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Advanced biliary tract cancer has a poor prognosis. Cisplatin and gemcitabine is the standard first-line chemotherapy regimen, but no robust evidence is available for second-line chemotherapy. The aim of this study was to determine the benefit derived from second-line FOLFOX (folinic acid, fluorouracil, and oxaliplatin) chemotherapy in advanced biliary tract cancer. The ABC-06 clinical trial was a phase 3, open-label, randomised trial done in 20 sites with expertise in managing biliary tract cancer across the UK. Adult patients (aged ≥18 years) who had histologically or cytologically verified locally advanced or metastatic biliary tract cancer (including cholangiocarcinoma and gallbladder or ampullary carcinoma) with documented radiological disease progression to first-line cisplatin and gemcitabine chemotherapy and an Eastern Cooperative Oncology Group performance status of 0–1 were randomly assigned (1:1) centrally to active symptom control (ASC) and FOLFOX or ASC alone. FOLFOX chemotherapy was administered intravenously every 2 weeks for a maximum of 12 cycles (oxaliplatin 85 mg/m2, L-folinic acid 175 mg [or folinic acid 350 mg], fluorouracil 400 mg/m2 [bolus], and fluorouracil 2400 mg/m2 as a 46-h continuous intravenous infusion). Randomisation was done following a minimisation algorithm using platinum sensitivity, serum albumin concentration, and stage as stratification factors. The primary endpoint was overall survival, assessed in the intention-to-treat population. Safety was also assessed in the intention-to-treat population. The study is complete and the final results are reported. This trial is registered with ClinicalTrials.gov, NCT01926236, and EudraCT, 2013-001812-30. Between March 27, 2014, and Jan 4, 2018, 162 patients were enrolled and randomly assigned to ASC plus FOLFOX (n=81) or ASC alone (n=81). Median follow-up was 21·7 months (IQR 17·2–30·8). Overall survival was significantly longer in the ASC plus FOLFOX group than in the ASC alone group, with a median overall survival of 6·2 months (95% CI 5·4–7·6) in the ASC plus FOLFOX group versus 5·3 months (4·1–5·8) in the ASC alone group (adjusted hazard ratio 0·69 [95% CI 0·50–0·97]; p=0·031). The overall survival rate in the ASC alone group was 35·5% (95% CI 25·2–46·0) at 6 months and 11·4% (5·6–19·5) at 12 months, compared with 50·6% (39·3–60·9) at 6 months and 25·9% (17·0–35·8) at 12 months in the ASC plus FOLFOX group. Grade 3–5 adverse events were reported in 42 (52%) of 81 patients in the ASC alone group and 56 (69%) of 81 patients in the ASC plus FOLFOX group, including three chemotherapy-related deaths (one each due to infection, acute kidney injury, and febrile neutropenia). The most frequently reported grade 3–5 FOLFOX-related adverse events were neutropenia (ten [12%] patients), fatigue or lethargy (nine [11%] patients), and infection (eight [10%] patients). The addition of FOLFOX to ASC improved median overall survival in patients with advanced biliary tract cancer after progression on cisplatin and gemcitabine, with a clinically meaningful increase in 6-month and 12-month overall survival rates. To our knowledge, this trial is the first prospective, randomised study providing reliable, high-quality evidence to allow an informed discussion with patients of the potential benefits and risks from second-line FOLFOX chemotherapy in advanced biliary tract cancer. Based on these findings, FOLFOX should become standard-of-care chemotherapy in second-line treatment for advanced biliary tract cancer and the reference regimen for further clinical trials. Cancer Research UK, StandUpToCancer, AMMF (The UK Cholangiocarcinoma Charity), and The Christie Charity, with additional funding from The Cholangiocarcinoma Foundation and the Conquer Cancer Foundation Young Investigator Award for translational research.

Edwards and colleagues’ article on safety-netting in consultations is both useful and interesting.1 Safety-netting was never a part of my learning in either medical school or in GP training, despite looking at several different consultation models—although admittedly this was many years ago. I’ve adopted safety-netting over the years but it’s good to see it described and affirmed as a legitimate clinical tool to be used in evaluating and following up patients, rather than aggressive investigation and treatment of undifferentiated illness at the outset.

The Ensembl Variant Effect Predictor is a powerful toolset for the analysis, annotation, and prioritization of genomic variants in coding and non-coding regions. It provides access to an extensive collection of genomic annotation, with a variety of interfaces to suit different requirements, and simple options for configuring and extending analysis. It is open source, free to use, and supports full reproducibility of results. The Ensembl Variant Effect Predictor can simplify and accelerate variant interpretation in a wide range of study designs.

One of the potential risks associated with subsurface storage of CO 2 is the seepage of CO 2 through existing faults and fractures. There have been a number of studies devoted to this topic. Some of these studies show that geochemistry, especially mineralization, plays an important role in rendering the faults as conduits for CO 2 movement while others show that mineralization due to CO 2 injection can result in seep migration and flow diversion. Therefore, understanding the changes in reservoir properties due to pore alterations is important to ensure safe long term CO 2 storage in the subsurface. We study the changes in the Representative Elementary Volume (REV) of a rock due to reactive kinetics over a time, using a statistical approach and pore-scale CO 2 -rock interactiondata. The goal of this study is to obtain the REV of a rock property that accounts for pore-scale changes over time due to reactive kinetics, and we call this as spatiotemporal REV. Scale-up results suggest that the REV changes with time when CO 2 -rock interaction is considered. It is hypothesized that the alteration in pore structure introduces more heterogeneity in the rock, and because of this the magnitude of REV increases. It is possible that these noticeable changes in REV at pore-scale may have an impact when analyzed at the reservoir scale.

Purpose – The purpose of this paper is to operationalize the subjective measures of business performance and assessing their justification for use in place of objective measures of business performance. Design/methodology/approach – The study is based on a sample survey of 171 companies listed on Bombay Stock Exchange, India. A cross-sectional descriptive research design has been used. Exploratory factor analysis was used to assess the factor structure and dimensionality of objective and subjective measures of business performance. The psychometric properties of these measures and their interrelationship have been assessed through confirmatory factor analysis. Findings – The study finds a strong positive correlation between subjective business performance and objective business performance. The study finds it justified to use the subjective measures of business performance. Research limitations/implications – Response bias may have crept in because of self-reported measure used for the study. Future researchers may cross-verify the subjective perception of respondents with data available from the records of the firms. Second, the study focuses only on financial and operational indicators of performance. The future studies may widen the scope of business performance by incorporating the interests of other stakeholders like suppliers, government, environment and society in general. Practical implications – The strategy researchers confronting the challenge of adopting appropriate measures of business performance can use either or both of subjective and objective performance measures, as suggested in this study. The study has suggestions for strategic decision makers regarding measurement of business performance in terms of financial as well as operational indicators. Originality/value – The study operationalizes and validates two measures of performance, namely, subjective business performance and objective business performance. The study contributes to the strategic management literature by providing evidence for association between objective and subjective measures of performance.

PurposeThe objective of this research is to identify and prioritize the critical factors that influence the adoption of blockchain technology within the banking sector.Design/methodology/approachA well-known theoretical framework, the “Technology Organization Environment (TOE),” was chosen to analyze what criteria and sub-criteria affect blockchain adoption in the banking sector after a thorough assessment of the prior literature. Following that, 3 evaluation criteria and 14 sub-criteria were selected and verified using expert opinion. A survey design was created, and data for the study has been collected from various information technology (IT) managers/officers in the banking sector. A fuzzy analytic hierarchy process (Fuzzy-AHP) was then used to meet the purpose of the research.FindingsThe study identified that the organizational dimension is the most significant criteria for blockchain adoption in the banking sector, followed by the environmental dimension. In contrast, the technological dimension is the least influential criterion. Clientele pressure, IT resources, financial resources, pressure from competitors and relative advantage are the most influential sub-criteria for blockchain adoption.Research limitations/implicationsThis study provides valuable insights to bank managers, blockchain and IT developers, third-party service providers and policymakers. For instance, adopting the same blockchain platform is easier for both large and small banks for banking operations by using third-party service provider. At the same time, banks should have the banks' own core team to implement the blockchain-based systems or to have control over the third-party service providers during the adoption stage.Originality/valueTo the best of the authors' knowledge, no empirical studies have used a holistic organizational context to understand the factors influencing the adoption of blockchain technology from traditional to blockchain-based banking systems.

Hot corrosion is a critical problem in a wide range of high-temperature applications. Ni–20Cr alloy is frequently used in such applications owing to its good hot-corrosion resistance. In the current work, thick Ni–20Cr plates in a thickness range of 6–10 mm were fabricated using cold spray-based additive manufacturing (CSAM). High-pressure cold spraying was used with nitrogen as the propellant gas. Pre- (substrate heating, SH) and post-heat treatments (hot isostatic pressing, HIP) were also performed to comprehend the changes in the deposit properties. The deposits were subjected to microstructural and mechanical characterization to explore the potential of cold spraying for CSAM of Ni–20Cr standalone products. The cold-sprayed plates were successfully developed without any oxide formation. HIP treatment was found to be useful to reduce porosity. The cold-sprayed substrate-heated Ni–20Cr deposits exhibited excellent oxidation resistance at a high temperature of 900 °C.

Magic-angle twisted bilayer graphene (MATBG) exhibits a range of correlated phenomena that originate from strong electron–electron interactions. These interactions make the Fermi surface highly susceptible to reconstruction when ±1, ±2 and ±3 electrons occupy each moiré unit cell, and lead to the formation of various correlated phases 1 – 4 . Although some phases have been shown to have a non-zero Chern number 5 , 6 , the local microscopic properties and topological character of many other phases have not yet been determined. Here we introduce a set of techniques that use scanning tunnelling microscopy to map the topological phases that emerge in MATBG in a finite magnetic field. By following the evolution of the local density of states at the Fermi level with electrostatic doping and magnetic field, we create a local Landau fan diagram that enables us to assign Chern numbers directly to all observed phases. We uncover the existence of six topological phases that arise from integer fillings in finite fields and that originate from a cascade of symmetry-breaking transitions driven by correlations 7 , 8 . These topological phases can form only for a small range of twist angles around the magic angle, which further differentiates them from the Landau levels observed near charge neutrality. Moreover, we observe that even the charge-neutrality Landau spectrum taken at low fields is considerably modified by interactions, exhibits prominent electron–hole asymmetry, and features an unexpectedly large splitting between zero Landau levels (about 3 to 5 millielectronvolts). Our results show how strong electronic interactions affect the MATBG band structure and lead to correlation-enabled topological phases. Correlation-driven topological phases with different Chern numbers are observed in magic-angle twisted bilayer graphene in modest magnetic fields, indicating that strong electronic interactions can lead to topologically non-trivial phases.

Research summary: Innovation requires inventors to have both new knowledge and the ability to combine and configure knowledge (i.e., combinatory knowledge), and such knowledge may flow through networks. We argue that both combinatory knowledge and new knowledge are accessed through collaboration networks, but that inventors' abilities to access such knowledge depends on its location in the network. Combinatory knowledge transfers from direct contacts, but not easily from indirect contacts. In contrast, new knowledge transfers from both direct and indirect contacts, but is far more likely to be new and useful when it comes from indirect contacts. Exploring knowledge flows in 69,476 patents and 89,930 unique inventors reveals evidence that combinatory knowledge from direct contacts and new knowledge from indirect contacts significantly affects innovative performance. Managerial summary: Inventors often combine ideas to create innovations. To do this, they need ideas to combine and they need the ability to combine those ideas. Inventors can get ideas to combine as well as the ability to combine ideas through prior co-workers. Prior co-workers can share ideas that may be relevant for the inventor's project and can tell the inventor about other things that other people are working on, especially people the inventor may not know. This can help inventors easily learn about ideas from friends-of-friends. The ability to combine ideas, however, is much harder to pass on. Prior co-workers must carefully work with the inventor to teach him or her the complex processes of combining ideas. This means that it is very hard to learn how to combine knowledge from a friend-of-a-friend, but it may be possible to learn from prior co-workers. We explore this phenomenon in the social relationships of software inventors.