Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial

BACKGROUND: The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer. METHODS: We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1:1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m(2) gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m(2) oral capecitabine administered for 21 days followed by 7 days' rest (one cycle). Randomisation was based on a minimisation routine, and country was used as a stratification factor. The primary endpoint was overall survival, measured as the time from randomisation until death from any cause, and assessed in the intention-to-treat population. Toxicity was analysed in all patients who received trial treatment. This trial was registered with the EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434. FINDINGS: Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28·0 months (95% CI 23·5-31·5) compared with 25·5 months (22·7-27·9) in the gemcitabine group (hazard ratio 0·82 [95% CI 0·68-0·98], p=0·032). 608 grade 3-4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3-4 adverse events in 196 of 366 patients in the gemcitabine group. INTERPRETATION: The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma

Measuring spirometry in a lung cancer screening cohort highlights possible underdiagnosis and misdiagnosis of Chronic Obstructive Pulmonary Disease

Introduction: Chronic Obstructive Pulmonary Disease (COPD) is underdiagnosed, and measurement of spirometry alongside low-dose computed tomography (LDCT) screening for lung cancer is one strategy to increase earlier diagnosis of this disease. // Methods: Ever-smokers at high risk of lung cancer were invited to the Yorkshire Lung Screening Trial for a Lung Health Check (LHC) comprising LDCT screening, pre-bronchodilator spirometry and smoking cessation service. In this cross-sectional study we present data on participant demographics, respiratory symptoms, lung function, emphysema on imaging and both self-reported and primary care diagnoses of COPD. Multivariable logistic regression analysis identified factors associated with possible underdiagnosis and misdiagnosis of COPD in this population, with airflow obstruction (AO) defined as FEV1/FVC ratio <0.70. // Results: Of 3,920 LHC attendees undergoing spirometry, 17% had undiagnosed AO with respiratory symptoms, representing potentially undiagnosed COPD. Compared to those with a primary care COPD code, this population had milder symptoms, better lung function, and were more likely to be current smokers (p≤0.001 for all comparisons). Of 836 attendees with a primary care COPD code who underwent spirometry, 19% did not have AO, potentially representing misdiagnosed COPD, although symptom burden was high. // Discussion: Spirometry offered alongside LDCT screening can potentially identify cases of undiagnosed and misdiagnosed COPD. Future research should assess the downstream impact of these findings to determine if any meaningful changes to treatment and outcomes occurs, and also to assess the impact on co-delivering spirometry on other parameters of LDCT screening performance such as participation and adherence. Additionally, work is needed to better understand the aetiology of respiratory symptoms in those with misdiagnosed COPD, to ensure this highly symptomatic group receive evidence-based interventions

VERITAS (Venus Emissivity, Radio science, InSAR, Topography, And Spectroscopy): Discovering the Secrets of a Lost Habitable World

VERITAS is a selected Discovery mission launching in 2028. It will investigate Venus’ geologic evolution and processes that affect rock planetary habitability. Venus’ present condition is a geodynamic analog for early Earth, when the lithosphere was hotter and thinner, plate tectonics and continents began to form, and life emerged. Earth no longer retains a clear record of how these processes began, but Venus may have active subduction—the necessary first step to initiate plate tectonics, as well as analogs of continents. VERITAS will test whether Venus’ tessera plateaus represent the only analogs of continents in the solar system, which formed on Earth when massive quantities of basalt melted in the presence of water. VERITAS will use numerous methods to search for current volcanism and tectonism, including subduction. VERITAS produces global, foundational datasets using two instruments, the Venus Interferometric Synthetic Aperture Radar (VISAR) and the Venus Emissivity Mapper (VEM), plus a gravity science investigation. The VISAR X-band measurements include: 1) a global digital elevation model (DEM) with 250 m postings, 6 m height accuracy, 2) Synthetic aperture radar (SAR) imaging at 30 m horizontal resolution globally, 3) SAR imaging at 15 m for >25% of the surface, and 4) surface deformation from repeat pass interferometry (RPI) at 2 cm precision for >12 targeted areas. VEM covers >70% of the surface in six NIR bands located within five atmospheric windows sensitive to Fe mineralogy, plus eight atmospheric bands for calibration and water vapor measurements, with SNR ≫ VIRTIS. It is a near IR spectral imager with optimized spectral bands for observing the surface of Venus that supports the determination of rock type and the search for active and recent volcanism. VERITAS will use a low circular orbit (< 250 km) and Ka-band uplink and downlink to create a global gravity field with 3 mGal accuracy at 155 km (d&o 123) resolution. VERTIAS also constrains core size and state, using radar tie points to help find k2, the phase lag, and MOIF

Yorkshire Lung Screening Trial (YLST): protocol for a randomised controlled trial to evaluate invitation to community-based low-dose CT screening for lung cancer versus usual care in a targeted population at risk

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ. INTRODUCTION: Lung cancer is the world's leading cause of cancer death. Low-dose computed tomography (LDCT) screening reduced lung cancer mortality by 20% in the US National Lung Screening Trial. Here, we present the Yorkshire Lung Screening Trial (YLST), which will address key questions of relevance for screening implementation. METHODS AND ANALYSIS: Using a single-consent Zelen's design, ever-smokers aged 55-80 years registered with a general practice in Leeds will be randomised (1:1) to invitation to a telephone-based risk-assessment for a Lung Health Check or to usual care. The anticipated number randomised by household is 62 980 individuals. Responders at high risk will be invited for LDCT scanning for lung cancer on a mobile van in the community. There will be two rounds of screening at an interval of 2 years. Primary objectives are (1) measure participation rates, (2) compare the performance of PLCOM2012 (threshold ≥1.51%), Liverpool Lung Project (V.2) (threshold ≥5%) and US Preventive Services Task Force eligibility criteria for screening population selection and (3) assess lung cancer outcomes in the intervention and usual care arms. Secondary evaluations include health economics, quality of life, smoking rates according to intervention arm, screening programme performance with ancillary biomarker and smoking cessation studies. ETHICS AND DISSEMINATION: The study has been approved by the Greater Manchester West research ethics committee (18-NW-0012) and the Health Research Authority following review by the Confidentiality Advisory Group. The results will be disseminated through publication in peer-reviewed scientific journals, presentation at conferences and on the YLST website. TRIAL REGISTRATION NUMBERS: ISRCTN42704678 and NCT03750110

The Atacama Cosmology Telescope: Reionization kSZ trispectrum methodology and limits

Patchy reionization generates kinematic Sunyaev-Zeldovich (kSZ) anisotropies in the cosmic microwave background (CMB). Large-scale velocity perturbations along the line of sight modulate the small-scale kSZ power spectrum, leading to a trispectrum (or four-point function) in the CMB that depends on the physics of reionization. We investigate the challenges in detecting this trispectrum and use tools developed for CMB lensing, such as realization-dependent bias subtraction and cross-correlation based estimators, to counter uncertainties in the instrumental noise and assumed CMB power spectrum. We also find that both lensing and extragalactic foregrounds can impart larger trispectrum contributions than the reionization kSZ signal. We present a range of mitigation methods for both of these sources of contamination, validated on microwave-sky simulations. We use ACT DR6 and Planck data to calculate an upper limit on the reionization kSZ trispectrum from a measurement dominated by foregrounds. The upper limit is about 50 times the signal predicted from recent simulations.Comment: Measurements and covariances will be made public upon publicatio

The Venus Emissivity Mapper Concept

Based on experience gained from using the VIRTIS instrument on Venus Express to observe the surface of Venus and the new high temperature laboratory experiments, we have developed the multispectral Venus Emissivity Mapper (VEM) to study the surface of Venus. VEM imposes minimal requirements on the spacecraft and mission design and can therefore be added to any future Venus mission. Ideally, the VEM instrument will be combined with a high-resolution radar mapper to provide accurate topographic information, as it will be the case for the NASA Discovery VERITAS mission or the ESA EnVision M5 proposal

The Venus Emissivity Mapper ─ Obtaining Global Mineralogy of Venus from Orbit on the ESA EnVision and NASA VERITAS missions to Venus.

International audienc

The Atacama Cosmology Telescope: Detection of Patchy Screening of the Cosmic Microwave Background

Spatial variations in the cosmic electron density after reionization generate cosmic microwave background anisotropies via Thomson scattering, a process known as the ``patchy screening" effect. In this paper, we propose a new estimator for the patchy screening effect that is designed to mitigate biases from the dominant foreground signals. We use it to measure the cross-correlation between \textit{unWISE} galaxies and patchy screening, the latter measured by the Atacama Cosmology Telescope and \textit{Planck} satellite. We report the first detection of the patchy screening effect, with the statistical significance of the cross-correlation exceeding $7\sigma$. This measurement directly probes the distribution of electrons around these galaxies and provides strong evidence that gas is more extended than the underlying dark matter. By comparing our measurements to electron profiles extracted from simulations, we demonstrate the power of these observations to constrain galaxy evolution models. Requiring only the 2D positions of objects and no individual redshifts or velocity estimates, this approach is complementary to existing gas probes, such as those based on the kinetic Sunyaev-Zeldovich effect.Comment: See Schutt et al for a detailed comparison of patchy screening estimators. 17 pages with 8 figure

A Gammaherpesvirus Cooperates with Interferon-alpha/beta-Induced IRF2 to Halt Viral Replication, Control Reactivation, and Minimize Host Lethality

The gammaherpesviruses, including Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), establish latency in memory B lymphocytes and promote lymphoproliferative disease in immunocompromised individuals. The precise immune mechanisms that prevent gammaherpesvirus reactivation and tumorigenesis are poorly defined. Murine gammaherpesvirus 68 (MHV68) is closely related to EBV and KSHV, and type I (alpha/beta) interferons (IFNαβ) regulate MHV68 reactivation from both B cells and macrophages by unknown mechanisms. Here we demonstrate that IFNβ is highly upregulated during latent infection, in the absence of detectable MHV68 replication. We identify an interferon-stimulated response element (ISRE) in the MHV68 M2 gene promoter that is bound by the IFNαβ-induced transcriptional repressor IRF2 during latency in vivo. The M2 protein regulates B cell signaling to promote establishment of latency and reactivation. Virus lacking the M2 ISRE (ISREΔ) overexpresses M2 mRNA and displays uncontrolled acute replication in vivo, higher latent viral load, and aberrantly high reactivation from latency. These phenotypes of the ISREΔ mutant are B-cell-specific, require IRF2, and correlate with a significant increase in virulence in a model of acute viral pneumonia. We therefore identify a mechanism by which a gammaherpesvirus subverts host IFNαβ signaling in a surprisingly cooperative manner, to directly repress viral replication and reactivation and enforce latency, thereby minimizing acute host disease. Since we find ISREs 5′ to the major lymphocyte latency genes of multiple rodent, primate, and human gammaherpesviruses, we propose that cooperative subversion of IFNαβ-induced IRFs to promote latent infection is an ancient strategy that ensures a stable, minimally-pathogenic virus-host relationship