ECOG-ACRIN (E4805) Randomized Phase II Study to Determine the Effect of 2 Different Doses of Aflibercept in Patients with Metastatic Renal Cell Carcinoma

Background—Aflibercept is a recombinantly-produced fusion protein that has potent anti-VEGF activity. We tested whether aflibercept has clinical activity in clear cell renal cell carcinoma (ccRCC). The recommended Phase 2 dose was 4 mg/kg but several patients treated at 1 mg/kg demonstrated prolonged progression-free survival (PFS). We therefore tested both doses in a parallel group randomized trial. Methods—Eligible patients (pts) had histologically confirmed advanced or metastatic ccRCC and previous treatments including prior exposure to a VEGF RTKI. Patients received aflibercept (either 1 mg/kg or 4 mg/kg) day 1 of a 14-day cycle until progression. Patients randomized to 1 mg/kg could crossover to 4 mg/kg at progression. The primary endpoint was proportion alive and progression-free at 8 weeks. A Simon 2-stage design was used for each arm with 33 and 24 eligible pts/arm enrolled in stages 1 and 2. Results—94 pts were enrolled, 59 and 35 to 4 mg and 1 mg doses, respectively. 72% had 1 prior tx most commonly sunitinib. 16 eligible pts crossed over at progression to the 4 mg dose. Most common adverse events were hypertension, proteinuria, and fatigue. Only 4 pts reported Grade 4 or higher toxicity. With 36/59 (61%) pts PFS at 8 wks, the 4-mg/kg dose met protocol specified efficacy criteria. Conclusions—Aflibercept is active in previously treated ccRCC and may be worthy of further study

New WMO certified megaflash lightning extremes for flash distance (768 km) and duration (17.01 seconds) recorded from space

Initial global extremes in lightning duration and horizontal distance were established in 2017 (Lang et al. 2017) by an international panel of atmospheric lightning scientists and engineers assembled by the WMO. The subsequent launch of NOAA’s latest GOES-16/17 satellites with their Geostationary Lightning Mappers (GLMs) enabled extreme lightning to be monitored continuously over the western hemisphere up to 55° latitude for the first time. As a result, the former lightning extremes were more than doubled in 2019 to 709 km for distance and 16.730 s for duration (Peterson et al. 2020). Continued detection and analysis of lightning “megaflashes” (Sequin, 2021) has now revealed two flashes that even exceed those 2019 records. As part of the ongoing work of the WMO in detection and documentation of global weather extremes (e.g., El Fadli et al. 2013; Merlone et al. 2010), an international WMO evaluation committee was created to critically adjudicate these two GLM megaflash cases as new records for extreme lightning.We thank S. A. Rutledge and two other reviewers for their valuable comments. M. J. Peterson was supported by the U.S. Department of Energy through the Los Alamos National Laboratory (LANL) Laboratory Directed Research and Development (LDRD) program under project number 20200529ECR. Los Alamos National Laboratory is operated by Triad National Security, LLC, for the National Nuclear Security Administration of U.S. Department of Energy (Contract 89233218CNA000001). T. Logan supported by a NOAA Grant NA16OAR4320115 “Lightning Mapper Array Operation in Oklahoma and the Texas Gulf Coast Region to Aid Preparation for the GOES-R GLM.” I. Kolmasova was supported by GACR Grant 20-09671. S. D. Zhang was supported by a NOAA Grant NNH19ZDA001N-ESROGSS. The participation of J. Montanya in this work is supported by research Grant ESP2017-86263-C4-2-R funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe,” by the “European Union”; and Grants PID2019-109269RB-C42 funded by MCIN/AEI/10.13039/501100011033.Peer ReviewedPostprint (author's final draft

The biogeophysical effects of idealized land cover and land management changes in Earth system models

Land cover and land management change (LCLMC) has been highlighted for its critical role in mitigation scenarios in terms of both global mitigation and local adaptation. Yet, the climate effect of individual LCLMC options, their dependence on the background climate, and the local vs. non-local responses are still poorly understood across different Earth system models (ESMs). Here we simulate the climatic effects of LCLMC using three state-of-the-art ESMs, including the Community Earth System Model (CESM), the Max Planck Institute for Meteorology Earth System Model (MPI-ESM), and the European Consortium Earth System Model (EC-EARTH). We assess the LCLMC effects using four idealized experiments: (i) a fully afforested world, (ii) a world fully covered by cropland, (iii) a fully afforested world with extensive wood harvesting, and (iv) a full cropland world with extensive irrigation. In these idealized sensitivity experiments performed under present-day climate conditions, the effects of the different LCLMC strategies represent an upper bound for the potential of global mitigation and local adaptation. To disentangle the local and non-local effects from the LCLMC, a checkerboard-like LCLMC perturbation, i.e. alternating grid boxes with and without LCLMC, is applied. The local effects of deforestation on surface temperature are largely consistent across the ESMs and the observations, with a cooling in boreal latitudes and a warming in the tropics. However, the energy balance components driving the change in surface temperature show less consistency across the ESMs and the observations. Additionally, some biases exist in specific ESMs, such as a strong albedo response in CESM mid-latitudes and a soil-thawing-driven warming in boreal latitudes in EC-EARTH. The non-local effects on surface temperature are broadly consistent across ESMs for afforestation, though larger model uncertainty exists for cropland expansion. Irrigation clearly induces a cooling effect; however, the ESMs disagree regarding whether these are mainly local or non-local effects. Wood harvesting is found to have no discernible biogeophysical effects on climate. Our results overall underline the potential of ensemble simulations to inform decision-making regarding future climate consequences of land-based mitigation and adaptation strategies.ISSN:2190-4987ISSN:2190-497

The International Surface Pressure Databank version 2

The International Surface Pressure Databank (ISPD) is the world's largest collection of global surface and sea-level pressure observations. It was developed by extracting observations from established international archives, through international cooperation with data recovery facilitated by the Atmospheric Circulation Reconstructions over the Earth (ACRE) initiative, and directly by contributing universities, organizations, and countries. The dataset period is currently 1768–2012 and consists of three data components: observations from land stations, marine observing systems, and tropical cyclone best track pressure reports. Version 2 of the ISPD (ISPDv2) was created to be observational input for the Twentieth Century Reanalysis Project (20CR) and contains the quality control and assimilation feedback metadata from the 20CR. Since then, it has been used for various general climate and weather studies, and an updated version 3 (ISPDv3) has been used in the ERA-20C reanalysis in connection with the European Reanalysis of Global Climate Observations project (ERA-CLIM). The focus of this paper is on the ISPDv2 and the inclusion of the 20CR feedback metadata. The Research Data Archive at the National Center for Atmospheric Research provides data collection and access for the ISPDv2, and will provide access to future versions

Tumor Microvessel Density as a Prognostic Marker in High-Risk Renal Cell Carcinoma Patients Treated on ECOG-ACRIN E2805

Purpose—Increased vascularity is a hallmark of renal cell carcinoma (RCC). Microvessel density (MVD) is one measurement of tumor angiogenesis; however, its utility as a biomarker of outcome is unknown. ECOG-ACRIN 2805 (E2805) enrolled 1,943 resected high-risk RCC patients randomized to adjuvant sunitinib, sorafenib, or placebo. We aimed to determine the prognostic and predictive role of MVD in RCC. Experimental Design—We obtained pretreatment primary RCC nephrectomy tissues from 822 patients on E2805 and constructed tissue microarrays. Using quantitative immunofluorescence, we measured tumor MVD as the area of CD34-expressing cells. We determined the association with disease-free survival (DFS), overall survival (OS), treatment arm, and clinicopathologic variables. Results—High MVD (above the median) was associated with prolonged OS for the entire cohort (p = 0.021) and for patients treated with placebo (p = 0.028). The association between high MVD and OS was weaker in patients treated with sunitinib or sorafenib (p = 0.060). MVD was not associated with DFS (p = 1.00). On multivariable analysis, MVD remained independently associated with improved OS (p = 0.013). High MVD correlated with Fuhrman grade 1–2 (p \u3c 0.001), clear cell histology (p \u3c 0.001), and absence of necrosis (p \u3c 0.001) but not with gender, age, sarcomatoid features, lymphovascular invasion, or tumor size. Conclusions—High MVD in resected high-risk RCC patients is an independent prognostic, rather than predictive, biomarker of improved OS. Further studies should assess whether incorporating MVD into clinical models will enhance our ability to predict outcome and if low MVD can be used for selection of high-risk patients for adjuvant therapy trials

Progress in detection and projection of climate change in Spain since the 2010 CLIVAR-Spain regional climate change assessment report

Special Issue on climate over the Iberian Peninsula: an overview of CLIVAR-Spain coordinated science

A New Phenotype in Candida-Epithelial Cell Interaction Distinguishes Colonization- versus Vulvovaginal Candidiasis- Associated Strains

Vulvovaginal candidiasis (VVC) affects nearly 3/4 of women during their lifetime, and its symptoms seriously reduce quality of life. Although Candida albicans is a common commensal, it is unknown if VVC results from a switch from a commensal to pathogenic state, if only some strains can cause VVC, and/or if there is displacement of commensal strains with more pathogenic strains. We studied a set of VVC and colonizing C. albicans strains to identify consistent in vitro phenotypes associated with one group or the other. We find that the strains do not differ in overall genetic profile or behavior in culture media (i.e., multilocus sequence type [MLST] profile, rate of growth, and filamen- tation), but they show strikingly different behaviors during their interactions with vaginal epithelial cells. Epithelial infections with VVC-derived strains yielded stronger fungal prolif- eration and shedding of fungi and epithelial cells. Transcriptome sequencing (RNA-seq) analysis of representative epithelial cell infections with selected pathogenic or commensal isolates identified several differentially activated epithelial signaling pathways, including the integrin, ferroptosis, and type I interferon pathways; the latter has been implicated in damage protection. Strikingly, inhibition of type I interferon signaling selectively increases fungal shedding of strains in the colonizing cohort, suggesting that increased shedding correlates with lower interferon pathway activation. These data suggest that VVC strains may intrinsically have enhanced pathogenic potential via differential elicitation of epithelial responses, including the type I interferon pathway. Therefore, it may eventually be possible to evaluate pathogenic potential in vitro to refine VVC diagnosis

Ambient-aware continuous care through semantic context dissemination

Background: The ultimate ambient-intelligent care room contains numerous sensors and devices to monitor the patient, sense and adjust the environment and support the staff. This sensor-based approach results in a large amount of data, which can be processed by current and future applications, e. g., task management and alerting systems. Today, nurses are responsible for coordinating all these applications and supplied information, which reduces the added value and slows down the adoption rate. The aim of the presented research is the design of a pervasive and scalable framework that is able to optimize continuous care processes by intelligently reasoning on the large amount of heterogeneous care data. Methods: The developed Ontology-based Care Platform (OCarePlatform) consists of modular components that perform a specific reasoning task. Consequently, they can easily be replicated and distributed. Complex reasoning is achieved by combining the results of different components. To ensure that the components only receive information, which is of interest to them at that time, they are able to dynamically generate and register filter rules with a Semantic Communication Bus (SCB). This SCB semantically filters all the heterogeneous care data according to the registered rules by using a continuous care ontology. The SCB can be distributed and a cache can be employed to ensure scalability. Results: A prototype implementation is presented consisting of a new-generation nurse call system supported by a localization and a home automation component. The amount of data that is filtered and the performance of the SCB are evaluated by testing the prototype in a living lab. The delay introduced by processing the filter rules is negligible when 10 or fewer rules are registered. Conclusions: The OCarePlatform allows disseminating relevant care data for the different applications and additionally supports composing complex applications from a set of smaller independent components. This way, the platform significantly reduces the amount of information that needs to be processed by the nurses. The delay resulting from processing the filter rules is linear in the amount of rules. Distributed deployment of the SCB and using a cache allows further improvement of these performance results