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Los pacientes con CPNM metastásico portadores de una fusión del gen ROS1 suelen experimentar un control prolongado de la enfermedad con inhibidores de la tirosina quinasa (TKI) dirigidos a ROS1, aunque hay una heterogeneidad clínica significativa, debida en parte a la presencia de alteraciones genómicas concurrentes. Presentamos el caso de un paciente con CPNM metastásico, con fusión de ROS1 acompañada de una mutación en KRAS p.G12C detectada durante el diagnóstico, quien mantuvo la enfermedad bajo control durante un breve periodo con entrectinib, un TKI de ROS1. Cuando se observó progresión, el paciente continuó con entrectinib y comenzó a recibir sotorasib, un inhibidor de KRAS p.G12C de bajo peso molecular. Una línea celular derivada del paciente generada durante la progresión mientras recibía entrectinib demostró una mejor capacidad de respuesta a los TKI cuando se trató con entrectinib y sotorasib. La dependencia del crecimiento de la línea celular tanto con respecto a ROS1 como a KRAS p.G12C se reflejó además en las distintas vías de señalización corriente abajo activadas por cada impulsor. No se observó beneficio clínico con la terapia combinada de entrectinib y sotorasib, posiblemente debido a una amplificación evolutiva de KRAS p.G12C identificada en pruebas moleculares repetidas. Este caso respalda la necesidad de establecer perfiles moleculares amplios en pacientes con CPNM metastásico para disponer de información con posible valor terapéutico y pronóstico.

Blue-Green Infrastructure (BGI, including swales, green roofs, and wetlands) plays an important role in reducing vulnerability to climate change risks such as flooding, heat stress, and water shortages, while enhancing urban environments and quality of life for citizens. Understanding the perceptions that professional stakeholders have of BGI is fundamental in addressing barriers to implementation. A novel application of the Implicit Association Test (IAT) is developed to investigate and compare implicit (unconscious) perceptions of blue-green and grey infrastructure with explicit (conscious) attitudes. This is the first time an IAT about BGI has focused on professional stakeholders. Blue-green and grey infrastructure are perceived positively by the sample population. Overall, respondents implicitly and explicitly prefer BGI to grey infrastructure, and regard it as safer, tidier, more attractive, useful, valuable, and necessary. The individual positive explicit perceptions of grey infrastructure, nonetheless, suggest that integrated blue-green and grey systems may be preferable for professional stakeholders to incorporate into water management and climate change adaptation strategies.

Learning and Action Alliances (LAAs) are becoming an increasingly popular method for overcoming the challenges associated with participatory forms of governance, where decision making requires collaboration between stakeholders. In flood risk management, LAAs provide a mechanism through which institutional participants can come together, share knowledge, innovate, and devise solutions to ‘wicked’ problems. While the social learning generated at LAAs is now well understood, the mechanism by which this learning is translated into action is less so. In this paper, we argue that in order to maximise the potential for action, LAAs must attend to different elements of capacity building, in order that action can diffuse outwards, from the individual members of the LAA, to their organisations and society beyond. By investigating two UK case study examples, we illustrate how different elements might be utilised in combination, to maximise the potential for longer-term, longer-lasting change. We conclude that the architects of participatory processes, including LAAs, should attend to different elements of capacity building, and consider those best suited to their individual contexts and objectives.

Flood management is a complex issue in Chinese cities that exhibit high populations and have undergone rapid urbanization. Urban flood management (UFM) approaches can be used to mitigate urban flood risk. To address urban issues of poor water quality and urban surface flooding, the Sponge City Program (SCP) was initiated in 2013 in China. The SCP aims to provide an opportunity for Chinese cities to improve their current UFM practices. This study looks at Guiyang (a pilot sponge city located in SW China) as a case study to identify the challenges and opportunities of UFM in China. Guiyang is a valley city surrounded by a hilly landscape. Using interview records and flood data, we illustrate that the primary type of flood in Guiyang is fluvial rather than surface water flooding. In Guiyang, the current function and targets of the SCP have yet to engage with the catchment level flood management, instead mainly focusing on the site-specific context (i.e., community level). Catchment flood management planning (CFMP) and natural flood management (NFM) both address this problem and may be a more suitable approach to manage flood discharge from the upper and middle catchments in Guiyang. In addition, it is suggested that a mixed option combining “hard” infrastructure (e.g., reservoirs and floodwalls) with “soft” flood management measures (e.g., improving people awareness and participation) may improve urban flood resilience in Chinese cities.

Global cities face a range of water challenges, driven by increasingly frequent and extreme storm events, drier summers, accelerating urbanisation and reductions in public green space. Blue-Green Infrastructure (BGI) and Nature-Based Solutions (NBS) are increasingly being used to address challenges across the full water spectrum while tackling social, economic and environmental issues. In April 2021, the Royal Geographical Society (with IBG) hosted an online knowledge exchange event to explore the multiple co-benefits of Blue-Green Cities, and how these can overcome the biophysical, socio-political and societal barriers to innovation in urban flood and water management. This briefing paper draws together discussion from that event, framed by geographical research in the Blue-Green Cities (www.bluegreencities.ac.uk) and Urban Flood Resilience (www.urbanfloodresilience.ac.uk) projects, to give recommendations to enable greater implementation of BGI in policy and practice.

As global cities rethink their approaches to urban flood risk and water management in response to climate change, accelerating urbanisation and reductions in public green space, Blue-Green Infrastructure (BGI) is gaining increasing recognition due to the advantages of multifunctional BGI solutions over traditional piped drainage and grey infrastructure. BGI, including green and blue roofs, swales, rain gardens, street trees, ponds, urban wetlands, restored watercourses, reconnected floodplains, and re-naturalised rivers, is designed to turn ‘blue’ (or ‘bluer’) during rainfall events in order to reduce urban flood risk. In addition to managing flood risk and increasing water security, BGI generates a range of socio-cultural, economic and environmental co-benefits that help city authorities tackle other urban challenges and ultimately improve the quality of life of city dwellers.Extensive research over the last decade has focused on improving knowledge of BGI systems in several broad areas, including: hydrological and hydraulic modelling of water flow through BGI assets; biochemical assessments of sediment and water quality; public preferences; identification and evaluation of BGI co-benefits, and; BGI planning and governance. Emerging research into adaptation pathways, natural capital accounting and social practice approaches for understanding community preferences demonstrate how BGI research is moving beyond hydrodynamic modelling to explore decision making under future uncertainty and placing greater emphasis on the role of community preferences in designing BGI that is accepted and supported by those who directly benefit.This presentation will explore these emerging research areas, particularly focusing on the need for interdisciplinary research into BGI to enable the challenges and opportunities to be fully appreciated. Current knowledge gaps that present research opportunities in BGI will also be discussed, including the need for rigorous assessment criteria to determine the success of multifunctional BGI systems; greater investigation of the social benefits of BGI and the value people place on different types of BGI; the role of implicit perceptions in designing BGI assets, and; the role of urban watercourses as multifunctional BGI corridors able to safely convey stormwater while boosting water quality, providing multiple urban pathways (active transport, wildlife movements, etc.) and increasing green space in cities.

Patients with metastatic non-small cell lung cancer (NSCLC) positive for a ROS proto-oncogene 1 (ROS1) fusion usually experience significant disease response and long-term control while on treatment with a ROS1 targeting tyrosine kinase inhibitor (TKI) but significant clinical heterogeneity exists. The presence of co-occurring genomic alterations likely contribute to this diversity in clinical outcomes. Here, we report on a patient with metastatic NSCLC with a ROS1 fusion and Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C mutation detected at diagnosis who experienced a short duration of disease control on targeted therapy. The patient was initially treated with entrectinib, a ROS1 TKI, and, at progression, also received sotorasib, a small molecule inhibitor of KRAS G12C, in combination. Using specimens from therapeutically relevant time points including at diagnosis, at time of resistance to entrectinib, and at time of resistance to entrectinib and concurrent sotorasib, we performed broad next generation sequencing and FISH studies to detail the development of therapy resistance. Variant allele frequency of KRAS G12C was increased at each time point (3.2%, 74.2%, and 97%, respectively). A cell line was derived from the patient at time of progression on entrectinib therapy. In vitro testing of the cell line demonstrated increased TKI responsiveness when treated with entrectinib and sotorasib. Signaling pathway analysis of the cell line showed entrectinib inhibited phosphorylation of ROS1 and AKT, but not ERK. Sotorasib alone or in combination with entrectinib resulted in decreased phosphorylation of ERK. In vitro testing suggested efficacy with the combination of entrectinib and sotorasib. However, in clinical follow up the patient’s disease demonstrated progression on the combination, likely related to KRAS G12C amplification. This case supports the need for broad molecular profiling for potential therapeutic and prognostic information to personalize therapy in patients with metastatic NSCLC. Citation Format: Katherine Priest, Anh Le, Dara Aisner, Amanuail Gebregzabheir, Hala Nijmeh, Melanie Mandell, Kurtis Davies, Emily O'Donnell, Robert C. Doebele, Liming Bao, Erin L. Schenk. Evolution of therapy resistance through acquired KRAS amplification in ROS1 fusion KRAS G12C double positive NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5233.

Blue-Green infrastructure (BGI) is recognised internationally as an approach for managing urban water challenges while enhancing society and the environment through the provision of multiple co-benefits. This research employed an online survey to investigate the perceptions of BGI held by professional stakeholders in four cities with established BGI programs: Newcastle (UK), Ningbo (China), Portland (Oregon USA), and Rotterdam (Netherlands) (64 respondents). The results show that challenges associated with having too much water (e.g., pluvial and fluvial flood risk, water quality deterioration) are driving urban water management agendas. Perceptions of governance drivers for BGI implementation, BGI leaders, and strategies for improving BGI uptake, are markedly different in the four cities reflecting the varied local, regional and national responsibilities for BGI implementation. In addition to managing urban water, BGI is universally valued for its positive impact on residents’ quality of life, however, a transformative change in policy and practice towards truly multifunctional infrastructure is needed to optimise the delivery of multiple BGI benefits to address each city’s priorities and strategic objectives. Changes needed to improve BGI uptake, e.g., increasing the awareness of policy-makers to multifunctional BGI, has international relevance for other cities on their journeys to sustainable blue-green futures.

Blue-Green Infrastructure (BGI) is recognized as a viable strategy to manage stormwater and flood risk, and its multifunctionality may further enrich society through the provision of multiple cobenefits that extend far beyond the hydrosphere. Portland, Oregon, is an internationally renowned leader in the implementation of BGI and showcases many best practice examples. Nonetheless, a range of interdisciplinary barriers and uncertainties continue to cloud decision making and impede wider implementation of BGI. In this paper, we synthesize research conducted by the “Clean Water for All” (CWfA) research project and demonstrate that interdisciplinary evaluation of the benefits of Portland’s BGI, focusing on green street bioswales and the East Lents Floodplain Restoration Project, is essential to address biophysical and sociopolitical barriers. Effective interdisciplinary approaches require sustained interaction and collaboration to integrate disciplinary expertise toward a common problem-solving purpose, and strong leadership from researchers adapt at spanning disciplinary boundaries. While the disciplinary differences in methodologies were embraced in the CWfA project, and pivotal to providing evidence of the disparate benefits of multifunctional BGI, cross-disciplinary engagement, knowledge coproduction, and data exchanges during the research process were of paramount importance to reduce the potential for fragmentation and ensure research remained integrated. © 2020 The Authors. Journal of the American Water Resources Association published by Wiley Periodicals LLC on behalf of American Water Resources Association

Introduction The infant mortality rate (IMR) in the United States remains higher than most developed countries. To understand this public health issue and support state public health departments in displaying and analyzing data in ways that support learning, states participating in the Collaborative Improvement and Innovation Network to Reduce Infant Mortality (IM CoIIN) created statistical process control (SPC) charts for rare events. Methods State vital records data on live births and infant deaths was used to create U, T and G charts for Kansas and Alaska, two states participating in the IM CoIIN who sought methods to more effectively analyze IMR for subsets of their populations with infrequent number of deaths. The IMR and the number of days and number of births between infant deaths was charted for Kansas Non-Hispanic black population and six Alaska regions for the time periods 2013-2016 and 2011-2016, respectively. Established empirical patterns indicated points of special cause variation. Results The T and G charts for Kansas and G charts for Alaska depict points outside the upper control limit. These points indicate special cause variation and an increased number of days and/or births between deaths at these time periods. Discussion T and G charts offer value in examining rare events, and indicate special causes not detectable by U charts or other more traditional analytic methods. When small numbers make traditional analysis challenging, SPC has potential in the MCH field to better understand potential drivers of improvements in rare outcomes, inform decision making and take interventions to scale.

Sustainable Drainage Systems (SuDS) and Blue-Green infrastructure (BGI) provide a range of environmental, economic and social benefits in addition to managing water quantity and quality. Recognition of the multifunctionality of SuDS and BGI, and the specific benefits that may accrue to different beneficiaries, may facilitate partnership working towards multifunctional infrastructure that meets the strategic objectives of public and private organisations. We evaluate the multiple benefits of the Killingworth and Longbenton surface water management scheme, a Partnership Project in NE England jointly funded by Northumbrian Water, the Environment Agency and North Tyneside Council. Using CIRIA’s Benefits of SuDS Tool (BeST) and the Blue-Green Cities Multiple Benefits GIS Toolbox, we a) quantify and monetise six key benefits, b) assess two qualitative benefits, c) illustrate the spatial distribution of five non-flood benefits, and d) highlight locations with the greatest opportunity for multi-beneficial intervention. The Killingworth and Longbenton scheme generates; significant flood damage reduction benefits; improves water quality, habitat size, carbon sequestration, attractiveness of the area and property prices (amenity), and; reduces noise pollution. Utilisation of these complementary tools for multiple benefit evaluation shows promise as an aid to facilitate partnership working towards implementation of multifunctional SuDS and BGI.

Managing urban flood risk is a key global challenge of the twenty-first century. Drivers of future UK flood risk were identified and assessed by the Flood Foresight project in 2002–2004 and 2008; envisaging flood risk during the 2050s and 2080s under a range of scenarios for climate change and socio-economic development. This paper qualitatively reassesses and updates these drivers, using empirical evidence and advances in flood risk science, technology and practice gained since 2008. Of the original drivers, five have strengthened, three have weakened and 14 remain within their 2008 uncertainty bands. Rainfall, as impacted by climate change, is the leading source driver of future urban flood risk. Intra-urban asset deterioration, leading to increases in a range of consequential flood risks, is the primary pathway driver. Social impacts (risk to life and health, and the intangible impacts of flooding on communities) and continued capital investment in buildings and contents (leading to greater losses when newer buildings of higher economic worth are inundated) have strengthened as receptor drivers of urban flood risk. Further, we propose two new drivers: loss of floodable urban spaces and indirect economic impacts, which we suggest may have significant impacts on future urban flood risk. This article is part of the theme issue ‘Urban flood resilience’.

Achieving urban flood resilience at local, regional and national levels requires a transformative change in planning, design and implementation of urban water systems. Flood risk, wastewater and stormwater management should be re-envisaged and transformed to: ensure satisfactory service delivery under flood, normal and drought conditions, and enhance and extend the useful lives of ageing grey assets by supplementing them with multi-functional Blue-Green infrastructure. The aim of the multidisciplinary Urban Flood Resilience (UFR) research project, which launched in 2016 and comprises academics from nine UK institutions, is to investigate how transformative change may be possible through a whole systems approach. UFR research outputs to date are summarised under three themes. Theme 1 investigates how Blue-Green and Grey (BG + G) systems can be co-optimised to offer maximum flood risk reduction, continuous service delivery and multiple co-benefits. Theme 2 investigates the resource capacity of urban stormwater and evaluates the potential for interoperability. Theme 3 focuses on the interfaces between planners, developers, engineers and beneficiary communities and investigates citizens’ interactions with BG + G infrastructure. Focussing on retrofit and new build case studies, UFR research demonstrates how urban flood resilience may be achieved through changes in planning practice and policy to enable widespread uptake of BG + G infrastructure.

Preliminary results of the UK Urban Flood Resilience research consortium are presented and discussed, with the work being conducted against a background of future uncertainties with respect to changing climate and increasing urbanization. Adopting a whole systems approach, key themes include developing adaptive approaches for flexible engineering design of coupled grey and blue-green flood management assets; exploiting the resource potential of urban stormwater through rainwater harvesting, urban metabolism modelling and interoperability; and investigating the interactions between planners, developers, engineers and communities at multiple scales in managing flood risk. The work is producing new modelling tools and an extensive evidence base to support the case for multifunctional infrastructure that delivers multiple, environmental, societal and economic benefits, while enhancing urban flood resilience by bringing stormwater management and green infrastructure together.

Growing urban populations, changes in rainfall patterns and ageing infrastructure represent significant challenges for urban water management (UWM). There is a critical need for research into how cities should adapt to become resilient to these impacts under uncertain futures. UWM challenges in the Ebbsfleet Garden City (UK) were investigated via a participatory process and potential sustainable solutions were explored using a System Dynamics Model (SDM). Collaborative development of the SDM by the Ebbsfleet Learning and Action Alliance developed stakeholders’ understanding of future UWM options and enabled a structured exploration of interdependencies within the current UWM system. Discussion by stakeholders resulted in a focus on potable water use and the development of the SDM to investigate how residential potable water consumption in the Ebbsfleet Garden City might be reduced through a range of interventions, e.g., socio-environmental and economic policy incentives. The SDM approach supports decision-making at a strategic, system-wide level, and facilitates exploration of the long-term consequences of alternative strategies, particularly those that are difficult to include in quantitative models. While an SDM can be developed by experts alone, building it collaboratively allows the process to benefit from local knowledge, resulting in a collective learning process and increased potential for adoption.

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Urban flooding has become a serious issue in most Chinese cities due to rapid urbanization and extreme weather, as evidenced by severe events in Beijing (2012), Ningbo (2013), Guangzhou (2015), Wuhan (2016), Shenzhen (2019), and Chongqing (2020). The Chinese “Sponge City Program” (SCP), initiated in 2013 and adopted by 30 pilot cities, is developing solutions to manage urban flood risk, purify stormwater, and provide water storage opportunities for future usage. Emerging challenges to the continued implementation of Sponge Cities include (1) uncertainty regarding future hydrological conditions related to climate change projections, which complicates urban planning and designing infrastructure that will be fit for purpose over its intended operating life, and (2) the competing priorities of stakeholders and their reluctance to make trade-offs, which obstruct future investment in the SCP. Nature-Based Solutions (NBS) is an umbrella concept that emerged from Europe, which encourages the holistic idea of considering wider options that combine “Blue–Green” practices with traditional engineering to deliver “integrated systems of Blue–Green–Grey infrastructure”. NBS includes interventions making use of natural processes and ecosystem services for functional purposes, and this could help to improve current pilot SCP practices. This manuscript reviews the development of the SCP, focusing on its construction and design aspects, and discusses how approaches using NBS could be included in the SCP to tackle not only urban water challenges but also a wide range of social and environmental challenges, including human health, pollution (via nutrients, metals, sediments, plastics, etc.), flood risk, and biodiversity.

This research was performed as part of an interdisciplinary project programme undertaken by the Blue‐Green Cities (BGC) Research Consortium (www.bluegreencities.ac.uk) and Portland‐Vancouver ULTRA (Urban Long‐term Research Area) project (www.fsl.orst.edu/eco-p/ultra) as part of the EPSRC “Clean Water for All” (CWfA) initiative. This work was supported by the Engineering and Physical Sciences Research Council [grant numbers EP/K013661/1, EP/N008103/1]; and the National Science Foundation [grant number 0948983]. Additional contributions were received from the UK Environment Agency, Rivers Agency (Northern Ireland) and Institute for Sustainable Solutions (Portland State University, USA). The June 2015 Ningbo Knowledge Exchange Workshop and Symposium received additional funding from the Ningbo Association of Science and Technology and the Institute of Asia and Pacific Studies. We thank the City of Portland Bureau of Environmental Services and Johnson Creek Watershed Council for their kind support and sharing of data and expertise.

Understanding public perceptions of Sustainable Drainage Systems (SuDS) is critical for addressing barriers to their implementation. Perceptions are typically evaluated using explicit measures (e.g. questionnaires) that are subject to biases and may not fully capture attitudes towards SuDS. A novel image-based application of the Implicit Association Test is developed to investigate unconscious perceptions of SuDS in public greenspace and combined with explicit tests to evaluate perceptions of greenspace with and without SuDS, focusing on a sample population in Newcastle-upon-Tyne. Greenspace with or without SuDS is perceived positively by the sample population. Overall, respondents implicitly and explicitly prefer greenspace without SuDS and perceive greenspace without SuDS as more attractive, tidier and safer. The wide distribution of scores for SuDS, nonetheless, suggests a range of opinions and illustrates the complex nature of preferences for the use of greenspace. That the strongly negative explicit scores were not reflected in the implicit tests may suggest that explicit attitudes towards tidiness and safety may not be deep-rooted and are subject to social bias. Combined explicit and implicit tests may help us to understand any disconnect between expressed positive attitudes to natural spaces and behaviours around them and inform SuDS design to increase public acceptance. This article is part of the theme issue ‘Urban flood resilience’.

There is a recognised need for a fundamental change in how the UK manages urban water and flood risk in response to increasingly frequent rainfall events coupled with planned urban expansion. Approaches centred on ‘living with and making space for water’ are increasingly adopted internationally. Nonetheless, widespread implementation of Blue-Green infrastructure (BGI) is currently hampered by barriers that impede uptake and innovation. We investigate the barriers to implementation of BGI in Newcastle, UK, through a series of semi-structured interviews with professional stakeholders. We identify and categorise 17 types of barrier and identify targeted strategies to overcome the dominant barriers. We recommend promotion of BGI’s capacity to meet the objectives of multiple organisations and Local Authority departments, in addition to managing urban water. We conclude that strong business cases, supported by monetised evidence of benefits, and collaborative, inter-agency working could advance implementation of BGI within the current flood risk management legislation.

Fjord and continental shelf environments in the polar regions are host to some of the planet's most productive ecosystems and support economically important fisheries. Their productivity, however, is often critically dependent upon nutrient supply from upstream terrestrial environments delivered via river systems. In glacially fed coastal ecosystems, riverine nutrients are largely sourced from melting snow and ice. The largest and most extensive glacially fed coastal ecosystem in the Arctic is that bordering the Greenland Ice Sheet. The future primary productivity of this ecosystem, however, is uncertain. A potential increase in primary productivity driven by reduced sea ice extent and associated increased light levels may be curtailed by insufficient nutrient supply, and specifically nitrogen. Research on small valley glaciers indicates that glaciers are important sources of nitrogen to downstream environments. However, no data exist from ice sheet systems such as Greenland. Time series of nitrogen concentrations in runoff are documented from a large Greenland glacier, demonstrating seasonally elevated fluxes to the ocean. Fluxes are highest in mid-summer, when nitrogen limitation is commonly reported in coastal waters. It is estimated that approximately half of the glacially exported nitrogen is sourced from microbial activity within glacial sediments at the surface and bed of the ice sheet, doubling nitrogen fluxes in runoff. Summer dissolved inorganic nitrogen fluxes from the Greenland Ice Sheet (30–40 Gg) are a similar order of magnitude to those from a large Arctic river (Holmes et al., 2012). Nitrogen yields from the ice sheet (236 kg TDN km−2 a−1), however, are approximately double those from Arctic riverine catchments. We assert that this ice sheet nitrogen subsidy to Arctic coastal ecosystems may be important for understanding coastal biodiversity, productivity and fisheries and should be considered in future biogeochemical modelling studies of coastal marine productivity in the Arctic regions.