Rationale and design of the POLEM trial: avelumab plus fluoropyrimidine-based chemotherapy as adjuvant treatment for stage III mismatch repair deficient or POLE exonuclease domain mutant colon cancer: a phase III randomised study

BACKGROUND:10%-15% of early-stage colon cancers harbour either deficient mismatch repair (dMMR), microsatellite instability high (MSI-H) or POLE exonuclease domain mutations, and are characterised by high tumour mutational burden and increased lymphocytic infiltrate. Metastatic dMMR colon cancers are highly sensitive to immune checkpoint inhibition, and recent data show POLE-mutant tumours are similarly responsive. We are conducting a phase III randomised trial to determine if the addition of the anti-PD-L1 antibody avelumab following adjuvant chemotherapy improves disease-free survival (DFS) in patients with stage III dMMR/MSI-H or POLE mutant colon cancer and is a cost-effective approach for the UK National Health Service (NHS). METHODS:We are recruiting patients with completely resected, stage III colon cancer confirmed to have dMMR/MSI-H, locally or POLE exonuclease domain mutation on central testing. Eligible patients are randomised in a 1:1 ratio to standard fluoropyrimidine-based chemotherapy (capecitabine, oxaliplatin for 12 weeks or capecitabine for 24 weeks) or chemotherapy, followed by avelumab (10 mg/kg, 2 weekly for 24 weeks). Stratification is by chemotherapy received and MMR/MSI-H status. The primary endpoint is DFS. Secondary endpoints include overall survival, toxicity, quality of life and health resource use. The 3-year DFS rate in the control arm is expected to be ~75%. Avelumab is expected to improve the 3-year DFS rate by 12% (ie, 87%). Target accrual is 402 patients, which provides 80% power to detect an HR of 0.48 for DFS at a two-sided alpha of 0.05. This national, multicentre phase III trial is sponsored by the Royal Marsden NHS Foundation Trust and it is anticipated that approximately 40 centres in the UK will participate. This study opened to recruitment in August 2018. TRIAL REGISTRATION NUMBER:NCT03827044

Radar/rain-gauge comparisons on squall lines in Niamey, Niger for the AMMA

Massachusetts Institute of Technology C-band radar observations are integrated with rainfall measurements from an extensive network of gauges in Niamey, Niger, West Africa, for the African Monsoon and Multidisciplinary Analysis (AMMA). The large number of gauges available enabled Z e – R power-law relationships for the convective and stratiform regions of individual squall lines. The Z e – R relationships based solely on radar measurements directly over the gauges were developed for the estimate of rainfall and attendant latent heat release (by other AMMA investigators) where gauges were unavailable. The low prefactor values of the Z e – R power laws relative to like values for Z – R disdrometer power laws have contributions of order 1–2 dB from the use of the lowest beam tilt (0.57° ) and ∼1–2 dB by the radar reading low. (The sphere calibration and the Tropical Rainfall Measuring Mission TRMM—radar calibration are inconsistent at the 1–2 dB level for unknown reasons.) Radar/gauge comparisons are also shown for individual storms. Accurate, unbiased results for the convective regime require adjustment of the radar-to-gauge radials for attenuation. Beam filling problems and aliasing issues can often be identified in the case of outlier points. Copyright © 2010 Royal Meteorological SocietyPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/69205/1/548_ftp.pd

Hints of R-parity violation in B decays into τν\tau \nu

In this article we show that the recently observed enhanced semi-leptonic and leptonic decay rates of the B meson into \tau \nu modes can be explained within the frame work of R-parity violating (RPV) MSSM. In particular, RPV contributions involving the exchange of right-handed down-type squarks give a universal contribution to the B+ --> \tau \nu, B --> D \tau \nu and the B --> D* \tau \nu decays. We find that the masses and couplings that explain the enhanced B decay rates are phenomelogically viable and the squarks can possibly be observed at the LHC.Comment: 8 pages and 3 figures; Updated section 2 and 3, but results are unmodifie

Recent variability of the global ocean carbon sink

We present a new observation-based estimate of the global oceanic carbon dioxide (CO2) sink and its temporal variation on a monthly basis from 1998 through 2011 and at a spatial resolution of 1×1. This sink estimate rests upon a neural network-based mapping of global surface ocean observations of the partial pressure of CO2 (pCO2) from the Surface Ocean CO2 Atlas database. The resulting pCO2 has small biases when evaluated against independent observations in the different ocean basins, but larger randomly distributed differences exist particularly in high latitudes. The seasonal climatology of our neural network-based product agrees overall well with the Takahashi et al. (2009) climatology, although our product produces a stronger seasonal cycle at high latitudes. From our global pCO2 product, we compute a mean net global ocean (excluding the Arctic Ocean and coastal regions) CO2 uptake flux of −1.42 ± 0.53 Pg C yr−1, which is in good agreement with ocean inversion-based estimates. Our data indicate a moderate level of interannual variability in the ocean carbon sink (±0.12 Pg C yr−1, 1𝜎) from 1998 through 2011, mostly originating from the equatorial Pacific Ocean, and associated with the El Nino–Southern Oscillation. Accounting for steady state riverine and Arctic Ocean carbon fluxes our estimate further implies a mean anthropogenic CO2 uptake of −1.99 ± 0.59 Pg C yr−1 over the analysis period. From this estimate plus the most recent estimates for fossil fuel emissions and atmospheric CO2 accumulation, we infer a mean global land sink of −2.82 ± 0.85 Pg C yr−1 over the 1998 through 2011 period with strong interannual variation

Organic aerosol formation downwind from the Deepwater Horizon oil spill.

A large fraction of atmospheric aerosols are derived from organic compounds with various volatilities. A National Oceanic and Atmospheric Administration (NOAA) WP-3D research aircraft made airborne measurements of the gaseous and aerosol composition of air over the Deepwater Horizon (DWH) oil spill in the Gulf of Mexico that occurred from April to August 2010. A narrow plume of hydrocarbons was observed downwind of DWH that is attributed to the evaporation of fresh oil on the sea surface. A much wider plume with high concentrations of organic aerosol (>25 micrograms per cubic meter) was attributed to the formation of secondary organic aerosol (SOA) from unmeasured, less volatile hydrocarbons that were emitted from a wider area around DWH. These observations provide direct and compelling evidence for the importance of formation of SOA from less volatile hydrocarbons

Inverse modelling of carbonyl sulfide: implementation, evaluation and implications for the global budget

Carbonyl sulfide (COS) has the potential to be used as a climate diagnostic due to its close coupling to the biospheric uptake of CO2 and its role in the formation of stratospheric aerosol. The current understanding of the COS budget, however, lacks COS sources, which have previously been allocated to the tropical ocean. This paper presents a first attempt at global inverse modelling of COS within the 4-dimensional variational data-assimilation system of the TM5 chemistry transport model (TM5-4DVAR) and a comparison of the results with various COS observations. We focus on the global COS budget, including COS production from its precursors carbon disulfide (CS2) and dimethyl sulfide (DMS). To this end, we implemented COS uptake by soil and vegetation from an updated biosphere model (Simple Biosphere Model-SiB4). In the calculation of these fluxes, a fixed atmospheric mole fraction of 500 pmol mol-1 was assumed. We also used new inventories for anthropogenic and biomass burning emissions. The model framework is capable of closing the COS budget by optimizing for missing emissions using NOAA observations in the period 2000-2012. The addition of 432 Gg a-1 (as S equivalents) of COS is required to obtain a good fit with NOAA observations. This missing source shows few year-to-year variations but considerable seasonal variations. We found that the missing sources are likely located in the tropical regions, and an overestimated biospheric sink in the tropics cannot be ruled out due to missing observations in the tropical continental boundary layer. Moreover, high latitudes in the Northern Hemisphere require extra COS uptake or reduced emissions. HIPPO (HIAPER Pole-to-Pole Observations) aircraft observations, NOAA airborne profiles from an ongoing monitoring programme and several satellite data sources are used to evaluate the optimized model results. This evaluation indicates that COS mole fractions in the free troposphere remain underestimated after optimization. Assimilation of HIPPO observations slightly improves this model bias, which implies that additional observations are urgently required to constrain sources and sinks of COS. We finally find that the biosphere flux dependency on the surface COS mole fraction (which was not accounted for in this study) may substantially lower the fluxes of the SiB4 biosphere model over strong-uptake regions. Using COS mole fractions from our inversion, the prior biosphere flux reduces from 1053 to 851 Gg a-1, which is closer to 738 Gg a-1 as was found by Berry et al. (2013). In planned further studies we will implement this biosphere dependency and additionally assimilate satellite data with the aim of better separating the role of the oceans and the biosphere in the global COS budget..</p

Effects of data selection on the assimilation of AIRS data

The Atmospheric InfraRed Sounder (AIRS), flying aboard NASA's Earth Observing System (EOS) Aqua satellite with the Advanced Microwave Sounding Unit-A (AMSU-A), has been providing data for use in numerical weather prediction (NWP) and data assimilation systems (DAS) for over three years. The full AIRS data set is currently not transmitted in near-real-time (NRT) to the NWP centers. Instead, data sets with reduced spatial and spectral information are produced and made available in NRT. In this paper, we evaluate the use of different channel selections and error specifications. We achieved significant positive impact from the Aqua AIRS/AMSU-A combination in both hemispheres during our experimental time period of January 2003. The best results were obtained using a set of 156 channels that did not include any in the 6.7micron water vapor band. The latter have a large influence on both temperature and humidity analyses. If observation and background errors are not properly specified, the partitioning of temperature and humidity information from these channels will not be correct, and this can lead to a degradation in forecast skill. We found that changing the specified channel errors had a significant effect on the amount of data that entered into the analysis as a result of quality control thresholds that are related to the errors. However, changing the channel errors within a relatively small window did not significantly impact forecast skill with the 155 channel set. We also examined the effects of different types of spatial data reduction on assimilated data sets and NWP forecast skill. Whether we picked the center or the warmest AIRS pixel in a 3x3 array affected the amount of data ingested by the analysis but had a negligible impact on the forecast skill

TeV scale mirage mediation in NMSSM

We study the next-to-minimal supersymmetric standard model. We consider soft supersymmetry breaking parameters, which are induced by the mirage mediation mechanism of supersymmetry breaking. We concentrate on the mirage mediation, where the so-called mirage scale is the TeV scale. In this scenario, we can realize the up-type Higgs soft mass of O(200) GeV, while other masses such as gaugino masses and stop masses are heavy such as 1 TeV or more. Cancellation between the effective \mu-term and the down-type Higgs soft mass ameliorates the fine-tuning in the electroweak symmetry breaking even for \mu=O(500) GeV. The mixing between the doublet and singlet Higgs bosons is suppressed by (\lambda/\kappa)/tan\beta. Then the lightest doublet Higgs mass naturally reaches 125 GeV lifted by the new quartic coupling. The higgsino and singlino are light and their linear combination is the lightest superparticle.Comment: 24 pages, 24 figures, Numerical analysis is replaced with the version calculated by NMSSMTools. Comments and references are added on the suppressed doublet-singlet mixing and cases in which the 125 GeV boson is the 2nd lightest CP-even scalar. The version accepted by JHE