Increased frequency of anti-Ma2 encephalitis associated with immune checkpoint inhibitors

Objective To report the induction of anti-Ma2 antibody-associated paraneoplastic neurologic syndrome (Ma2-PNS) in 6 patients after treatment with immune checkpoint inhibitors (ICIs). We also analyzed (1) patient clinical features compared with a cohort of 44 patients who developed Ma2-PNS without receiving ICI treatment and (2) the frequency of neuronal antibody detection before and after ICI implementation. Methods Retrospective nationwide study of all patients with Ma2-PNS developed during ICI treatment between 2017 and 2018. Results Our series of patients included 5 men and 1 woman (median age, 63 years). The patients were receiving nivolumab (n = 3), pembrolizumab (n = 2), or a combination of nivolumab and ipilimumab (n = 1) for treatment of neoplasms that included lung (n = 4) and kidney (n = 1) cancers and pleural mesothelioma (n = 1). Clinical syndromes comprised a combination of limbic encephalitis and diencephalitis (n = 3), isolated limbic encephalitis (n = 2), and a syndrome characterized by ophthalmoplegia and head drop (n = 1). No significant clinical difference was observed between our 6 patients and the overall cohort of Ma2-PNS cases. Post-ICI Ma2-PNS accounted for 35% of the total 17 Ma2-PNS diagnosed in our center over the 2017-2018 biennium. Eight cases had been detected in the preceding biennium 2015-2016, corresponding to a 112% increase of Ma2-PNS frequency since the implementation of ICIs in France. Despite ICI withdrawal and immunotherapy, 4/6 patients died, and the remaining 2 showed a moderate to severe disability. Conclusions We show a clear association between ICI use and increased diagnosis of Ma2-PNS. Physicians need to be aware that ICIs can trigger Ma2-PNS because clinical presentation can be challenging

The helicity amplitudes A1/2_{1/2} and A3/2_{3/2} for the D13(1520)_{13}(1520) resonance obtained from the γ⃗p⃗→pπ0\vec{\gamma} \vec{p} \to p \pi^0 reaction}

The helicity dependence of the $\vec{\gamma} \vec{p} \to p \pi^0$ reaction has been measured for the first time in the photon energy range from 550 to 790 MeV. The experiment, performed at the Mainz microtron MAMI, used a 4$\pi$-detector system, a circularly polarized, tagged photon beam, and a longitudinally polarized frozen-spin target. These data are predominantly sensitive to the $D_{13}(1520)$ resonance and are used to determine its parameters.Comment: 5 pages, 4 figure

First measurement of the Gerasimov-Drell-Hearn integral for Hydrogen from 200 to 800 MeV

A direct measurement of the helicity dependence of the total photoabsorption cross section on the proton was carried out at MAMI (Mainz) in the energy range 200 < E_gamma < 800 MeV. The experiment used a 4$\pi$ detection system, a circularly polarized tagged photon beam and a frozen spin target. The contributions to the Gerasimov-Drell-Hearn sum rule and to the forward spin polarizability $\gamma_0$ determined from the data are 226 \pm 5 (stat)\pm 12(sys) \mu b and -187 \pm 8 (stat)\pm 10(sys)10^{-6} fm^4, respectively, for 200 < E_\gamma < 800 MeV.Comment: 6 pages, 3 figures, 3 table

The first determination of Generalized Polarizabilities of the proton by a Virtual Compton Scattering experiment

Absolute differential cross sections for the reaction (e+p -> e+p+gamma) have been measured at a four-momentum transfer with virtuality Q^2=0.33 GeV^2 and polarization \epsilon = 0.62 in the range 33.6 to 111.5 MeV/c for the momentum of the outgoing photon in the photon-proton center of mass frame. The experiment has been performed with the high resolution spectrometers at the Mainz Microtron MAMI. From the photon angular distributions, two structure functions which are a linear combination of the generalized polarizabilities have been determined for the first time.Comment: 4 pages, 3 figure

Nomenclature for renal replacement therapy and blood purification techniques in critically ill patients: practical applications

This article reports the conclusions of the second part of a consensus expert conference on the nomenclature of renal replacement therapy (RRT) techniques currently utilized to manage acute kidney injury and other organ dysfunction syndromes in critically ill patients. A multidisciplinary approach was taken to achieve harmonization of definitions, components, techniques, and operations of the extracorporeal therapies. The article describes the RRT techniques in detail with the relevant technology, procedures, and phases of treatment and key aspects of volume management/fluid balance in critically ill patients. In addition, the article describes recent developments in other extracorporeal therapies, including therapeutic plasma exchange, multiple organ support therapy, liver support, lung support, and blood purification in sepsis. This is a consensus report on nomenclature harmonization in extracorporeal blood purification therapies, such as hemofiltration, plasma exchange, multiple organ support therapies, and blood purification in sepsis

Human physiologically based pharmacokinetic model for ACE inhibitors: ramipril and ramiprilat

BACKGROUND: The angiotensin-converting enzyme (ACE) inhibitors have complicated and poorly characterized pharmacokinetics. There are two binding sites per ACE (high affinity "C", lower affinity "N") that have sub-nanomolar affinities and dissociation rates of hours. Most inhibitors are given orally in a prodrug form that is systemically converted to the active form. This paper describes the first human physiologically based pharmacokinetic (PBPK) model of this drug class. METHODS: The model was applied to the experimental data of van Griensven et. al for the pharmacokinetics of ramiprilat and its prodrug ramipril. It describes the time course of the inhibition of the N and C ACE sites in plasma and the different tissues. The model includes: 1) two independent ACE binding sites; 2) non-equilibrium time dependent binding; 3) liver and kidney ramipril intracellular uptake, conversion to ramiprilat and extrusion from the cell; 4) intestinal ramipril absorption. The experimental in vitro ramiprilat/ACE binding kinetics at 4°C and 300 mM NaCl were assumed for most of the PBPK calculations. The model was incorporated into the freely distributed PBPK program PKQuest. RESULTS: The PBPK model provides an accurate description of the individual variation of the plasma ramipril and ramiprilat and the ramiprilat renal clearance following IV ramiprilat and IV and oral ramipril. Summary of model features: Less than 2% of total body ACE is in plasma; 35% of the oral dose is absorbed; 75% of the ramipril metabolism is hepatic and 25% of this is converted to systemic ramiprilat; 100% of renal ramipril metabolism is converted to systemic ramiprilat. The inhibition was long lasting, with 80% of the C site and 33% of the N site inhibited 24 hours following a 2.5 mg oral ramipril dose. The plasma ACE inhibition determined by the standard assay is significantly less than the true in vivo inhibition because of assay dilution. CONCLUSION: If the in vitro plasma binding kinetics of the ACE inhibitor for the two binding sites are known, a unique PBPK model description of the Griensven et. al. experimental data can be obtained

Reanalysis in Earth System Science: Towards Terrestrial Ecosystem Reanalysis

A reanalysis is a physically consistent set of optimally merged simulated model states and historical observational data, using data assimilation. High computational costs for modelled processes and assimilation algorithms has led to Earth system specific reanalysis products for the atmosphere, the ocean and the land separately. Recent developments include the advanced uncertainty quantification and the generation of biogeochemical reanalysis for land and ocean. Here, we review atmospheric and oceanic reanalyses, and more in detail biogeochemical ocean and terrestrial reanalyses. In particular, we identify land surface, hydrologic and carbon cycle reanalyses which are nowadays produced in targeted projects for very specific purposes. Although a future joint reanalysis of land surface, hydrologic and carbon processes represents an analysis of important ecosystem variables, biotic ecosystem variables are assimilated only to a very limited extent. Continuous data sets of ecosystem variables are needed to explore biotic-abiotic interactions and the response of ecosystems to global change. Based on the review of existing achievements, we identify five major steps required to develop terrestrial ecosystem reanalysis to deliver continuous data streams on ecosystem dynamics

Ground, Proximal, and Satellite Remote Sensing of Soil Moisture

Soil moisture (SM) is a key hydrologic state variable that is of significant importance for numerous Earth and environmental science applications that directly impact the global environment and human society. Potential applications include, but are not limited to, forecasting of weather and climate variability; prediction and monitoring of drought conditions; management and allocation of water resources; agricultural plant production and alleviation of famine; prevention of natural disasters such as wild fires, landslides, floods, and dust storms; or monitoring of ecosystem response to climate change. Because of the importance and wide‐ranging applicability of highly variable spatial and temporal SM information that links the water, energy, and carbon cycles, significant efforts and resources have been devoted in recent years to advance SM measurement and monitoring capabilities from the point to the global scales. This review encompasses recent advances and the state‐of‐the‐art of ground, proximal, and novel SM remote sensing techniques at various spatial and temporal scales and identifies critical future research needs and directions to further advance and optimize technology, analysis and retrieval methods, and the application of SM information to improve the understanding of critical zone moisture dynamics. Despite the impressive progress over the last decade, there are still many opportunities and needs to, for example, improve SM retrieval from remotely sensed optical, thermal, and microwave data and opportunities for novel applications of SM information for water resources management, sustainable environmental development, and food security

Tropical Peatland Hydrology Simulated With a Global Land Surface Model

Tropical peatlands are among the most carbon-dense ecosystems on Earth, and their water storage dynamics strongly control these carbon stocks. The hydrological functioning of tropical peatlands differs from that of northern peatlands, which has not yet been accounted for in global land surface models (LSMs). Here, we integrated tropical peat-specific hydrology modules into a global LSM for the first time, by utilizing the peatland-specific model structure adaptation (PEATCLSM) of the NASA Catchment Land Surface Model (CLSM). We developed literature-based parameter sets for natural (PEATCLSM(Trop,Nat)) and drained (PEATCLSM(Trop,Drain)) tropical peatlands. Simulations with PEATCLSM(Trop,Nat) were compared against those with the default CLSM version and the northern version of PEATCLSM (PEATCLSM(North,Nat)) with tropical vegetation input. All simulations were forced with global meteorological reanalysis input data for the major tropical peatland regions in Central and South America, the Congo Basin, and Southeast Asia. The evaluation against a unique and extensive data set of in situ water level and eddy covariance-derived evapotranspiration showed an overall improvement in bias and correlation compared to the default CLSM version. Over Southeast Asia, an additional simulation with PEATCLSM(Trop,Drain) was run to address the large fraction of drained tropical peatlands in this region. PEATCLSM(Trop,Drain) outperformed CLSM, PEATCLSM(North,Nat), and PEATCLSM(Trop,Nat) over drained sites. Despite the overall improvements of PEATCLSM(Trop,Nat) over CLSM, there are strong differences in performance between the three study regions. We attribute these performance differences to regional differences in accuracy of meteorological forcing data, and differences in peatland hydrologic response that are not yet captured by our model.Peer reviewe

Global snow mass measurements and the effect of stratigraphic detail on inversion of microwave brightness temperatures

Snow provides large seasonal storage of freshwater, and information about the distribution of snow mass as Snow Water Equivalent (SWE) is important for hydrological planning and detecting climate change impacts. Large regional disagreements remain between estimates from reanalyses, remote sensing and modelling. Assimilating passive microwave information improves SWE estimates in many regions but the assimilation must account for how microwave scattering depends on snow stratigraphy. Physical snow models can estimate snow stratigraphy, but users must consider the computational expense of model complexity versus acceptable errors. Using data from the National Aeronautics and Space Administration Cold Land Processes Experiment (NASA CLPX) and the Helsinki University of Technology (HUT) microwave emission model of layered snowpacks, it is shown that simulations of the brightness temperature difference between 19 GHz and 37 GHz vertically polarised microwaves are consistent with Advanced Microwave Scanning Radiometer-Earth Observing System (AMSR-E) and Special Sensor Microwave Imager (SSM/I) retrievals once known stratigraphic information is used. Simulated brightness temperature differences for an individual snow profile depend on the provided stratigraphic detail. Relative to a profile defined at the 10 cm resolution of density and temperature measurements, the error introduced by simplification to a single layer of average properties increases approximately linearly with snow mass. If this brightness temperature error is converted into SWE using a traditional retrieval method then it is equivalent to ±13 mm SWE (7% of total) at a depth of 100 cm. This error is reduced to ±5.6 mm SWE (3 % of total) for a two-layer model