Satellite laser ranging to GNSS-based Swarm orbits with handling of systematic errors

Satellite laser ranging (SLR) retroreflectors along with GNSS receivers are installed onboard numerous active low earth orbiters (LEOs) for the independent validation of GNSS-based precise orbit determination (POD) products. SLR validation results still contain many systematic errors that require special handling of various biases. For this purpose, we derive methods of reducing systematic effects affecting the SLR residuals to LEO Swarm satellites. We test solutions incorporating the estimation of range biases, station coordinate corrections, tropospheric biases, and horizontal gradients of the troposphere delays. When estimating range biases once per day, the standard deviation (STD) of Swarm-B SLR residuals is reduced from 10 to 8 mm for the group of high-performing SLR stations. The tropospheric biases estimated once per day, instead of range biases, further reduce the STD of residuals to the level of 6 mm. The systematic errors that manifest as dependencies of SLR residuals under different measurement conditions, e.g., elevation angle, are remarkably diminished. Furthermore, introducing troposphere biases allows for the comparison of the orbit quality between kinematic and reduced-dynamic orbits as the GPS-based orbit errors become more pronounced when SLR observations are freed from elevation-dependent errors. Applying tropospheric biases in SLR allows obtaining the consistency between the POD solution and SLR observations that are two times better than when neglecting to model of systematic effects and by 29% better when compared with solutions considering present methods of range bias handling

Realization of the terrestrial reference frame based on integrated SLR measurements to LEO, geodetic,and Galileo satellites

Numerous active low Earth orbiters (LEOs) and Global Navigation Satellite System (GNSS) satellites, including the Galileo constellation,are equipped with laser retroreflectors used for Satellite Laser Ranging (SLR). Moreover, most LEOs are equipped with GNSS receivers for precise orbit determination. SLR measurements to LEOs, GNSS, and geodetic satellites vary in terms of registered numbers of the normal points (NPs) or registered satellite passes. In 2016-2018, SLR measurements to LEOs constituted 81% of all NPs and 59% of all registered satellite passes, whereas 10% of NPs and 30% of satellite passes, respectively,were assigned to GNSS. The remaining SLR measurements, 9% of NPs and 11% of passes, were completed by geodetic satellites, including LAGEOS-1 and LAGEOS-2. In this study, we show that the SLR observations to Galileo, passive geodetic and active LEO satellites together with precise GNSS-based orbits of LEOs and Galileocan be used for the determination of SLR station coordinates.Station coordinates, as well as the realization of the ITRF, are typically determined using SLR observations to passive geodetic satellites, such as LAGEOS-1/2. Here, we use SLR observations to Galileo, LAGEOS-1/2, LARES, Sentinel-3A, SWARM-A/B/C, TerraSAR, Jason-2, GRACE-A/B satellites to investigate whether they can be applied for the reference frame realization and for deriving high-quality station coordinates. We present various types of solutions based on different solution lengths, different SLR ground network constraining, and the combination of different sets of satellites to investigate the best solution set-up and the relative weights for the variance scaling factors of normal equations. We compare our results with the standard LAGEOS-based solutions and show the consistency level of the results with respect to the classical SLR solutions. Combination of observations improves the station coordinates especially for those stations which provide more SLR observations to LEOs, and Galileo satellites than to LAGEOS

GNSS Visibility and Performance Implications for the GENESIS Mission

The GENESIS mission prepared for launch in 2027 integrates the four space-geodetic techniques on a single spaceborne platform in medium Earth orbit. With its unique observations and alternative tie concepts, the mission aims to contribute to an improved accuracy and homogeneity of future terrestrial reference system realizations. To assess the expected contribution of Global Navigation Satellite System (GNSS) tracking, a comprehensive GNSS coverage analysis is performed based on detailed link-budget simulations, taking into account the best available gain patterns and signal-specific transmit power estimates derived for this work from measurements of a high-gain dish antenna. The benefit of different receiver antenna concepts for the GENESIS spacecraft is assessed and it is demonstrated that a single-antenna system with either a nadir-looking or side-looking boresight is a viable alternative to the dual-antenna configuration considered in initial mission studies. Compared to terrestrial users and missions in low Earth orbit, GENESIS will collect GNSS signals transmitted at up to two times larger off-boresight angles. Only limited information on the actual transmit antenna phase patterns is presently available in this region, which hampers a quantitative assessment of the expected measurement and orbit determination accuracy. As such, a comprehensive release of manufacturer calibrations is encouraged for all blocks of GPS and Galileo satellites. In parallel, a need for in-flight characterization and calibration of the GNSS transmit antennas for off-boresight angles of up to 30 deg using observations of the GENESIS mission itself is expected. The impact of such calibrations on the overall quality of terrestrial reference frame parameters will need to be assessed in comprehensive simulations of global GNSS network solutions with joint processing of terrestrial and GENESIS GNSS observations

Acute interstitial nephritis associated with immune checkpoint inhibitors: a single-centre experience

Nefritis intersticial aguda; Inhibidors de punts de control; Biòpsia de ronyóNefritis intersticial aguda; Inhibidores de puntos de control; Biopsia renalAcute interstitial nephritis; Checkpoint inhibitors; Kidney biopsyBackground Checkpoint inhibitors (CPIs) are used to treat solid organ metastatic malignancies. They act by triggering a vigorous immune response against tumoural cells, preventing their proliferation and metastasis. However, this is not a selective response and can cause immune-related adverse events (irAEs). The kidney can potentially be damaged, with an incidence of irAEs of 1–4%. The most frequent type of toxicity described is acute interstitial nephritis (AIN). Methods We conducted a study of patients with solid organ metastatic malignancies treated with immunotherapy who developed acute renal injury and underwent kidney biopsy in the last 14 months at the Vall d’Hebron University Hospital. Results In all, 826 solid organ malignancies were treated with immunotherapy in our centre, 125 of them (15.1%) developed acute kidney injury (AKI), 23 (18.4% of AKI) visited the nephrology department and 8 underwent kidney biopsy. The most frequent malignancy was lung cancer, in five patients (62%), followed by two patients (25%) with melanoma and one patient (12%) with pancreatic cancer. Four patients (50%) had already received previous oncological therapy, and for the remaining four patients (50%), CPI was the first-line therapy. Five patients (62%) were treated with anti-programmed cell death protein 1, three patients (37%) received anti-programmed death ligand 1 and two (25%) patients were treated in combination with anti-cytotoxic T-lymphocyte antigen 4. The time between the start of CPI and the onset of the AKI ranged from 2 to 11 months. The most frequent urine findings were subnephrotic-range proteinuria, with a mean protein:creatinine ratio of 544 mg/g (standard deviation 147) and eosinophiluria. All patients were biopsied after being diagnosed with AIN. Three patients (37%) received treatment with pulses of methylprednisolone 250–500 mg/day and five patients (62%) received prednisone 1 mg/kg/day. Seven patients (87%) experienced recovery of kidney function and one patient (12%) progressed to chronic kidney disease. Conclusions We report on eight patients with CPI-related AIN diagnosed in the last 14 months at our centre. The novel immunotherapy treatment of metastatic solid organ malignancies carries a higher risk of irAEs. The kidney is one of the most commonly affected organs, frequently presenting as an AIN and exhibiting a favourable response to steroid treatment.The authors are current recipients of research grants from the Fondo de Investigación Sanitaria-Feder, ISCIII (PI17/00257) and Redinren (RD16/0009/0030). M.B. performed this work as the basis of her thesis at the Department de Medicina of Universitat Autònoma de Barcelona

European interlaboratory comparison investigations (ICI) and external quality assurance schemes (EQUAS) for the analysis of bisphenol A, S and F in human urine: Results from the HBM4EU project

The Human Biomonitoring for Europe initiative (HBM4EU) aims to study the exposure of citizens to chemicals and potentially associated health effects. One objective of this project has been to build a network of laboratories able to answer to the requirements of European human biomonitoring studies. Within the HBM4EU quality assurance and quality control scheme (QA/QC), a number of interlaboratory comparison investigations (ICIs) and external quality assurance schemes (EQUASs) were organized to ensure data consistency, comparability and reliability. Bisphenols are among the prioritized substance groups in HBM4EU, including bisphenol A (BPA), bisphenol S (BPS) and bisphenol F (BPF) in human urine. In four rounds of ICI/EQUAS, two target concentration levels were considered, related to around P25 and P95 of the typical exposure distribution observed in the European general population. Special attention was paid to the conjugated phase II metabolites known to be most dominant in samples of environmentally exposed individuals, through the analysis of both native samples and samples fortified with glucuronide forms. For the low level, the average percentage of satisfactory results across the four rounds was 83% for BPA, 71% for BPS and 62% for BPF. For the high level, the percentages of satisfactory results increased to 93% for BPA, 89% for BPS and 86% for BPF. 24 out of 32 participating laboratories (75%) were approved for the analyses of BPA in the HBM4EU project according to the defined criterion of Z-scores for both low and high concentration levels in at least two ICI/EQUAS rounds. For BPS and BPF, the number of qualified laboratories was 18 out of 27 (67%) and 13 out of 28 (46%), respectively. These results demonstrate a strong analytical capability for BPA and BPS in Europe, while improvements may be needed for BPF.We gratefully acknowledge funding by the European Union's Horizon 2020 research and innovation programme under the grant agreement No. 733032 HBM4EU. The authors would like to thank the HBM4EU Secretariat at the German Environment Agency for administrative support. The authors acknowledge all the participating and expert laboratories (Table A1, SM) that made the HBM4EU QA/QC programme possible as well as the Management and Advisory Boards of HBM4EU.S

Proficiency and Interlaboratory Variability in the Determination of Phthalate and DINCH Biomarkers in Human Urine: Results from the HBM4EU Project

A quality assurance/quality control program was implemented in the framework of the EU project HBM4EU to assess and improve the comparability of biomarker analysis and to build a network of competent laboratories. Four rounds of proficiency tests were organized for 15 phthalate and two DINCH urinary biomarkers (0.2-138 ng/mL) over a period of 18 months, with the involvement of 28 laboratories. A substantial improvement in performance was observed after the first round in particular, and by the end of the program, an average satisfactory performance rate of 90% was achieved. The interlaboratory reproducibility as derived from the participants' results varied for the various biomarkers and rounds, with an average of 24% for the biomarkers of eight single-isomer phthalates (e.g., DnBP and DEHP) and 43% for the more challenging biomarkers of the mixed-isomer phthalates (DiNP, DiDP) and DINCH. When the reproducibility was based only on the laboratories that consistently achieved a satisfactory performance, this improved to 17% and 26%, respectively, clearly demonstrating the success of the QA/QC efforts. The program thus aided in building capacity and the establishment of a network of competent laboratories able to generate comparable and accurate HBM data for phthalate and DINCH biomarkers in 14 EU countries. In addition, global comparability was ensured by including external expert laboratories.This study was part of the HBM4EU project receiving funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 733032. Co-funding was received from the Dutch Ministry of Agriculture, Nature and Food Quality (project KB 37-002-014-001/002).S

HCV activates somatic L1 retrotransposition–A potential hepatocarcinogenesis pathway

Hepatitis C virus (HCV) is a common cause of hepatocellular carcinoma (HCC). The activation and mutagenic consequences of L1 retrotransposons in virus-associated-HCC have been documented. However, the direct influence of HCV upon L1 elements is unclear, and is the focus of the present study. L1 transcript expression was evaluated in a publicly available liver tissue RNA-seq dataset from patients with chronic HCV hepatitis (CHC), as well as healthy controls. L1 transcript expression was significantly higher in CHC than in controls. L1orf1p (a L1 encoded protein) expression was observed in six out of 11 CHC livers by immunohistochemistry. To evaluate the influence of HCV on retrotransposition efficiency, in vitro engineered-L1 retrotransposition assays were employed in Huh7 cells in the presence and absence of an HCV replicon. An increased retrotransposition rate was observed in the presence of replicating HCV RNA, and persisted in cells after viral clearance due to sofosbuvir (PSI7977) treatment. Increased retrotransposition could be due to dysregulation of the DNA-damage repair response, including homologous recombination, due to HCV infection. Altogether these data suggest that L1 expression can be activated before oncogenic transformation in CHC patients, with HCV-upregulated retrotransposition potentially contributing to HCC genomic instability and a risk of transformation that persists post-viral clearance

Towards integration of general practitioner posts and accident and emergency departments: a case study of two integrated emergency posts in the Netherlands

<p>Abstract</p> <p>Background</p> <p>Accident and emergency (A&E) departments and general practitioner (GP) posts are often used inappropriately, leading to overcrowding. In the Netherlands, increasingly more integrated emergency posts (IEPs) are being created, integrating the care provided by GP posts and A&E departments, in order to improve the provision of the emergency care.</p> <p>Methods</p> <p>This explorative study compares the efficiency and patient and employee satisfaction in IEPs with those in two GP posts and two A&E departments. To this end, information was retrieved from hospital and GP patient records for the first quarter of the year before and of the year after the creation of IEPs. Patients and employees were sent a questionnaire to measure their satisfaction. Lastly, groups of hospital doctors, GPs, GP assistants, and nurses were interviewed.</p> <p>Results</p> <p>After the creation of IEPs, there was a shift of more than fifteen percent from secondary care to primary care for emergency consultations and waiting/consultation times were shortened by more than ten percent. Compared with the control settings, patients were more satisfied about telephone contact with an IEP, but professionals working at the IEP were less satisfied with several aspects of their work.</p> <p>Conclusion</p> <p>IEPs could be a promising innovation to organize emergency care more efficiently; however, it might take time to convince professionals of the possible advantages. Studies involving more IEPs and longer follow-up times are needed to determine whether such integration should be stimulated.</p

Evolution of ligand specificity in vertebrate corticosteroid receptors

<p>Abstract</p> <p>Background</p> <p>Corticosteroid receptors include mineralocorticoid (MR) and glucocorticoid (GR) receptors. Teleost fishes have a single MR and duplicate GRs that show variable sensitivities to mineralocorticoids and glucocorticoids. How these receptors compare functionally to tetrapod MR and GR, and the evolutionary significance of maintaining two GRs, remains unclear.</p> <p>Results</p> <p>We used up to seven steroids (including aldosterone, cortisol and 11-deoxycorticosterone [DOC]) to compare the ligand specificity of the ligand binding domains of corticosteroid receptors between a mammal (<it>Mus musculus</it>) and the midshipman fish (<it>Porichthys notatus</it>), a teleost model for steroid regulation of neural and behavioral plasticity. Variation in mineralocorticoid sensitivity was considered in a broader phylogenetic context by examining the aldosterone sensitivity of MR and GRs from the distantly related daffodil cichlid (<it>Neolamprologus pulcher</it>), another teleost model for neurobehavioral plasticity. Both teleost species had a single MR and duplicate GRs. All MRs were sensitive to DOC, consistent with the hypothesis that DOC was the initial ligand of the ancestral MR. Variation in GR steroid-specificity corresponds to nine identified amino acid residue substitutions rather than phylogenetic relationships based on receptor sequences.</p> <p>Conclusion</p> <p>The mineralocorticoid sensitivity of duplicate GRs in teleosts is highly labile in the context of their evolutionary phylogeny, a property that likely led to neo-functionalization and maintenance of two GRs.</p