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This work documents the ICON‐Earth System Model (ICON‐ESM V1.0), the first coupled model based on the ICON (ICOsahedral Non‐hydrostatic) framework with its unstructured, icosahedral grid concept. The ICON‐A atmosphere uses a nonhydrostatic dynamical core and the ocean model ICON‐O builds on the same ICON infrastructure, but applies the Boussinesq and hydrostatic approximation and includes a sea‐ice model. The ICON‐Land module provides a new framework for the modeling of land processes and the terrestrial carbon cycle. The oceanic carbon cycle and biogeochemistry are represented by the Hamburg Ocean Carbon Cycle module. We describe the tuning and spin‐up of a base‐line version at a resolution typical for models participating in the Coupled Model Intercomparison Project (CMIP). The performance of ICON‐ESM is assessed by means of a set of standard CMIP6 simulations. Achievements are well‐balanced top‐of‐atmosphere radiation, stable key climate quantities in the control simulation, and a good representation of the historical surface temperature evolution. The model has overall biases, which are comparable to those of other CMIP models, but ICON‐ESM performs less well than its predecessor, the Max Planck Institute Earth System Model. Problematic biases are diagnosed in ICON‐ESM in the vertical cloud distribution and the mean zonal wind field. In the ocean, sub‐surface temperature and salinity biases are of concern as is a too strong seasonal cycle of the sea‐ice cover in both hemispheres. ICON‐ESM V1.0 serves as a basis for further developments that will take advantage of ICON‐specific properties such as spatially varying resolution, and configurations at very high resolution., Plain Language Summary: ICON‐ESM is a completely new coupled climate and earth system model that applies novel design principles and numerical techniques. The atmosphere model applies a non‐hydrostatic dynamical core, both atmosphere and ocean models apply unstructured meshes, and the model is adapted for high‐performance computing systems. This article describes how the component models for atmosphere, land, and ocean are coupled together and how we achieve a stable climate by setting certain tuning parameters and performing sensitivity experiments. We evaluate the performance of our new model by running a set of experiments under pre‐industrial and historical climate conditions as well as a set of idealized greenhouse‐gas‐increase experiments. These experiments were designed by the Coupled Model Intercomparison Project (CMIP) and allow us to compare the results to those from other CMIP models and the predecessor of our model, the Max Planck Institute for Meteorology Earth System Model. While we diagnose overall satisfactory performance, we find that ICON‐ESM features somewhat larger biases in several quantities compared to its predecessor at comparable grid resolution. We emphasize that the present configuration serves as a basis from where future development steps will open up new perspectives in earth system modeling., Key Points: This work documents ICON‐ESM 1.0, the first version of a coupled model based on the ICON framework. Performance of ICON‐ESM is assessed by means of CMIP6 Diagnosis, Evaluation, and Characterization of Klima experiments at standard CMIP‐type resolution. ICON‐ESM reproduces the observed temperature evolution. Biases in clouds, winds, sea‐ice, and ocean properties are larger than in MPI‐ESM., European Union H2020 ESM2025, European Union H2020 COMFORT, European Union H2020ESiWACE2, Deutsche Forschungsgemeinschaft TRR181, Deutsche Forschungsgemeinschaft EXC 2037, European Union H2020, Deutscher Wetterdienst, Bundesministerium fuer Bildung und Forschung, http://esgf-data.dkrz.de/search/cmip6-dkrz/, https://mpimet.mpg.de/en/science/modeling-with-icon/code-availability, http://cera-www.dkrz.de/WDCC/ui/Compact.jsp?acronym=RUBY-0_ICON-_ESM_V1.0_Model

The recent introduction of immune checkpoint inhibitor therapy with anti- PD-1 agents has shown encouraging responses in gastrointestinal oncology. However, it is also known to possibly result in uncontrolled T cell autoreactivity, leading to a broad range of immune related adverse events. We present a patient who developed sequential immune-related hematologic and hepatic complications following pembrolizumab therapy for metastatic colon cancer. In particular, we describe in detail the histopathologic and immunohistochemical findings in the liver and bone marrow, adding to the spectrum of morphological changes which may be observed in association with PD-1 inhibitor therapy. The report also highlights the occurrence of these adverse reactions even after discontinuation of immunotherapy, eventually resulting in the death of the patient.

An amendment to this paper has been published and can be accessed via a link at the top of the paper. © 2020, Crown.

The MPI‐ESM1.2 is the latest version of the Max Planck Institute Earth System Model and is the baseline for the Coupled Model Intercomparison Project Phase 6 and current seasonal and decadal climate predictions. This paper evaluates a coupled higher‐resolution version (MPI‐ESM1.2‐HR) in comparison with its lower‐resolved version (MPI‐ESM1.2‐LR). We focus on basic oceanic and atmospheric mean states and selected modes of variability, the El Niño/Southern Oscillation and the North Atlantic Oscillation. The increase in atmospheric resolution in MPI‐ESM1.2‐HR reduces the biases of upper‐level zonal wind and atmospheric jet stream position in the northern extratropics. This results in a decrease of the storm track bias over the northern North Atlantic, for both winter and summer season. The blocking frequency over the European region is improved in summer, and North Atlantic Oscillation and related storm track variations improve in winter. Stable Atlantic meridional overturning circulations are found with magnitudes of ~16 Sv for MPI‐ESM1.2‐HR and ~20 Sv for MPI‐ESM1.2‐LR at 26°N. A strong sea surface temperature bias of ~5°C along with a too zonal North Atlantic current is present in both versions. The sea surface temperature bias in the eastern tropical Atlantic is reduced by ~1°C due to higher‐resolved orography in MPI‐ESM‐HR, and the region of the cold‐tongue bias is reduced in the tropical Pacific. MPI‐ESM1.2‐HR has a well‐balanced radiation budget and its climate sensitivity is explicitly tuned to 3 K. Although the obtained reductions in long‐standing biases are modest, the improvements in atmospheric dynamics make this model well suited for prediction and impact studies.

This paper provides an update on research in the relatively new and fast-moving field of decadal climate prediction, and addresses the use of decadal climate predictions not only for potential users of such information but also for improving our understanding of processes in the climate system. External forcing influences the predictions throughout, but their contributions to predictive skill become dominant after most of the improved skill from initialization with observations vanishes after about 6–9 years. Recent multimodel results suggest that there is relatively more decadal predictive skill in the North Atlantic, western Pacific, and Indian Oceans than in other regions of the world oceans. Aspects of decadal variability of SSTs, like the mid-1970s shift in the Pacific, the mid-1990s shift in the northern North Atlantic and western Pacific, and the early-2000s hiatus, are better represented in initialized hindcasts compared to uninitialized simulations. There is evidence of higher skill in initialized multimodel ensemble decadal hindcasts than in single model results, with multimodel initialized predictions for near-term climate showing somewhat less global warming than uninitialized simulations. Some decadal hindcasts have shown statistically reliable predictions of surface temperature over various land and ocean regions for lead times of up to 6–9 years, but this needs to be investigated in a wider set of models. As in the early days of El Niño–Southern Oscillation (ENSO) prediction, improvements to models will reduce the need for bias adjustment, and increase the reliability, and thus usefulness, of decadal climate predictions in the future.

Objective:: To report the results of a 24-month extension of a phase II trial assessing the efficacy, safety, and tolerability of the once-daily oral sphingosine-1-phosphate receptor modulator, fingolimod (FTY720), in relapsing multiple sclerosis (MS). METHODS:: In the randomized, double-blind, placebo-controlled core study, 281 patients received placebo or FTY720, 1.25 or 5.0 mg/day, for 6 months. During the subsequent dose-blinded extension, patients assigned to placebo were re-randomized to either dose of FTY720; those originally assigned to FTY720 continued at the same dose. Patients receiving FTY720 5.0 mg were switched to 1.25 mg during the month 15 to month 24 study visits. RESULTS:: Of 281 patients randomized in the core study, 250 (89%) entered the extension phase, and 189 (75.6%) received treatment for 24 months. During the core study, FTY720 significantly reduced gadolinium-enhanced (Gd) lesions and annualized relapse rate (ARR) compared with placebo, with no differences between doses. During the extension phase, patients who switched from placebo to FTY720 showed clear reductions in ARR and lesion counts compared with the placebo phase; ARR and lesion counts remained low in patients who continued FTY720 treatment. After 24 months, 79 to 91% of patients were free from Gd lesions and up to 77% of patients remained relapse free. FTY720 was well tolerated; no new safety concerns emerged during months 7 to 24 compared with the 6-month core study. CONCLUSIONS:: Once-daily oral treatment with FTY720, 1.25 or 5.0 mg, for up to 2 years, was well tolerated and was associated with low relapse rates and lesion activity. © 2009 AAN Enterprises, Inc.

An ensemble of yearly initialized decadal predictions is performed with the Max Planck Institute Earth System Model to examine the forecast skill for the period from 1901 to 2010. Compared to the more recent period (1960 to present day), the extended period leads to an enlargement of regions with significant anomaly correlation coefficients (ACC) for predicted surface temperatures. This arises from an increased contribution of the trend, which is also found in the uninitialized runs. Additionally, in the North Atlantic decadal variability plays a larger role over the extended period, with detrended time series showing higher ACC for the extended compared to the short period. Furthermore, in contrast to the uninitialized simulations, the initialized predictions capture the North Atlantic warming events during the 1920s and 1990s, together with some of the surface climate impacts including warm European summer temperatures and a northward shift of Atlantic tropical rainfall.

The predictability of the Quasi-Biennial Oscillation (QBO) is examined in initialised climate forecasts extending out to lead times of years. We use initialised retrospective predictions made with coupled ocean-atmosphere climate models that have an internally generated QBO. We demonstrate predictability of the QBO extending more than three years into the future, well beyond timescales normally associated with internal atmospheric processes. Correlation scores with observational analyses exceed 0.7 at a lead time of 12 months. We also examine the variation of predictability with season and QBO phase and find that skill is lowest in winter. An assessment of perfect predictability suggests that higher skill may be achievable through improved initialisation and climate modelling of the QBO, although this may depend on the realism of gravity wave source parametrizations in the models. Finally, we show that skilful prediction of the QBO itself does not guarantee predictability of the extratropical winter teleconnection that is important for surface winter climate prediction.

We assess the skill of retrospective multiyear forecasts of North Atlantic ocean characteristics obtained with ocean-atmosphere-sea ice models that are initialized with estimates from the observed ocean state. We show that these multimodel forecasts can skilfully predict surface and subsurface ocean variability with lead times of 2 to 9 years. We focus on assessment of forecasts of major well-observed oceanic phenomena that are thought to be related to the Atlantic meridional overturning circulation (AMOC). Variability in the North Atlantic subpolar gyre, in particular that associated with the Atlantic Multidecadal Oscillation, is skilfully predicted 2-9 years ahead. The fresh water content and heat content in major convection areas such as the Labrador Sea are predictable as well, although individual events are not captured. The skill of these predictions is higher than that of uninitialized coupled model simulations and damped persistence. However, except for heat content in the subpolar gyre, differences between damped persistence and the initialized predictions are not significant. Since atmospheric variability is not predictable on multiyear time scales, initialization of the ocean and oceanic processes likely provide skill. Assessment of relationships of patterns of variability and ocean heat content and fresh water content shows differences among models indicating that model improvement can lead to further improvements of the predictions. The results imply there is scope for skilful predictions of the AMOC. © 2013. American Geophysical Union. All Rights Reserved.

We examine the latest decadal predictions performed with the coupled model MPI-ESM as part of the Coupled Model Intercomparison Project Phase 5 (CMIP5). We use ensembles of uninitialized and yearly initialized experiments to estimate the forecast skill for surface air temperature. Like for its precursor, the initialisation of MPI-ESM improves forecast skill for yearly and multi-yearly means, predominately over the North Atlantic for all lead times. Over the tropical Pacific, negative skill scores reflect a systematic error in the initialisation. We also examine the forecast skill of multi-year seasonal means. Skill scores of winter means are predominantly positive over northern Europe. In contrast, summer to autumn means reveal positive skill scores over central and south-eastern Europe. The skill scores of summer means are attributable to an observed pressure-gradient response to the North Atlantic surface temperatures.

The possibility of a rapid collapse in the strength of the Atlantic meridional overturning circulation (AMOC), with associated impacts on climate, has long been recognized. The suggested basis for this risk is the existence of two stable regimes of the AMOC (on and off), and such bistable behaviour has been identified in a range of simplified climate models. However, up to now, no state-of-the-art atmosphere-ocean coupled global climate model (AOGCM) has exhibited such behaviour, leading to the interpretation that the AMOC is more stable than simpler models indicate. Here we demonstrate AMOC bistability in the response to freshwater perturbations in the FAMOUS AOGCM - the most complex AOGCM to exhibit such behaviour to date. The results also support recent suggestions that the direction of the net freshwater transport at the southern boundary of the Atlantic by the AMOC may be a useful physical indicator of the existence of bistability. We also present new estimates for this net freshwater transport by the AMOC from a range of ocean reanalyses which suggest that the Atlantic AMOC is currently in a bistable regime, although with large uncertainties. More accurate observational constraints, and an improved physical understanding of this quantity, could help narrow uncertainty in the future evolution of the AMOC and to assess the risk of a rapid AMOC collapse. Copyright 2011 by the American Geophysical Union.