ROSARL: Reward-Only Safe Reinforcement Learning

An important problem in reinforcement learning is designing agents that learn to solve tasks safely in an environment. A common solution is for a human expert to define either a penalty in the reward function or a cost to be minimised when reaching unsafe states. However, this is non-trivial, since too small a penalty may lead to agents that reach unsafe states, while too large a penalty increases the time to convergence. Additionally, the difficulty in designing reward or cost functions can increase with the complexity of the problem. Hence, for a given environment with a given set of unsafe states, we are interested in finding the upper bound of rewards at unsafe states whose optimal policies minimise the probability of reaching those unsafe states, irrespective of task rewards. We refer to this exact upper bound as the "Minmax penalty", and show that it can be obtained by taking into account both the controllability and diameter of an environment. We provide a simple practical model-free algorithm for an agent to learn this Minmax penalty while learning the task policy, and demonstrate that using it leads to agents that learn safe policies in high-dimensional continuous control environments

MABp1 as a novel antibody treatment for advanced colorectal cancer: a randomised, double-blind, placebo-controlled, phase 3 study.

BACKGROUND: MABp1, an antibody that targets interleukin 1α, has been associated with antitumour activity and relief of debilitating symptoms in patients with advanced colorectal cancer. We sought to establish the effect of MABp1 with a new primary endpoint in patients with advanced colorectal cancer. METHODS: Eligible patients for the double-blind phase of this ongoing, placebo-controlled, randomised, phase 3 trial, had metastatic or unresectable disease, Eastern Cooperative Oncology Group performance status score 1 or 2, systemic inflammation, weight loss, and other disease-related morbidities associated with poor prognosis, and were refractory to oxaliplatin and irinotecan. Patients were randomly assigned 2:1 to receive either MABp1 or placebo. Randomisation codes were obtained from a centrally held list via an interactive web response system. Patients received an intravenous infusion of 7·5 mg/kg MABp1 or placebo given every 2 weeks for 8 weeks. The primary endpoint was assessed in patients who received at least one dose of MABp1 or placebo (modified intention-to-treat population), and was a composite of stable or increased lean body mass and stability or improvement in two of three symptoms (pain, fatigue, or anorexia) at week 8 compared with baseline measurements. This study is registered with ClinicalTrials.gov, number NCT02138422. FINDINGS: Patients were enrolled between May 20, 2014, and Sept 2, 2015. The double-blind phase of the study was completed on Nov 3, 2015. Of 333 patients randomly assigned treatment, 207 received at least one dose of MABp1 and 102 at least one dose of placebo. 68 (33%) and 19 (19%) patients, respectively, achieved the primary endpoint (relative risk 1·76, 95% CI 1·12-2·77, p=0·0045). The most common grade 3-4 adverse events in the MABp1 group compared with in the placebo group were anaemia (eight [4%] of 207 vs five [5%] of 102 patients), increased concentration of alkaline phosphatase (nine [4%] vs two [2%]), fatigue (six [3%] vs seven [7%]), and increased concentration of aspartate aminotransferase (six [3%] vs two [2%]). After 8 weeks, 17 (8%) patients in the MABp1 group and 11 (11%) in the placebo group had died, but no death was judged to be related to treatment. The incidence of serious adverse events was not significantly different in the MABp1 group and placebo groups (47 [23%] vs 33 [32%], p=0·07). INTERPRETATION: The primary endpoint was a useful means of measuring clinical performance in patients. MABp1 might represent a new standard in the management of advanced colorectal cancer. FUNDING: XBiotech

Energy Consumption, Carbon Emissions and Global Warming Potential of Wolfberry Production in Jingtai Oasis, Gansu Province, China

During the last decade, China's agro-food production has increased rapidly and been accompanied by the challenge of increasing greenhouse gas (GHG) emissions and other environmental pollutants from fertilizers, pesticides, and intensive energy use. Understanding the energy use and environmental impacts of crop production will help identify environmentally damaging hotspots of agro-production, allowing environmental impacts to be assessed and crop management strategies optimized. Conventional farming has been widely employed in wolfberry (Lycium barbarum) cultivation in China, which is an important cash tree crop not only for the rural economy but also from an ecological standpoint. Energy use and global warming potential (GWP) were investigated in a wolfberry production system in the Yellow River irrigated Jingtai region of Gansu. In total, 52 household farms were randomly selected to conduct the investigation using questionnaires. Total energy input and output were 321,800.73 and 166,888.80 MJ ha−1, respectively, in the production system. The highest share of energy inputs was found to be electricity consumption for lifting irrigation water, accounting for 68.52%, followed by chemical fertilizer application (11.37%). Energy use efficiency was 0.52 when considering both fruit and pruned wood. Nonrenewable energy use (88.52%) was far larger than the renewable energy input. The share of GWP of different inputs were 64.52% electricity, 27.72% nitrogen (N) fertilizer, 5.07% phosphate, 2.32% diesel, and 0.37% potassium, respectively. The highest share was related to electricity consumption for irrigation, followed by N fertilizer use. Total GWP in the wolfberry planting system was 26,018.64 kg CO2 eq ha−1 and the share of CO2, N2O, and CH4 were 99.47%, 0.48%, and negligible respectively with CO2 being dominant. Pathways for reducing energy use and GHG emission mitigation include: conversion to low carbon farming to establish a sustainable and cleaner production system with options of raising water use efficiency by adopting a seasonal gradient water pricing system and advanced irrigation techniques; reducing synthetic fertilizer use; and policy support: smallholder farmland transfer (concentration) for scale production, credit (small- and low-interest credit) and tax breaks

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

The genomic landscape of juvenile myelomonocytic leukemia

Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm (MPN) of childhood with a poor prognosis. Mutations in NF1, NRAS, KRAS, PTPN11 and CBL occur in 85% of patients, yet there are currently no risk stratification algorithms capable of predicting which patients will be refractory to conventional treatment and therefore be candidates for experimental therapies. In addition, there have been few other molecular pathways identified aside from the Ras/MAPK pathway to serve as the basis for such novel therapeutic strategies. We therefore sought to genomically characterize serial samples from patients at diagnosis through relapse and transformation to acute myeloid leukemia in order to expand our knowledge of the mutational spectrum in JMML. We identified recurrent mutations in genes involved in signal transduction, gene splicing, the polycomb repressive complex 2 (PRC2) and transcription. Importantly, the number of somatic alterations present at diagnosis appears to be the major determinant of outcome

Measurement of the inclusive isolated-photon cross section in pp collisions at √s = 13 TeV using 36 fb−1 of ATLAS data

The differential cross section for isolated-photon production in pp collisions is measured at a centre-of-mass energy of 13 TeV with the ATLAS detector at the LHC using an integrated luminosity of 36.1 fb. The differential cross section is presented as a function of the photon transverse energy in different regions of photon pseudorapidity. The differential cross section as a function of the absolute value of the photon pseudorapidity is also presented in different regions of photon transverse energy. Next-to-leading-order QCD calculations from Jetphox and Sherpa as well as next-to-next-to-leading-order QCD calculations from Nnlojet are compared with the measurement, using several parameterisations of the proton parton distribution functions. The predictions provide a good description of the data within the experimental and theoretical uncertainties. [Figure not available: see fulltext.