C‐reactive protein flare‐response predicts long‐term efficacy to first‐line anti‐PD‐1‐based combination therapy in metastatic renal cell carcinoma

Objectives Immune checkpoint blockade (IO) has revolutionised the treatment of metastatic renal cell carcinoma (mRCC). Early C-reactive protein (CRP) kinetics, especially the recently introduced CRP flare-response phenomenon, has shown promising results to predict IO efficacy in mRCC, but has only been studied in second line or later. Here, we aimed to validate the predictive value of early CRP kinetics for 1st-line treatment of mRCC with αPD-1 plus either αCTLA-4 (IO+IO) or tyrosine kinase inhibitor (IO+TKI). Methods In this multicentre retrospective study, we investigated the predictive potential of early CRP kinetics during 1st-line IO therapy. Ninety-five patients with mRCC from six tertiary referral centres with either IO+IO (N = 59) or IO+TKI (N = 36) were included. Patients were classified as CRP flare-responders, CRP responders or non-CRP responders as previously described, and their oncological outcome was compared. Results Our data validate the predictive potential of early CRP kinetics in 1st-line immunotherapy in mRCC. CRP responders, especially CRP flare-responders, had significantly prolonged progression-free survival (PFS) compared with non-CRP responders (median PFS: CRP flare-responder: 19.2 months vs. responders: 16.2 vs. non-CRP responders: 5.6, P < 0.001). In both the IO+IO and IO+TKI subgroups, early CRP kinetics remained significantly associated with improved PFS. CRP flare-response was also associated with long-term response ≥ 12 months. Conclusions Early CRP kinetics appears to be a low-cost and easy-to-implement on-treatment biomarker to predict response to 1st-line IO combination therapy. It has potential to optimise therapy monitoring and might represent a new standard of care biomarker for immunotherapy in mRCC

Poröse Transportschichten für die Polymerelektrolytmembran-Wasserelektrolyse

Water electrolysis uses electrical energy to split up water into oxygen and hydrogen. Hydrogenis relevant for future energy systems, among others it can serve as a storage medium for electrical energy from renewable energy converters like photovoltaic or wind energy systems. The polymer electrolye membrane water electrolyzer is considered to be especially suitable for this kind of application. In polymer electrolyte membrane water electrolyzers, water is fed through the so-called porous transport layer to the catalyst layer, where the water splitting takes place. These porous transport layers have to ensure the transport of water to the catalyst layer, the removal ofthe produced gas as well as the electrical contacting of the electrode. Therefore they influence the mass transport and the corresponding overvoltages and consequently the efficiency of the water electrolysis process. The goal of this work was to compare different porous transport layers with respect to their mass transport properties. This was done by comparing different kinds of porous transport layers, partly manufactured as part of this work and partly sourced from suppliers. These materials were electrochemically characterized in cell operation and compared with respect to their mass transport properties. By means of radiography methods (synchrotron and neutron radiation), the local mass transport in the electrolysis cells and within the porous transport layers was examined. A pore network model was used to simulate the mass transport within the porous transport layer and the simulation results were correlated with experimental results. This allowed to obtain the following findings: • The porous transport layers manufactured using tape casting yielded pore structure dependent cell efficiencies and mass transport overvoltages, with porosities of 27−30% (sintering temperatures of 800−850°C) showing the best cell efficiencies. • Analyzing the gas bubble discharge from the water saturated porous transport layer using synchrotron radiography enabled the observation of a current density dependent number of selective transport pathways for the produced gas. Characterizing the local gas- and water distribution using neutron radiography allowed to explain the globally observed und porosity dependent mass transport overvoltages. • Leveraging simulations of the gas and water transport within the porous transport layers, the limiting current densities for a continuous operation of electrolyzer cells could be derived. These were more than an order of magnitude smaller for materials with a porosity of 13% compared to materials with a porosity of greater or equal 27%

Simulation of a Full Fuel Cell Membrane Electrode Assembly Using Pore Network Modeling

A pore network model has been applied to a both sides of a fuel cell membrane electrode assembly. The model includes gas transport in the gas diffusion layers and catalyst layers, proton transport in the catalyst layers and membrane, and percolation of liquid water. This paper presents an iterative algorithm to simulate a steady state isothermal cell with a 3D pore network model for constant voltage boundary condition. The proposed algorithm provides a simple method to couple the results of the anode and the cathode sides by iteratively solving the uncoupled equations of the transport processes. It was found that local water blockages at the GDL/CL interface not only affect concentration polarization, but also might change ohmic polarization of the cell. Depending on the liquid water configuration in the porous electrodes, the protons generated in the anode need to travel longer paths to reach the active sites of the cathode; consequently, the IR loss will be increased in the presence of liquid water. This finding highlights the strength of pore network models which resolve discrete water blockages in the electrode

Is the radiographic subsidence of stand-alone cages associated with adverse clinical outcomes after cervical spine fusion? An observational cohort study with 2-year follow-up outcome scoring

BACKGROUND: The stand-alone treatment of degenerative cervical spine pathologies is a proven method in clinical practice. However, its impact on subsidence, the resulting changes to the profile of the cervical spine and the possible influence of clinical results compared to treatment with additive plate osteosynthesis remain under discussion until present. METHODS: This study was designed as a retrospective observational cohort study to test the hypothesis that radiographic subsidence of cervical cages is not associated with adverse clinical outcomes. 33 cervical segments were treated surgically by ACDF with stand-alone cage in 17 patients (11 female, 6 male), mean age 56 years (33–82 years), and re-examined after eight and twenty-six months (mean) by means of radiology and score assessment (Medical Outcomes Study Short Form (MOS-SF 36), Oswestry Neck Disability Index (ONDI), painDETECT questionnaire and the visual analogue scale (VAS)). RESULTS: Subsidence was observed in 50.5% of segments (18/33) and 70.6% of patients (12/17). 36.3% of cases of subsidence (12/33) were observed after eight months during mean time of follow-up 1. After 26 months during mean time of follow-up 2, full radiographic fusion was seen in 100%. MOS-SF 36, ONDI and VAS did not show any significant difference between cases with and without subsidence in the two-sample t-test. Only in one type of scoring (painDETECT questionnaire) did a statistically significant difference in t-Test emerge between the two groups (p = 0.03; α = 0.05). However, preoperative painDETECT score differ significantly between patients with subsidence (13.3 falling to 12.6) and patients without subsidence (7.8 dropped to 6.3). CONCLUSIONS: The radiological findings indicated 100% healing after stand-alone treatment with ACDF. Subsidence occurred in 50% of the segments treated. No impact on the clinical results was detected in the medium-term study period

In-operande Synchrotoron X-Ray and Neutron Radiography Studies of Polymer Electrolyte Membrane Water Electrolyzers

We study how conflict in a contest game is influenced by rival parties being groups and by group members being able to punish each other. Our main motivation stems from the analysis of socio-political conflict. The relevant theoretical prediction in our setting is that conflict expenditures are independent of group size and independent of whether punishment is available or not. We find, first, that our results contradict the independence of groupsize prediction: conflict expenditures of groups are substantially larger than those of individuals, and both are substantially above equilibrium. Towards the end of the experiment material losses in groups are 257% of the predicted level. There is, however, substantial heterogeneity in the investment behaviour of individual group members. Second, allowing group members to punish each other after individual contributions to the contest effort are revealed leads to even larger conflict expenditures. Now material losses are 869% of the equilibrium level and there is much less heterogeneity in individual group members' investments. These results contrast strongly with those from public goods experiments where punishment enhances efficiency and leads to higher material payoffs