantial, because the addition of enzalutamide may result in subtherapeutic cabazitaxel exposure. Clin Cancer Res; 24(3); 541–6. ©2017 AACR.

Purpose Carpal coalitions are common and usually incidental to the indication for wrist radiographs. It is not clear if, or when, carpal coalitions cause pain. The aim of this study was to assess the prevalence of incidental carpal coalitions by evaluating radiographs taken for various indications and to test the association of demographic variables and ordering indications with the finding of a carpal coalition. Methods We reviewed 1,119 posteroanterior wrist radiographs for the presence of carpal coalition. We used bivariate and multivariate analyses to assess demographic factors for their independent associations with the presence of carpal coalitions and to compare the difference in the prevalence of carpal coalitions between radiographs obtained to evaluate traumatic wrist pain (623 wrists), nontraumatic wrist pain (175 wrists), and other reasons (321 wrists). Results Radiographs of 98 out of 1,119 patients (8.8%) showed a carpal coalition. Carpal coalitions were equally likely on radiographs obtained for traumatic wrist pain and nontraumatic wrist pain. Patients with no wrist trauma or wrist pain were less likely to have a carpal coalition on their radiograph. Conclusions We consider carpal coalitions an unlikely cause of wrist pain. The lower prevalence in radiographs obtained for causes other than wrist trauma or wrist pain remains unexplained, although it may be spurious. In the evaluation of a patient with nonspecific wrist pain, clinicians should be careful ascribing symptoms to anatomical variations on radiographs. These incidental findings should not usually affect management. Type of study/level of evidence Diagnostic III.

Gaia Early Data Release 3 (Gaia EDR3) gives trigonometric parallaxes for nearly 1.5 billion sources. Inspection of the EDR3 data for sources identified as quasars reveals that their parallaxes are biased, that is systematically offset from the expected distribution around zero, by a few tens of microarcsec. We attempt to map the main dependencies of the parallax bias in EDR3. In principle this could provide a recipe for correcting the EDR3 parallaxes. For faint sources the quasars provide the most direct way to estimate parallax bias. In order to extend this to brighter sources and a broader range of colours, we use differential methods based on physical pairs (binaries) and sources in the Large Magellanic Cloud. The functional forms of the dependencies are explored by mapping the systematic differences between EDR3 and DR2 parallaxes. The parallax bias is found to depend in a non-trivial way on (at least) the magnitude, colour, and ecliptic latitude of the source. Different dependencies apply to the five- and six-parameter solutions in EDR3. While it is not possible to derive a definitive recipe for the parallax correction, we give tentative expressions to be used at the researcher's discretion and point out some possible paths towards future improvements., Comment: 32 pages, 30 figures. Submitted to Astronomy & Astrophysics. Revised version where typos in (A.3) have been corrected. For associated code, see https://www.cosmos.esa.int/web/gaia/edr3-code (code was not affected by the typos)

Riello, M., et al., [Context] Gaia Early Data Release 3 (Gaia EDR3) contains astrometry and photometry results for about 1.8 billion sources based on observations collected by the European Space Agency Gaia satellite during the first 34 months of its operational phase. [Aims] In this paper, we focus on the photometric content, describing the input data, the algorithms, the processing, and the validation of the results. Particular attention is given to the quality of the data and to a number of features that users may need to take into account to make the best use of the Gaia EDR3 catalogue. [Methods] The processing broadly followed the same procedure as for Gaia DR2, but with significant improvements in several aspects of the blue and red photometer (BP and RP) preprocessing and in the photometric calibration process. In particular, the treatment of the BP and RP background has been updated to include a better estimation of the local background, and the detection of crowding effects has been used to exclude affected data from the calibrations. The photometric calibration models have also been updated to account for flux loss over the whole magnitude range. Significant improvements in the modelling and calibration of the Gaia point and line spread functions have also helped to reduce a number of instrumental effects that were still present in DR2. Results. Gaia EDR3 contains 1.806 billion sources with G-band photometry and 1.540 billion sources with GBP and GRP photometry. The median uncertainty in the G-band photometry, as measured from the standard deviation of the internally calibrated mean photometry for a given source, is 0.2 mmag at magnitude G = 10-14, 0.8 mmag at G ≈ 17, and 2.6 mmag at G ≈ 19. The significant magnitude term found in the Gaia DR2 photometry is no longer visible, and overall there are no trends larger than 1 mmag mag-1. Using one passband over the whole colour and magnitude range leaves no systematics above the 1% level in magnitude in any of the bands, and a larger systematic is present for a very small sample of bright and blue sources. A detailed description of the residual systematic effects is provided. Overall the quality of the calibrated mean photometry in Gaia EDR3 is superior with respect to DR2 for all bands., The Gaia photometric data processing has been financially supported by (in alphabetical order by country): the Tenure Track Pilot Programme of the Croatian Science Foundation and the Ecole Polytechnique Fédérale de Lausanne and the Project TTP-2018-07-1171 Mining the Variable Sky, with funds of the Croatian-Swiss Research Programme; the Agenzia Spaziale Italiana (ASI) through contracts I/037/08/0, I/058/10/0, 2014-025-R.0, 2014-025-R.1.2015 and 2018-24-HH.0 to the Italian Istituto Nazionale di Astrofisica (INAF), and INAF; the Spanish Ministry of Science, Innovation and University (MICIU/FEDER, UE) through grants RTI2018-095076-B-C21, ESP2016-80079-C2-1-R, and the Institute of Cosmos Sciences University of Barcelona (ICCUB, Unidad de Excelencia “María de Maeztu”) through grants MDM-2014-0369 and CEX2019-000918-M; the United Kingdom Particle Physics and Astronomy Research Council (PPARC), the United Kingdom Science and Technology Facilities Council (STFC), and the United Kingdom Space Agency (UKSA) through the following grants to the University of Bristol, the University of Cambridge, the University of Edinburgh, the University of Leicester, the Mullard Space Sciences Laboratory of University College London, and the United Kingdom Rutherford Appleton Laboratory (RAL): PP/D006511/1, PP/D006546/1, PP/D006570/1, ST/I000852/1, ST/J005045/1, ST/K00056X/1, ST/K000209/1, ST/K000756/1, ST/L006561/1, ST/N000595/1, ST/N000641/1, ST/N000978/1, ST/N001117/1, ST/S000089/1, ST/S000976/1, ST/S001123/1, ST/S001948/1, ST/S002103/1, and ST/V000969/1.

Context. Gaia Early Data Release 3 (Gaia EDR3) provides accurate astrometry for about 1.6 million compact (QSO-like) extragalactic sources, 1.2 million of which have the best-quality five-parameter astrometric solutions., Aims. The proper motions of QSO-like sources are used to reveal a systematic pattern due to the acceleration of the solar systembarycentre with respect to the rest frame of the Universe. Apart from being an important scientific result by itself, the acceleration measured in this way is a good quality indicator of the Gaia astrometric solution., Methods. Theeffect of the acceleration was obtained as a part of the general expansion of the vector field of proper motions in vector spherical harmonics (VSH). Various versions of the VSH fit and various subsets of the sources were tried and compared to get the most consistent result and a realistic estimate of its uncertainty. Additional tests with the Gaia astrometric solution were used to get a better idea of the possible systematic errors in the estimate., Results. Our best estimate of the acceleration based on Gaia EDR3 is (2.32 +/- 0.16) x 10(-10) m s(-2) (or 7.33 +/- 0.51 km s(-1) Myr-1) towards alpha = 269.1 degrees +/- 5.4 degrees, delta = -31.6 degrees +/- 4.1 degrees, corresponding to a proper motion amplitude of 5.05 +/- 0.35 mu as yr(-1). This is in good agreement with the acceleration expected from current models of the Galactic gravitational potential. We expect that future Gaia data releases will provide estimates of the acceleration with uncertainties substantially below 0.1 mu as yr(-1).

Norovirus constitutes the most frequently identified infectious cause of disease outbreaks associated with untreated recreational water. When investigating outbreaks related to surface water, a One Health approach is insightful. Historically, there has been a focus on potential contamination of recreational water by bird droppings and a recent publication demonstrating human noroviruses in bird faeces suggested this should be investigated in future water‐related norovirus outbreaks. Here, we describe a One Health approach investigating a norovirus outbreak in a natural playground. On social media, a large amount of waterfowl were reported to defecate near these playground premises leading to speculations about their potential involvement. Surface water, as well as human and bird faecal specimens, was tested for human noroviruses. Norovirus was found to be the most likely cause of the outbreak but there was no evidence for transmission via waterfowl. Cases had become known on social media prior to notification to the public health service underscoring the potential of online media as an early warning system. In view of known risk factors, advice was given for future outbreak investigations and natural playground design.

Partial denervation of the wrist can benefit patients with chronic wrist pain. A complication of partial denervation is loss of proprioception and hypesthesia on the dorsal side of the hand. Our aim is to evaluate whether the sensory branches of the posterior interosseous nerve could contribute to the loss of proprioception and sensation. The branching pattern of the posterior interosseous nerve was studied in 20 cadaveric hands. The terminal branches of the posterior interosseous nerve reached the metacarpophalangeal joints in three specimens (15%), the midshaft of the metacarpals in three specimens (15%), carpometacarpal joints in 11 specimens (55%), and the scapholunate joint in three specimens (15%). The finding that terminal branches of the posterior interosseous nerve can reach the metacarpals and the metacarpophalangeal joints indicates that the posterior nerve may contribute to the proprioception and sensation of the dorsal side of the hand. Clin. Anat., 33:678-682, 2020. © 2019 Wiley Periodicals, Inc.

Regorafenib exposure could potentially be influenced by an interaction with acid-reducing drugs. In this crossover trial, patients were randomized into two sequence groups consisting of three phases: regorafenib intake alone, regorafenib with concomitant esomeprazole, and regorafenib with esomeprazole 3 hours prior. The primary end point was the relative difference (RD) in geometric means for regorafenib 0–24-hour area under the concentration-time curve (AUC 0–24h ) and was analyzed by a linear mixed model in 14 patients. AUC 0–24h for regorafenib alone was 55.9 μg·hour/mL (coefficient of variance (CV): 40%), and for regorafenib with concomitant esomeprazole or with esomeprazole 3 hours prior AUC 0–24h was 53.7 μg·hour/mL (CV: 34%) and 53.6 μg·hour/mL (CV: 43%), respectively. No significant differences were identified when regorafenib alone was compared with regorafenib with concomitant esomeprazole (RD: −3.9%; 95% confidence interval (CI): −20.5 to 16.1%; P = 1.0) or regorafenib with esomeprazole 3 hours prior (RD: −4.1%; 95% CI: −22.8 to 19.2%; P = 1.0). These findings indicate that regorafenib and esomeprazole can be safely combined in clinical practice.

Tamoxifen is a prodrug that is primarily metabolized into the pharmacologically active metabolite endoxifen and eventually into inactive metabolites. The herb curcumin may increase endoxifen exposure by affecting phase II metabolism. We compared endoxifen and tamoxifen exposure in breast cancer patients with or without curcumin, and with addition of the bio-enhancer piperine. Tamoxifen (20&ndash, 30mg per day (q.d.)) was either given alone, or combined with curcumin (1200 mg three times daily (t.i.d.)) +/&minus, piperine (10 mg t.i.d.). The primary endpoint of this study was the difference in geometric means for the area under the curve (AUC) of endoxifen. Genotyping was performed to determine CYP2D6 and CYP3A4 phenotypes. The endoxifen AUC0&ndash, 24h decreased with 7.7% (95%CI: &minus, 15.4 to 0.7%, p = 0.07) with curcumin and 12.4% (95%CI: &minus, 21.9 to &minus, 1.9%, p = 0.02) with curcumin and piperine, compared to tamoxifen alone. Tamoxifen AUC0&ndash, 24h showed similar results. For patients with an extensive CYP2D6 metabolism phenotype (EM), effects were more pronounced than for intermediate CYP2D6 metabolizers (IMs). In conclusion, the exposure to tamoxifen and endoxifen was significantly decreased by concomitant use of curcumin (+/&minus, piperine). Therefore, co-treatment with curcumin could lower endoxifen concentrations below the threshold for efficacy (potentially 20&ndash, 40% of the patients), especially in EM patients.

Purpose The natural course of the pathophysiology of Kienbock disease is uncertain. Shortening of the radius is believed to modify the pathophysiology by addressing mechanical influences on the lunate. The aim of this study was to compare the radiographic progression of Kienbock disease among patients who had radial shortening osteotomy and patients who had no surgical treatment, with a minimum 1-year interval between radiographs. Methods Among 207 patients with Kienbock disease, we included all 48 eligible patients who had either radial shortening osteotomy or nonsurgical treatment and 2 sets of wrist radiographs available a minimum of 1 year apart. We compared changes in carpal height ratio, Stahl index, and carpal angles between the 2 sets of radiographs and between radial shortening osteotomy and nonsurgical treatment. Results We found, on average, a small decrease in the carpal height ratio and the Stahl index in patients who did and did not have surgery, with no differences between the 2 groups. Nearly half of the patients had no decrease in the carpal height ratio and/or the Stahl index. Conclusions Radiographic progression of Kienbock over 1 year or more seems slight on average regardless of treatment. Future research might address the probability of and factors associated with radiographic progression of Kienbock disease. Type of study/level of evidence Prognostic IV.

Individuals who experience musculoskeletal trauma may construe the experience as unjust and themselves as victims. Perceived injustice is a cognitive construct comprised by negative appraisals of the severity of loss as a consequence of injury, blame, injury-related loss, and unfairness. It has been associated with worse physical and psychological outcomes in the context of chronic health conditions. The purpose of this study is to explore the association of perceived injustice to pain intensity and physical function in patients with orthopaedic trauma.A total of 124 orthopaedic trauma patients completed the Injustice Experience Questionnaire (IEQ), the PROMIS Physical Function Computer Adaptive Testing (CAT), the PROMIS Pain Intensity instruments, the short form Patient Health Questionnaire for depression (PHQ-2), the short form Pain Self-Efficacy Questionnaire (PSEQ-2), and the short form Pain Catastrophizing Scale (PCS-4) on a tablet computer. A stepwise linear regression model was used to identify the best combination of predictors explaining variance in PROMIS Physical Function and PROMIS Pain Intensity.The IEQ was associated with PROMIS Physical Function (r=-0.36; P0.001) and PROMIS Pain Intensity (r=0.43; P0.001). In multivariable analysis, however, Caucasian race (β=5.1, SE: 2.0, P=0.013, 95% CI: 1.1-9.2), employed work status (β=5.1, SE: 1.5, P=0.001, 95% CI: 2.1-8.2), any cause of injury other than sports, mvc, or fall (β=7.7, SE: 2.1, P0.001, 95% CI: 3.5-12), and higher self-efficacy (PSEQ-2; β=0.93, SE: 0.23, P0.001, 95% CI: 0.48-1.4) were selected as part of the best model predicting variance in PROMIS Physical Function. Only a higher degree of catastrophic thinking (PCS-4; β=1.2, SE: 0.12, P0.001, 95% CI: 0.99 to 1.5) was selected as important in predicting higher PROMIS Pain Intensity.Perceived injustice was associated with both physical function and pain intensity in bivariate correlations, but was not deemed as an important predictor when assessed along with other demographic and psychosocial variables in multivariable analysis. This study confirms prior research on the pivotal role of catastrophic thinking and self-efficacy in reports of pain intensity and physical function in patients with acute traumatic musculoskeletal pain.

Unfortunately, the original version of the article was published with incorrect copyright as “© Springer Science + Business Media, LLC, part of Springer Nature 2020”.

Multikinase inhibitors (MKIs), including the tyrosine kinase inhibitors (TKIs), have rapidly become an established factor in daily (hemato)-oncology practice. Although the oral route of administration offers improved flexibility and convenience for the patient, challenges arise in the use of MKIs. As MKIs are prescribed extensively, patients are at increased risk for (severe) drug–drug interactions (DDIs). As a result of these DDIs, plasma pharmacokinetics of MKIs may vary significantly, thereby leading to high interpatient variability and subsequent risk for increased toxicity or a diminished therapeutic outcome. Most clinically relevant DDIs with MKIs concern altered absorption and metabolism. The absorption of MKIs may be decreased by concomitant use of gastric acid-suppressive agents (e.g. proton pump inhibitors) as many kinase inhibitors show pH-dependent solubility. In addition, DDIs concerning drug (uptake and efflux) transporters may be of significant clinical relevance during MKI therapy. Furthermore, since many MKIs are substrates for cytochrome P450 isoenzymes (CYPs), induction or inhibition with strong CYP inhibitors or inducers may lead to significant alterations in MKI exposure. In conclusion, DDIs are of major concern during MKI therapy and need to be monitored closely in clinical practice. Based on the current knowledge and available literature, practical recommendations for management of these DDIs in clinical practice are presented in this review.

Background & Aims: Cholangiocarcinoma is an aggressive hepatobiliary malignancy originating from biliary tract epithelium. Whether cholangiocarcinoma is responsive to immune checkpoint antibody therapy is unknown, and knowledge of its tumor immune microenvironment is limited. We aimed to characterize tumor-infiltrating lymphocytes (TILs) in cholangiocarcinoma and assess functional effects of targeting checkpoint molecules on TILs. Methods: We isolated TILs from resected tumors of patients with cholangiocarcinoma and investigated their compositions compared with their counterparts in tumor-free liver (TFL) tissues and blood, by flow cytometry and immunohistochemistry. We measured expression of immune co-stimulatory and co-inhibitory molecules on TILs, and determined whether targeting these molecules improved ex vivo functions of TILs. Results: Proportions of cytotoxic T cells and natural killer cells were decreased, whereas regulatory T cells were increased in tumors compared with TFL. While regulatory T cells accumulated in tumors, the majority of cytotoxic and helper T cells were sequestered at tumor margins, and natural killer cells were excluded from the tumors. The co-stimulatory receptor GITR and co-inhibitory receptors PD1 and CTLA4 were over-expressed on tumor-infiltrating T cells compared with T cells in TFL and blood. Antagonistic targeting of PD1 or CTLA4 or agonistic targeting of GITR enhanced effector molecule production and T cell proliferation in ex vivo stimulation of TILs derived from cholangiocarcinoma. The inter-individual variations in TIL responses to checkpoint treatments were correlated with differences in TIL immune phenotype. Conclusions: Decreased numbers of cytotoxic immune cells and increased numbers of suppressor T cells that over-express co-inhibitory receptors suggest that the tumor microenvironment in cholangiocarcinoma is immunosuppressive. Targeting GITR, PD1 or CTLA4 enhances effector functions of tumor-infiltrating T cells, indicating that these molecules are potential immunotherapeutic targets for patients with cholangiocarcinoma. Lay summary: The defense functions of immune cells are suppressed in cholangiocarcinoma tumors. Stimulating or blocking “immune checkpoint” molecules expressed on tumor-infiltrating T cells can enhance the defense functions of these cells. Therefore, these molecules may be promising targets for therapeutic stimulation of immune cells to eradicate the tumors and prevent cancer recurrence in patients with cholangiocarcinoma.