Region 11 MELD Na Exception Prospective Study

Introduction. Hyponatremia complicates cirrhosis and predicts short term mortality, including adverse outcomes before and after liver transplantation. Material and methods. From April 1, 2008, through April 2, 2010, all adult candidates for primary liver transplantation with cirrhosis, listed in Region 11 with hyponatremia, were eligible for sodium (Na) exception. Results. Patients with serum sodium (SNa) less than 130 mg/dL, measured two weeks apart and within 30 days of Model for End Stage Liver Disease (MELD) exception request, were given preapproved Na exception. MELD Na was calculated [MELD + 1.59 (135-SNa/30 days)]. MELD Na was capped at 22, and subject to standard adult recertification schedule. On data end of follow-up, December 28, 2010, 15,285 potential U.S. liver recipients met the inclusion criteria of true MELD between 6 and 22. In Region 11, 1,198 of total eligible liver recipients were listed. Sixty-two (5.2%) patients were eligible for Na exception (MELD Na); 823 patients (68.7%) were listed with standard MELD (SMELD); and 313 patients (26.1%) received HCC MELD exception. Ninety percent of MELD Na patients and 97% of HCC MELD patients were transplanted at end of follow up, compared to 49% of Region 11 standard MELD and 40% of U.S.A. standard MELD (USA MELD) patients (p \u3c 0.001); with comparable dropout rates (6.5, 1.6, 6.9, 9% respectively; p = 0.2). MELD Na, HCC MELD, Region 11 SMELD, and USA MELD post-transplant six-month actual patient survivals were similar (92.9, 92.8, 92.2, and 93.9 %, respectively). Conclusion. The Region 11 MELD Na exception prospective trial improved hyponatremic cirrhotic patient access to transplant equitably, and without compromising transplant efficacy

A Gaussian-processes approach to fitting for time-variable spherical solar wind in pulsar timing data

Propagation effects are one of the main sources of noise in high-precision pulsar timing. For pulsars below an ecliptic latitude of 5°, the ionized plasma in the solar wind can introduce dispersive delays of order 100 µs around solar conjunction at an observing frequency of 300 MHz. A common approach to mitigate this assumes a spherical solar wind with a time-constant amplitude. However, this has been shown to be insufficient to describe the solar wind. We present a linear, Gaussian-process piecewise Bayesian approach to fit a spherical solar wind of time-variable amplitude, which has been implemented in the pulsar software RUN_ENTERPRISE. Through simulations, we find that the current EPTA+InPTA data combination is not sensitive to such variations; however, solar wind variations will become important in the near future with the addition of new InPTA data and data collected with the low-frequency LOFAR telescope. We also compare our results for different high-precision timing data sets (EPTA+InPTA, PPTA, and LOFAR) of 3 ms pulsars (J0030+0451, J1022+1001, J2145−0450), and find that the solar-wind amplitudes are generally consistent for any individual pulsar, but they can vary from pulsar to pulsar. Finally, we compare our results with those of an independent method on the same LOFAR data of the three millisecond pulsars. We find that differences between the results of the two methods can be mainly attributed to the modelling of dispersion variations in the interstellar medium, rather than the solar wind modelling

Validation of global ionospheric models using long-term observations of pulsar Faraday rotation with the LOFAR radio telescope

Broad band pulsar radiation can be effectively used to monitor the properties of the magneto-ionic media through which it propagates. Faraday rotation calculated from polarised pulsar observations provides an integrated product of electron densities and the line-of-sight component of the magnetic field in the intervening plasma. In particular, a time-variable effect mainly associated with the rapidly changing column density of the Earth’s ionosphere and plasmasphere heavily dominates the observed Faraday rotation of pulsar radiation. In this work, we aim to carry out a performance test of three GNSS-based models of the ionosphere using observations of PSR J0332+5434 taken with the LOw Frequency ARray (LOFAR). As it was shown in Porayko et al. (Month Not Roy Astron Soc 483(3):4100–4113, 2019. https://doi.org/10.1093/mnras/sty3324. arXiv:1812.01463), the conventional single layer model (SLM), which assumes that the ionosphere is a thin slab at a fixed effective height, is not capable of fully accounting for the ionospheric Faraday rotation in pulsar data. The simplified physics of the SLM is upgraded within IRI-Plas (International Reference Ionosphere and Plasmasphere) extended SLM and the dual-layer voxel TOmographic Model of the Ionosphere (TOMION), both of which partially account for the thickness and vertical dynamics of the terrestrial plasma. Although the last two improve the reconstruction of the ionospheric Faraday rotation, none of the considered models completely purge the observed residual variations. With this study, we show that the long term LOFAR observations of Faraday rotation of pulsars provide an excellent tool to test and improve models of the magneto-ionic content of the Earth’s atmosphere.This work has been partially supported by the EU project 101007599 - PITHIA-NRF. N.P. is supported by the Max-Planck Society as part of the “LEGACY” collaboration with the Chinese Academy of Sciences on low-frequency gravitational wave astronomy. N.P. is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Projektnummer PO 2758/1–1, through the Walter–Benjamin programme. J.P.W.V. acknowledges support by the Deutsche Forschungsgemeinschaft (DFG) through the Heisenberg programme (Project No. 433075039). J.K. is financially supported by the D-LOFAR II (grant 05A20PB1). We would like to thank V. Venkatraman Krishnan and anonymous referees for carefully reading the paper. This paper is based on data obtained with the German stations of the International LOFAR Telescope (ILT), constructed by ASTRON van Haarlem et al. (2013) and operated by the GLOW consortium (https://www.glowconsortium.de/) during station-owners time and proposals LC0_014, LC1_048, LC2_011, LC3_029, LC4_025, LT5_001, LC9_039, LT10_014. We made use of data from Jülich (DE605) LOFAR station supported by the BMBF Verbundforschung project D-LOFAR I (grant 05A08LJ1); and the Norderstedt (DE609) LOFAR station funded by the BMBF Verbundforschung project D-LOFAR II (grant 05A11LJ1). The observations of the German LOFAR stations were carried out in the stand-alone GLOW mode, which is technically operated and supported by the Max-Planck-Institut für Radioastronomie, the Forschungszentrum Jülich and Bielefeld University. We acknowledge support and operation of the GLOW network, computing and storage facilities by the FZ-Jülich, the MPIfR and Bielefeld University and financial support from BMBF D-LOFAR III (grant 05A14PBA) and D-LOFAR IV (grants 05A17PBA and 05A17PC1), and by the states of Nordrhein-Westfalia and Hamburg.Open Access funding enabled and organized by Projekt DEAL.Peer reviewe

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

Region 11 MELD Na exception prospective study

Introduction. Hyponatremia complicates cirrhosis and predicts short term mortality, including adverse outcomes before and after liver transplantation.Material and methods. From April 1, 2008, through April 2, 2010, all adult candidates for primary liver transplantation with cirrhosis, listed in Region 11 with hyponatremia, were eligible for sodium (Na) exception.Results. Patients with serum sodium (SNa) less than 130 mg/dL, measured two weeks apart and within 30 days of Model for End Stage Liver Disease (MELD) exception request, were given preapproved Na exception. MELD Na was calculated [MELD + 1.59 (135-SNa/30 days)]. MELD Na was capped at 22, and subject to standard adult recertification schedule. On data end of follow-up, December 28, 2010, 15,285 potential U.S. liver recipients met the inclusion criteria of true MELD between 6 and 22. In Region 11, 1,198 of total eligible liver recipients were listed. Sixty-two (5.2%) patients were eligible for Na exception (MELD Na); 823 patients (68.7%) were listed with standard MELD (SMELD); and 313 patients (26.1%) received HCC MELD exception. Ninety percent of MELD Na patients and 97% of HCC MELD patients were transplanted at end of follow up, compared to 49% of Region 11 standard MELD and 40% of U.S.A. standard MELD (USA MELD) patients (p < 0.001); with comparable dropout rates (6.5, 1.6, 6.9, 9% respectively; p = 0.2). MELD Na, HCC MELD, Region 11 SMELD, and USA MELD post-transplant six-month actual patient survivals were similar (92.9, 92.8, 92.2, and 93.9 %, respectively).Conclusion. The Region 11 MELD Na exception prospective trial improved hyponatremic cirrhotic patient access to transplant equitably, and without compromising transplant efficacy

Region 11 MELD Na exception prospective study

"INTRODUCTION: Hyponatremia complicates cirrhosis and predicts short term mortality, including adverse outcomes before and after liver transplantation. MATERIAL AND METHODS: From April 1, 2008, through April 2, 2010, all adult candidates for primary liver transplantation with cirrhosis, listed in Region 11 with hyponatremia, were eligible for sodium (Na) exception. RESULTS: Patients with serum sodium (SNa) less than 130 mg/dL, measured two weeks apart and within 30 days of Model for End Stage Liver Disease (MELD) exception request, were given preapproved Na exception. MELD Na was calculated [MELD + 1.59 (135-SNa/30 days)]. MELD Na was capped at 22, and subject to standard adult recertification schedule. On data end of follow-up, December 28, 2010, 15,285 potential U.S. liver recipients met the inclusion criteria of true MELD between 6 and 22. In Region 11, 1,198 of total eligible liver recipients were listed. Sixty-two (5.2%) patients were eligible for Na exception (MELD Na); 823 patients (68.7%) were listed with standard MELD (SMELD); and 313 patients (26.1%) received HCC MELD exception. Ninety percent of MELD Na patients and 97% of HCC MELD patients were transplanted at end of follow up, compared to 49% of Region 11 standard MELD and 40% of U.S.A. standard MELD (USA MELD) patients (p < 0.001); with comparable dropout rates (6.5, 1.6, 6.9, 9% respectively; p = 0.2). MELD Na, HCC MELD, Region 11 SMELD, and USA MELD post-transplant six-month actual patient survivals were similar (92.9, 92.8, 92.2, and 93.9 %, respectively). CONCLUSION: The Region 11 MELD Na exception prospective trial improved hyponatremic cirrhotic patient access to transplant equitably, and without compromising transplant efficacy.

Physician predictions of graft survival following liver transplantation

Introduction. Due to the scarcity of cadaveric livers, clinical judgment must be used to avoid futile transplants. However, the accuracy of human judgment for predicting outcomes following liver transplantation is unknown. The study aim was to assess expert clinicians’ ability to predict graft survival and to compare their performance to published survival models. Materials and methods. Pre-transplant case summaries were prepared based on 16 actual, randomly selected liver transplants. Clinicians specializing in the care of liver transplant patients were invited to assess the likelihood of 90-day graft survival for each case using (1) a 4-point Likert scale ranging from poor to excellent, and (2) a visual analog scale denoting the probability of survival. Four published models were also used to predict survival for the 16 cases. Results. Completed instruments were received from 50 clinicians. Prognostic estimates on the two scales were highly correlated (median r=0.88). Individual clinicians’ predictive ability was 0.61±0.13, by area under the receiver operating characteristic curve. The performance of published models was MELD 0.59, Desai 0.66, Ghobrial 0.61, and Thuluvath 0.45. For three cases, clinicians consistently overestimated the probability of survival (87±10%, 89±9%, 86±9%); these patients had early graft failures caused by postoperative complications. Discussion. Clinicians varied in their ability to predict survival for a set of pre-transplant scenarios, but performed similarly to published models. When clinicians overestimated the chance of transplant success, either sepsis or hepatic artery thrombosis was involved; such events may be hard to predict before surgery

Periodicity search in the timing of the 25 millisecond pulsars from the second data release of the European pulsar timing array

In this work, we investigated the presence of strictly periodic, as well as quasi-periodic signals, in the timing of the 25 millisecond pulsars from the EPTA DR2 dataset. This is especially interesting in the context of the recent hints of a gravitational wave background in these data, and the necessary further study of red-noise timing processes, which are known to behave quasi-periodically in some normal pulsars. We used Bayesian timing models developed through the run_enterprise pipeline: a strict periodicity was modelled as the influence of a planetary companion on the pulsar, while a quasi-periodicity was represented as a Fourier-domain Gaussian process. We found that neither model would clearly improve the timing models of the 25 millisecond pulsars in this dataset. This implies that noise and parameter estimates are unlikely to be biased by the presence of a (quasi-)periodicity in the timing data. Nevertheless, the results for PSRs J1744−1134 and J1012+5307 suggest that the standard noise models for these pulsars may not be sufficient. We also measure upper limits for the projected masses of planetary companions around each of the 25 pulsars. The data of PSR J1909−3744 yielded the best mass limits, such that we constrained the 95-percentile to ∼2 × 10−4 M⊕ (roughly the mass of the dwarf planet Ceres) for orbital periods between 5 d–17 yr. These are the best pulsar planet mass limits to date