Toxic Epidermal Necrolysis after Pemetrexed and Cisplatin for Non-Small Cell Lung Cancer in a Patient with Sharp Syndrome

Background: Pemetrexed is an antifolate drug approved for maintenance and second-line therapy, and, in combination with cisplatin, for first-line treatment of advanced nonsquamous non-small cell lung cancer. The side-effect profile includes fatigue, hematological and gastrointestinal toxicity, an increase in hepatic enzymes, sensory neuropathy, and pulmonary and cutaneous toxicity in various degrees. Case Report: We present the case of a 58-year-old woman with history of Sharp's syndrome and adenocarcinoma of the lung, who developed toxic epidermal necrolysis after the first cycle of pemetrexed, including erythema, bullae, extensive skin denudation, subsequent systemic inflammation and severe deterioration in general condition. The generalized skin lesions occurred primarily in the previous radiation field and responded to immunosuppressive treatment with prednisone. Conclusion: Although skin toxicity is a well-known side effect of pemetrexed, severe skin reactions after pemetrexed administration are rare. Caution should be applied in cases in which pemetrexed is given subsequent to radiation therapy, especially in patients with pre-existing skin diseases

Antigenic “Hot- Spots” on the TSH Receptor Hinge Region

The TSH receptor (TSHR) hinge region was previously considered an inert scaffold connecting the leucine-rich ectodomain to the transmembrane region of the receptor. However, mutation studies have established the hinge region to be an extended hormone-binding site in addition to containing a region which is cleaved thus dividing the receptor into α|’ (A) and β (B) subunits. Furthermore, we have shown in-vitro that monoclonal antibodies directed to the cleaved part of the hinge region (often termed “neutral” antibodies) can induce thyroid cell apoptosis in the absence of cyclic AMP signaling. The demonstration of neutral antibodies in patients with Graves' disease suggests their potential involvement in disease pathology thus making the hinge a potentially important antigenic target. Here we examine the evolution of the antibody immune response to the entire TSHR hinge region (aa280–410) after intense immunization with full-length TSHR cDNA in a mouse (BALB/c) model in order to examine the immunogenicity of this critical receptor structure. We found that TSHR hinge region antibodies were detected in 95% of the immunized mice. The antibody responses were largely restricted to residues 352–410 covering three major epitopes and not merely confined to the cleaved portion. These data indicated the presence of novel antigenic “hotspots” within the carboxyl terminus of the hinge region and demonstrate that the hinge region of the TSHR contains an immunogenic pocket that is involved in the highly heterogeneous immune response to the TSHR. The presence of such TSHR antibodies suggests that they may play an active role in the immune repertoire marshaled against the TSHR and may influence the Graves' disease phenotype

The reliability of two visual motor integration tests used with children

Occupational therapists often assess the visual motor integration (VMI) skills of children and young people. It is important that therapists use tools with strong psychometric properties. This study aims to examine the reliability of 2 VMI tests. Ninety-two children between the ages of 5 and 17 years (response rate of 31%) completed 2 VMI tests: the Developmental Test of Visual Motor Integration (DTVMI) and the Full Range Test of Visual Motor Integration (FRTVMI). Cronbach\u27s alpha coefficient was used to examine the internal consistency of the 2 VMI tests whereas Spearman\u27s rho correlation was used to evaluate the test&ndash;retest reliability, intrarater reliability, and interrater reliability of the 2 VMI tests. The Cronbach\u27s alpha coefficient for the DTVMI was .82 and .72 for the FRTVMI. The test&ndash;retest reliability coefficient was .73 (p = .000) for the DTVMI and .49 (p = .05) for the FRTVMI. The interrater correlation was significant for both the DTVMI at .94 (p = .000) and FRTVMI at .68 (p = .001). The DTVMI intrarater reliability correlation result was .90 (p = .000) and the FRTVMI at .85 (p = .000). Overall, the DTVMI exhibited a higher level of reliability than the FRTVMI. Both VMI tests appear to exhibit reasonable levels of reliability and are recommended for use with children and young people.<br /

Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab.

The mechanisms by which immune checkpoint blockade modulates tumor evolution during therapy are unclear. We assessed genomic changes in tumors from 68 patients with advanced melanoma, who progressed on ipilimumab or were ipilimumab-naive, before and after nivolumab initiation (CA209-038 study). Tumors were analyzed by whole-exome, transcriptome, and/or T cell receptor (TCR) sequencing. In responding patients, mutation and neoantigen load were reduced from baseline, and analysis of intratumoral heterogeneity during therapy demonstrated differential clonal evolution within tumors and putative selection against neoantigenic mutations on-therapy. Transcriptome analyses before and during nivolumab therapy revealed increases in distinct immune cell subsets, activation of specific transcriptional networks, and upregulation of immune checkpoint genes that were more pronounced in patients with response. Temporal changes in intratumoral TCR repertoire revealed expansion of T cell clones in the setting of neoantigen loss. Comprehensive genomic profiling data in this study provide insight into nivolumab\u27s mechanism of action

Results from the Super Cryogenic Dark Matter Search (SuperCDMS) experiment at Soudan

We report the result of a blinded search for Weakly Interacting Massive Particles (WIMPs) using the majority of the SuperCDMS Soudan dataset. With an exposure of 1690 kg days, a single candidate event is observed, consistent with expected backgrounds. This analysis (combined with previous Ge results) sets an upper limit on the spin-independent WIMP--nucleon cross section of $1.4 \times 10^{-44}$ ($1.0 \times 10^{-44}$) cm$^2$ at 46 GeV/$c^2$. These results set the strongest limits for WIMP--germanium-nucleus interactions for masses $>$12 GeV/$c^2$

The ICON Earth System Model Version 1.0

This work documents ICON-ESM 1.0, the first version of a coupled model based 19 on the ICON framework 20 • Performance of ICON-ESM is assessed by means of CMIP6 DECK experiments 21 at standard CMIP-type resolution 22 • ICON-ESM reproduces the observed temperature evolution. Biases in clouds, winds, 23 sea-ice, and ocean properties are larger than in MPI-ESM. Abstract 25 This work documents the ICON-Earth System Model (ICON-ESM V1.0), the first cou-26 pled model based on the ICON (ICOsahedral Non-hydrostatic) framework with its un-27 structured, icosahedral grid concept. The ICON-A atmosphere uses a nonhydrostatic dy-28 namical core and the ocean model ICON-O builds on the same ICON infrastructure, but 29 applies the Boussinesq and hydrostatic approximation and includes a sea-ice model. The 30 ICON-Land module provides a new framework for the modelling of land processes and 31 the terrestrial carbon cycle. The oceanic carbon cycle and biogeochemistry are repre-32 sented by the Hamburg Ocean Carbon Cycle module. We describe the tuning and spin-33 up of a base-line version at a resolution typical for models participating in the Coupled 34 Model Intercomparison Project (CMIP). The performance of ICON-ESM is assessed by 35 means of a set of standard CMIP6 simulations. Achievements are well-balanced top-of-36 atmosphere radiation, stable key climate quantities in the control simulation, and a good 37 representation of the historical surface temperature evolution. The model has overall bi-38 ases, which are comparable to those of other CMIP models, but ICON-ESM performs 39 less well than its predecessor, the Max Planck Institute Earth System Model. Problem-40 atic biases are diagnosed in ICON-ESM in the vertical cloud distribution and the mean 41 zonal wind field. In the ocean, sub-surface temperature and salinity biases are of con-42 cern as is a too strong seasonal cycle of the sea-ice cover in both hemispheres. ICON-43 ESM V1.0 serves as a basis for further developments that will take advantage of ICON-44 specific properties such as spatially varying resolution, and configurations at very high 45 resolution. 46 Plain Language Summary 47 ICON-ESM is a completely new coupled climate and earth system model that ap-48 plies novel design principles and numerical techniques. The atmosphere model applies 49 a non-hydrostatic dynamical core, both atmosphere and ocean models apply unstruc-50 tured meshes, and the model is adapted for high-performance computing systems. This 51 article describes how the component models for atmosphere, land, and ocean are cou-52 pled together and how we achieve a stable climate by setting certain tuning parameters 53 and performing sensitivity experiments. We evaluate the performance of our new model 54 by running a set of experiments under pre-industrial and historical climate conditions 55 as well as a set of idealized greenhouse-gas-increase experiments. These experiments were 56 designed by the Coupled Model Intercomparison Project (CMIP) and allow us to com-57 pare the results to those from other CMIP models and the predecessor of our model, the 58 Max Planck Institute for Meteorology Earth System Model. While we diagnose overall 59 satisfactory performance, we find that ICON-ESM features somewhat larger biases in 60 several quantities compared to its predecessor at comparable grid resolution. We empha-61 size that the present configuration serves as a basis from where future development steps 62 will open up new perspectives in earth system modellin

International Survey of Patients With IBS: Symptom Features and Their Severity, Health Status, Treatments, and Risk Taking to Achieve Clinical Benefit

While clinicians generally make treatment decisions in IBS related to the type of symptoms, other factors such as the perceived severity and the risks patients are willing to tolerate for effective treatment are also important to consider. These factors are not fully understood