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The existing medium-resolution land cover time series produced under the European Space Agency's Climate Change Initiative provides 29 years (1992–2020) of annual land cover maps at 300 m resolution, allowing for a detailed study of land change dynamics over the contemporary era. Because models need two-dimensional parameters rather than two-dimensional land cover information, the land cover classes must be converted into model-appropriate plant functional types (PFTs) to apply this time series to Earth system and land surface models. The first-generation cross-walking table that was presented with the land cover product prescribed pixel-level PFT fractional compositions that varied by land cover class but that lacked spatial variability. Here we describe a new ready-to-use data product for climate modelling: spatially explicit annual maps of PFT fractional composition at 300 m resolution for 1992–2020, created by fusing the 300 m medium-resolution land cover product with several existing high-resolution datasets using a globally consistent method. In the resulting data product, which has 14 layers for each of the 29 years, pixel values at 300 m resolution indicate the percentage cover (0 %–100 %) for each of 14 PFTs, with pixel-level PFT composition exhibiting significant intra-class spatial variability at the global scale. We additionally present an updated version of the user tool that allows users to modify the baseline product (e.g. re-mapping, re-projection, PFT conversion, and spatial sub-setting) to meet individual needs. Finally, these new PFT maps have been used in two land surface models – Organising Carbon and Hydrology in Dynamic Ecosystems (ORCHIDEE) and the Joint UK Land Environment Simulator (JULES) – to demonstrate their benefit over the conventional maps based on a generic cross-walking table. Regional changes in the fractions of trees, short vegetation, and bare-soil cover induce changes in surface properties, such as the albedo, leading to significant changes in surface turbulent fluxes, temperature, and vegetation carbon stocks. The dataset is accessible at https://doi.org/10.5285/26a0f46c95ee4c29b5c650b129aab788 (Harper et al., 2023).

Background Prostate cancer is the most common cancer in men in the developed world, with most deaths caused by advanced and metastatic disease which has no curative options. Here, we identified Mbtps2 alteration to be associated with metastatic disease in an unbiased in vivo screen and demonstrated its regulation of fatty acid and cholesterol metabolism. Methods The Sleeping Beauty transposon system was used to randomly alter gene expression in the PtenNull murine prostate. MBTPS2 was knocked down by siRNA in LNCaP, DU145 and PC3 cell lines, which were then phenotypically investigated. RNA-Seq was performed on LNCaP cells lacking MBTPS2, and pathways validated by qPCR. Cholesterol metabolism was investigated by Filipin III staining. Results Mbtps2 was identified in our transposon-mediated in vivo screen to be associated with metastatic prostate cancer. Silencing of MBTPS2 expression in LNCaP, DU145 and PC3 human prostate cancer cells reduced proliferation and colony forming growth in vitro. Knockdown of MBTPS2 expression in LNCaP cells impaired cholesterol synthesis and uptake along with reduced expression of key regulators of fatty acid synthesis, namely FASN and ACACA. Conclusion MBTPS2 is implicated in progressive prostate cancer and may mechanistically involve its effects on fatty acid and cholesterol metabolism.

Advanced and metastatic prostate cancer is often incurable, but its dependency on certain molecular alterations may provide the basis for targeted therapies. A growing body of research has demonstrated that peroxisome proliferator-activated receptor gamma (PPARγ) is amplified as prostate cancer progresses. PPARγ has been shown to support prostate cancer growth through its roles in fatty acid synthesis, mitochondrial biogenesis, and co-operating with androgen receptor signalling. Interestingly, splice variants of PPARγ may have differing and contrasting roles. PPARγ itself is a highly druggable target, with agonists having been used for the past two decades in treating diabetes. However, side effects associated with these compounds have currently limited clinical use of these drugs in prostate cancer. Further understanding of PPARγ and novel techniques to target it, may provide therapies for advanced prostate cancer.

Reliable and useful future projections of water scarcity are vital for incorporating into climate policy and national adaptation plans for building climate resilience. However, projections of water scarcity are often based on hydrology models which do not include an important climate feedback affecting the water cycle: the response of plant physiology to rising atmospheric CO2, or “physiological forcing”. With higher atmospheric CO2, plant physiology can affect the water cycle in two contradictory ways. Plant stomata do not open as widely in higher CO2, and therefore transpiration rates are lower, leaving relatively more water in the ground increasing runoff and soil moisture. However, faster rates of photosynthesis with higher CO2 also encourages greater leaf area, and thus higher overall canopy transpiration (even though transpiration of an individual stomata still decreases). The influence of physiological forcing on physical quantities within the water cycle such as transpiration and runoff have been well studied; however, there is a requirement to quantify how this translates to human impacts and more policy-relevant metrics on water resources, such as the water scarcity index. I will present findings from experiments using the Joint UK Land Environmental Simulator (JULES) forced with four earth system models which quantify and highlight the importance of including the plant physiological response in water-related impact studies.

Land Surface Models (LSMs) simulate various biophysical processes of the terrestrial land surface. They have been developed for a variety of applications, including assessing the impact of modifying a particular process on the ecosystem as a whole, e.g., the impact of climate change on hydrology. Due to their great complexity, developing these models is a continuous and laborious process. For example, the JULES (Joint UK Land Environment Simulator) model is developed by a broad community of inter-disciplinary researchers. However, despite the high level of model development, some processes face parsimonious parameterisation. One of these processes is the routing of surface runoff as simulated by the TRIP (Total Runoff Integrating Pathways) scheme [1]. In its current global parameterisation, TRIP uses uniform velocity and meandering characteristics for the entire land surface regardless of the physiography of the actual river system.Our work aims to improve the surface runoff's routing by optimising the effective velocity and meandering ratio parameters. In a sample of 360 global river basins, these parameters are correlated with physiographic characteristics to derive a method of extrapolation at the global scale. The development and application of the method were based on river discharge from the global GRDC database [2] and basin-scale physiographic attributes from the HydroATLAS database [3]. A factorial experiment was performed from a combination of 20 setups of effective velocity values and 12 meandering ratios, resulting in a total of 198 simulations. Two optimisation methods were developed; in the first method, the optimum routing parameters are defined for the best NSE improvement with the least deviation from the default routing parameters, whereas in the second method a uniform parameter set was assigned based on a categorisation of the basins. Neural Networks were used for regression and classification, respectively for each method, correlating the optimal routing parameters with the physiographic attributes at the river basin scale. The trained neural networks were applied to the HydroATLAS attributes to extrapolate the routing parameters at the global scale. Simulations of the newly developed river routing configuration showed improved skill in simulating river flow at the global scale (NSE increased by 0.13 on average over 360 global river basins), especially regarding the temporal response. Finally, the present work resulted in a publicly available branch of the JULES code, where spatially varying routing parameters can be introduced, contrary to the globally fixed set. [1] Oki, T., & Sud, Y. C. (1998). Design of Total Runoff Integrating Pathways (TRIP) - A Global River Channel Network. Earth Interactions, 2(1), 1–37. https://doi.org/10.1175/1087-3562(1998)0022.3.CO;2[2] GRDC. (n.d.). The Global Runoff Data Centre, 56068 Koblenz, Germany, 56068 Koblenz, Germany. 56068 Koblenz, Germany.[3] Linke, S., Lehner, B., Ouellet Dallaire, C., Ariwi, J., Grill, G., Anand, M., Beames, P., Burchard-Levine, V., Maxwell, S., Moidu, H., Tan, F., Thieme, M. (2019). Global hydro-environmental sub-basin and river reach characteristics at high spatial resolution. Scientific Data 6: 283. doi: https://doi.org/10.1038/s41597-019-0300-6 Acknowledgement: This work is based upon work from COST Action 19139 - PROCLIAS, supported by COST (European Cooperation in Science and Technology).

The existing CCI Medium Resolution land cover (MRLC) product delineates 22 primary and 15 secondary land cover classes at 300-meter resolution with global coverage and an annual time step extending from 1992 to the present. Previously, translation of the land cover classes into the plant functional types (PFTs) used by the Earth system and land surface models required the use of the CCI global cross-walking table that defines, for each land cover class, an invariant PFT fractional composition for every pixel of the class regardless of geographic location. Here, we present a new time series data product that circumvents the need for a cross-walking table. We use a quantitative, globally consistent method that fuses the 300-meter MRLC product with a suite of existing high-resolution datasets to develop spatially explicit annual maps of PFT fractional composition at 300 meters. The new PFT product exhibits intraclass spatial variability in PFT fractional cover at the 300-meter pixel level and is complementary to the MRLC maps since the derived PFT fractions maintain consistency with the original land cover class legend. This was only possible by ingesting several key 30m resolution global binary maps like the urban, the open water, the tree cover, and the tree height while controlling their compatibility thanks to the MRLC maps. This dataset is a significant step forward towards ready-to-use PFT descriptions for climate modelling at the pixel level. For each of the 29 years, 14 new maps are produced (one for each of 14 PFTs: bare soil, surface water, permanent snow and ice, built, managed grasses, natural grasses, and trees and shrubs each split into broadleaved evergreen, broadleaved deciduous, needleleaved evergreen, and needleleaved deciduous), with data values at 300-meter resolution indicating the percentage cover (0–100%) of the PFT in the given year. Based on land surface model simulations (ORCHIDEE and JULES models), we find significant differences in simulated carbon, water, and energy fluxes in some regions using the new PFT data product relative to the global cross-walking table applied to the MRLC maps. We additionally provide an updated user tool to assist in creating model-ready products to meet individual user needs (e.g., re-mapping, re-projection, PFT conversion, and spatial sub-setting).

Additional detail of materials and methods used. Figure 1. Flow chart detailing dose escalation schema. Figure 2. MVA-EBNA1/LMP2 Vaccination does not alter broad subsets of immune cells. Figure 3. EBNA1 antibody response before and after MVA-EL vaccination. Table 1 MHC class I and II restricted epitope peptides in EBNA1 and LMP2 used as targets in ELIspot assays. Table 2 Summary of EBNA1- and LMP2-specific immune responses stimulated by vaccination of UK NPC patients.

Purpose: Epstein–Barr virus (EBV) is associated with several cancers in which the tumor cells express EBV antigens EBNA1 and LMP2. A therapeutic vaccine comprising a recombinant vaccinia virus, MVA-EL, was designed to boost immunity to these tumor antigens. A phase I trial was conducted to demonstrate the safety and immunogenicity of MVA-EL across a range of doses.Experimental Design: Sixteen patients in the United Kingdom (UK) with EBV-positive nasopharyngeal carcinoma (NPC) received three intradermal vaccinations of MVA-EL at 3-weekly intervals at dose levels between 5 × 107 and 5 × 108 plaque-forming units (pfu). Blood samples were taken at screening, after each vaccine cycle, and during the post-vaccination period. T-cell responses were measured using IFNγ ELISpot assays with overlapping EBNA1/LMP2 peptide mixes or HLA-matched epitope peptides. Polychromatic flow cytometry was used to characterize functionally responsive T-cell populations.Results: Vaccination was generally well tolerated. Immunity increased after vaccination to at least one antigen in 8 of 14 patients (7/14, EBNA1; 6/14, LMP2), including recognition of epitopes that vary between EBV strains associated with different ethnic groups. Immunophenotypic analysis revealed that vaccination induced differentiation and functional diversification of responsive T-cell populations specific for EBNA1 and LMP2 within the CD4 and CD8 compartments, respectively.Conclusions: MVA-EL is safe and immunogenic across diverse ethnicities and thus suitable for use in trials against different EBV-positive cancers globally as well as in South-East Asia where NPC is most common. The highest dose (5 × 108 pfu) is recommended for investigation in current phase IB and II trials. Clin Cancer Res; 20(19); 5009–22. ©2014 AACR.

Up to 1,000 drowning deaths occur every year on Lake Victoria in East Africa. Nocturnal thunderstorms are one of the main culprits for the high winds and waves that cause fishing boats to capsize. The High Impact Weather Lake System (HIGHWAY) project was established to develop an Early Warning System for Lake Victoria. Prior to HIGHWAY, weather forecasts for the lake were overly general and not trusted. Under the HIGHWAY project, forecasters from weather service offices in East Africa worked with leaders of fishing communities and Beach Management Units to develop marine forecasts and hazardous-weather warnings that were meaningful to fishermen and other stakeholders. Forecasters used high-resolution satellite, radar, and lightning observations collected during a HIGHWAY field campaign, along with guidance from numerical weather prediction models and a 4.4-km resolution Tropical Africa model, to produce specific forecasts and warnings for 10 zones over the lake. Forecasts were communicated to thousands of people by radio broadcasters, local intermediaries, and via smartphones using the WhatsApp application. Fishermen, ferry-boat operators, and lakeside communities used the new marine forecasts to plan their daytime and nighttime activities on the lake. A socioeconomic benefits study conducted by HIGHWAY found that ∼75% of the people are now using the forecasts to decide if and when to travel on the lake. Significantly, a 30% reduction in drowning fatalities on the lake is likely to have occurred, which, when combined with the reduction in other weather-related losses, generates estimated socioeconomic benefits of $44 million per year due to the HIGHWAY project activities; the new marine forecasts and warnings are helping to save lives and property.

The existing medium-resolution land cover time series produced under the European Space Agency's Climate Change Initiative provides 29 years (1992–2020) of annual land cover maps at 300-m resolution, allowing for a detailed study of land change dynamics over the contemporary era. Because models need 2D parameters rather than 2D land cover information, the land cover classes must be converted into model-appropriate plant functional types (PFTs) to apply this time series to Earth system and land surface models. The first generation cross-walking table that was presented with the land cover product prescribed pixel-level PFT fractional compositions that varied by land cover class but lacked spatial variability. Here we describe a new ready-to-use data product for climate modelling: spatially explicit annual maps of PFT fractional composition at 300 m resolution for 1992–2020, created by fusing the 300 m medium-resolution land cover product with several existing high-resolution datasets using a globally consistent method. In the resulting data product, which has 14 layers for each of the 29 years, pixel values at 300-m resolution indicate the percentage cover (0–100 %) for each of 14 PFTs, with pixel-level PFT composition exhibiting significant intra-class spatial variability at the global scale. We additionally present an updated version of the user tool that allows users to modify the baseline product (e.g., re-mapping, re-projection, PFT conversion, and spatial sub-setting) to meet individual needs. Finally, these new PFT maps have been used in two land surface models - ORCHIDEE and JULES - to demonstrate their benefit over the conventional maps based on a generic cross-walking table. Regional changes in the fractions of trees, short vegetation, and bare soil cover induce changes in surface properties, such as the albedo, leading to significant changes in surface turbulent fluxes, temperature, and vegetation carbon stocks.

We assessed current understandings in interpretation of Bayesian and traditional statistical results within the clinical researcher (non-statistician) community.Within a 22-question survey, including demographics and experience and comfort levels with Bayesian analyses, we included questions on how to interpret both Bayesian and traditional statistical outputs. We also assessed whether Bayesian or traditional interpretations are considered more useful.Among the 323 respondent clinicians, 42.4% and 36.5% chose the correct interpretations of the posterior probability and 95% credible interval, respectively. Only 11.5% of respondents interpreted the p-value correctly and 23.5% interpreted the 95% confidence interval correctly.Based on these survey results, we conclude that most of these clinicians face uncertainty when attempting to interpret results from both Bayesian and traditional statistical outputs. When presented with accurate interpretations, clinicians generally conclude that Bayesian results are more useful than conventional ones. We believe there is a need for education of clinicians in statistical interpretation in ways that are customized to this audience.

Defensive repositioning strategies (shifts) have become more prevalent in Major League Baseball in recent years. In 2018, batters faced some form of the shift in 34% of their plate appearances (Sawchik, Travis. 2019. “Don’t Worry, MLB–Hitters Are Killing The Shift On Their Own.” FiveThirtyEight, January 17, 2019. Also available at fivethirtyeight.com/features/dont-worry-mlb-hitters-are-killing-the-shift-on-their-own/). Most teams use a shift that overloads one side of the infield and adjusts the positioning of the outfield. In this work we describe a mathematical approach to the positioning of players over the entire field of play without the limitations of traditional positions or current methods of shifting. The model uses historical data for individual batters, and it leaves open the possibility of fewer than four infielders. The model also incorporates risk penalties for positioning players too far from areas of the field in which extra-base hits are more likely. This work is meant to serve as a decision-making tool for coaches and managers to best use their defensive assets. Our simulations show that an optimal positioning with three infielders lowered predicted batting average on balls in play (BABIP) by 5.9% for right-handers and by 10.3% for left-handers on average when compared to a standard four-infielder placement of players.

The Leeds Africa Climate Hackathon aimed to generate user-relevant narratives of possible future climate in East and West Africa relevant to hydroelectric power generation and agriculture respectively. Here we discuss how the virtual hackathon was organised, present the results, and examine the lessons learned from running such a hackathon. We found East African hydroelectric power generation will need to store more water during heavier rain events and cope with longer drought periods in future. Agriculture in Ghana will face a much greater possibility of severe droughts by mid-century especially if 1.5 degC global warming targets are not met.

AIMS Limited data exists on outcomes following SRS for brainstem metastases (BSM). The purpose of this audit was to explore the use of SRS using Cyberknife for BSM at a single centre; reporting rates of toxicity and survival outcomes. METHOD Patients undergoing SRS for BSM from 2013 to 2021 were identified from a prospective database. Clinical characteristics were collected including; gender, age, histology and KPS. The use of previous WBRT, the volume and the dose delivered to the BSM were also recorded. All target volumes were peer reviewed by a neuro-radiologist. RESULTS 41 patients with a BSM were identified. The median age was 62 years (range 35-78). Histology was lung 15 (36.6%), breast 13 (31.7%) and other 13(31.7%). The median brainstem target volume was 0.36cc (range 0.01 – 5.63cc). 32 patients had single fraction (dose range 14.5 to 18Gy) and 9 patients had 3 fractions (dose range 17-24Gy). 7 patients had previous WBRT. Median overall survival was 242 days (range 19-1213). A radiological response or stable disease was seen in 26 out of 30 patients with post SRS imaging available for review. 2 patients developed a 6th nerve palsy. 12 patients required a prolonged course of dexamethasone. No statistically significant relationship was observed between patient age, brainstem lesion size or fractionation and the need for prolonged use of dexamethasone but there was a trend with lung cancer patients requiring prolonged dexamethasone (p=0.06). CONCLUSION Brainstem SRS is viable option with an acceptable late toxicity profile. Updated information on survival and local control will be presented.

Africa is poised for a revolution in the quality and relevance of weather predictions, with potential for great benefits in terms of human and economic security. This revolution will be driven by recent international progress in nowcasting, numerical weather prediction, theoretical tropical dynamics, and forecast communication, but will depend on suitable scientific investment being made. The commercial sector has recognized this opportunity and new forecast products are being made available to African stakeholders. At this time, it is vital that robust scientific methods are used to develop and evaluate the new generation of forecasts. The Global Challenges Research Fund (GCRF) African Science for Weather Information and Forecasting Techniques (SWIFT) project represents an international effort to advance scientific solutions across the fields of nowcasting, synoptic and short-range severe weather prediction, subseasonal-to-seasonal (S2S) prediction, user engagement, and forecast evaluation. This paper describes the opportunities facing African meteorology and the ways in which SWIFT is meeting those opportunities and identifying priority next steps. Delivery and maintenance of weather forecasting systems exploiting these new solutions requires a trained body of scientists with skills in research and training, modeling and operational prediction, and communications and leadership. By supporting partnerships between academia and operational agencies in four African partner countries, the SWIFT project is helping to build capacity and capability in African forecasting science. A highlight of SWIFT is the coordination of three weather forecasting “Testbeds”—the first of their kind in Africa—which have been used to bring new evaluation tools, research insights, user perspectives, and communications pathways into a semioperational forecasting environment.

This paper investigates the value of weather and climate information at different timescales for decision making in the Tanzanian disaster risk reduction sector using non-monetary approaches. Interviews and surveys were conducted with institutions responsible for disaster management at national, regional and district level. A range of values were identified including: 1) making informed decisions for disaster preparedness, response, recovery and restoration related activities; 2) tailoring of directives and actions based on sectoral impacts; 3) identification of hotspot areas for diseases outbreaks and surplus food production. However, while, a number of guidelines, policies, acts and regulations for disaster risk reduction exist it is not clear how well they promote the use of weather and climate information across climate sensitive sectors. Nonetheless, we find that well-structured disaster risk reduction coordination across sectors and institutions from the national to district level exists, although there is a need for further development of integrated Early Warning Systems, and a common platform to evaluate effectiveness and usefulness of weather warnings and advisories. Key challenges to address in increasing the uptake of weather warnings and advisories include language barriers, limited dissemination to rural areas, and limited awareness of forecasts. Based on the findings of this study, we recommend further quantitative evaluation of the skill of the severe weather warnings issued by the Tanzania Meteorological Authority, and an assessment of how decisions and actions are made by recipients of the warnings in the disaster risk reduction sector at different stages in the warning, response and recovery process.

Background The onset of the COVID-19 pandemic necessitated rapid changes to the practice of head and neck oncology in UK. There was a delay between the onset of the pandemic and the release of guidelines from cancer societies and networks, leading to a variable response of individual centres. This survey was conducted to assess the pre-Covid-19 pandemic standard of practice for head and neck oncology patients and the treatment modifications introduced during the first wave of the pandemic in UK. Methodology The UK National Cancer Research Institute (NCRI) Head and Neck Clinical Studies Group initiated a multi-centre survey using questionnaire to investigate the effect on feeding tube practice, radiotherapy (RT) fractionation and volumes, use of chemotherapy in the neo-adjuvant, concurrent and palliative setting, the use of immunotherapy in the palliative setting, access to radiology and histopathology services, and availability of surgical procedures. Results 30 centres were approached across UK; 23 (76.7%) centres responded and were included in the survey. There were differences in the standard practices in feeding tube policy, RT dose and fractionation as well as concurrent chemotherapy use. 21 (91%) participating centres had at least one treatment modification. 15 (65%) centres initiated a change in radical RT; changing to either a hypofractionation or acceleration schedule. For post-operative RT 10 centres (43.5%) changed to a hypofractionation schedule. 12 (52.2%) centres stopped neo-adjuvant chemotherapy for all patients; 13 (56.5%) centres followed selective omission of chemotherapy in concurrent chemo-radiotherapy patients, 17 (73.9%) centres changed first-line chemotherapy treatment to pembrolizumab (following NHS England’s interim guidance) and 8 (34.8%) centres stopped the treatment early or offered delays for patients that have been already on systemic treatment. The majority of centres did not have significant changes associated with surgery, radiology, histopathology and dental screening. Conclusion There are variations in the standard of practice and treatment modifications for head and neck cancer patients during Covid-19 pandemic. A timely initiative is required to form a consensus on head and neck cancer management in the UK and other countries.

AIMS The De-ESCALaTE study showed an overall survival advantage for the administration of synchronous cisplatin chemotherapy with radiotherapy in low-risk oropharyngeal cancer when compared with synchronous cetuximab. During the trial, a radiotherapy quality assurance protocol amendment permitted centres to swap from the original radiotherapy contouring protocol (incorporating the whole oropharynx into the high-dose clinical target volume (CTV); anatomical protocol) to a protocol that incorporated the gross tumour volume with a 10 mm margin into the CTV (volumetric protocol). The purpose of this study was to examine both toxicity and tumour control related to this protocol amendment. MATERIALS AND METHODS Overall survival and recurrence at 2 years were used to compare tumour control in the two contouring cohorts. For toxicity, the cohorts were compared by both the number of severe (grades 3-5) and all grades acute and late toxicities. In addition, quality of life and swallowing were compared using EORTC-C30 and MD Anderson Dysphagia Inventory, respectively. RESULTS Of 327 patients included in this study, 185 were contoured according to the anatomical protocol and 142 by the volumetric protocol. The two cohorts were well balanced, with the exception of significantly more patients in the anatomical cohort undergoing prophylactic feeding tube insertion (P < 0.001). With a minimum of 2 years of follow-up there was no significant difference in overall survival or recurrence between the two contouring protocols. Similarly, there was no significant difference in the rate of reported severe or all grades acute or late toxicity and no sustained significant difference in quality of life. However, there was a significant difference in favour of volumetric contouring in several domains of the MD Anderson Dysphagia Inventory questionnaire at 1 year, which persisted to 2 years in the dysphagia functional (P = 0.002), dysphagia physical (P = 0.009) and dysphagia overall function (P = 0.008) domains. CONCLUSION In the context of the unplanned post-hoc analysis of a randomised trial, measurable improvement in long-term dysphagia has been shown following a reduction in the CTV. Further reductions in the CTV should be subject to similar scrutiny within the confines of a prospective study.

Simple Summary Nivolumab is an anti-PD-1 monoclonal antibody that has been approved in the management of recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) with evidence of progression within 6 months of platinum-based chemotherapy. Most of the evidence regarding the use of nivolumab in this setting is provided within clinical trials with strict inclusion criteria. This multicenter retrospective cohort study evaluates the real-world outcomes of nivolumab use in four major cancer centers in England. This study demonstrates similar progression free survival and overall survival as that seen in the CHECKMATE-141 study. In addition, it demonstrates that nivolumab tends to be well tolerated, with only a 15% rate of immune-related toxicity. Our findings support the findings of other real-world studies that demonstrate improved progression free survival and potentially overall survival for those who have immune-related toxicity. Abstract Nivolumab is an anti-PD-1 monoclonal antibody currently used as immunotherapy for patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) with evidence of disease progression after platinum-based chemotherapy. This study evaluates real-world safety and treatment outcomes of non-trial nivolumab use. A retrospective multicenter cohort study of patients with recurrent/metastatic HNSCC treated with nivolumab between January 2017 and March 2020 was performed. Overall, 123 patients were included. The median age was 64 years, the majority of patients were male (80.5%) and had a smoking history (69.9%). Primary outcomes included overall response rate (ORR) of 19.3%, median progression-free survival (PFS) of 3.9 months, 1-year PFS rate of 16.8%, a median overall survival (OS) of 6.5 months and 1-year OS rate of 28.6%. These results are comparable to the CHECKMATE-141 study. Of 27 patients who had PD-L1 status tested, positive PD-L1 status did not significantly affect PFS (p = 0.86) or OS (p = 0.84). Nivolumab was well tolerated with only 15.1% experiencing immune-related toxicities (IRT) and only 6.7% of patients stopping due to toxicity. The occurrence of IRT appeared to significantly affect PFS (p = 0.01) but not OS (p = 0.07). Nivolumab in recurrent/metastatic HNSCC is well tolerated and may be more efficacious in patients who develop IRT.

Aims Following stereotactic radiosurgery (SRS), brain metastases can increase in size in up to a third of cases. Conventional magnetic resonance imaging (MRI) has a limited role to distinguish between tumour recurrence and SRS-induced changes, which can impact patient management. Delayed contrast MRI treatment response assessment maps (TRAM) use the principle of contrast clearance seen in other tumours, where high vascularity shows a rapid rise in contrast as well as rapid clearance, whereas areas of damaged or low vascularity show accumulation of contrast. We aimed to assess the ability of delayed contrast MRI and multiparametric MRI techniques of diffusion-weighted imaging (DWI), perfusion-weighted imaging (PWI) and MR spectroscopy (MRS) to distinguish between radiation-related effects and tumour tissue, as these techniques assess tissue physiological and metabolic information. Method A retrospective review was performed on 23 patients who had delayed contrast and multiparametric MRI between October 2018 to April 2020. Studies were restricted to cases with brain metastases enlarging post-SRS with uncertainty at the MDT meeting regarding progression or treatment-related change, impacting the patient’s management. MRI was performed at 3T including DWI, PWI, MRS with short and intermediate echo times, and 3D T1 MPRAGE at 3-5, 20-30 and 70-90 minutes after administration of intravenous contrast. Contrast clearance analysis was performed by selecting an enhancing region of interest (ROI), measuring signal intensities at the three different timepoints and taking apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) values from the ROI. Choline/Creatine values were calculated from a single-voxel (10 mm isotropic) encompassing the entire contrast-enhancing lesion. Outcome was established from MRI follow-up at 6 months, with a stable or responding lesion considered treatment-related changes and increase considered progression. Results Across 23 patients, 24 metastases were assessed. Two patients were excluded as appropriate follow-up was not available. Sites of primary tumours included breast (n=8), lung (n=6), melanoma (n=4), neuroendocrine tumour from the lung (n=2) and renal cell carcinoma (n=2). Mean age was 56 years and 50% were female. In this cohort, 59% (n=13) were classified as having radiation-related changes on follow-up. Delayed MRI contrast clearance between the 3-5 and 70-90 minute imaging was significantly higher in cases of progression (23.6% vs. 2.5% decrease, p0%) for progression was 63%/100%/38%, PWI alone (rCBV cut-off 2.0) yielded results of 77%/75%/79% and for both Cho/Cr ratio alone (cut-off 1.8) and combined with TRAM, it was 90%/88%/92%. Neuroradiologist assessment of all techniques was 95%/100%/92%. Conclusion This study shows the effectiveness of delayed contrast and multiparametric MRI for treatment response assessment in patients with brain metastases treated by SRS in clinical practice. Although a delayed contrast MRI study is a very sensitive tool for detecting tumour progression, it lacks specificity. The accuracy of differentiating between tumour and treatment-related effects increases when delayed contrast MRI is used in combination with other advanced techniques such as MRS. By combining all these techniques, neuroradiologists had the highest accuracy, sensitivity and specificity for detecting progression in post-SRS brain metastases.

Convection-permitting ensemble prediction systems (CP-ENS) have been implemented in themid-latitudes for weather forecasting timescales over the past decade, enabled by the increase incomputational resources. Recently, efforts are being made to study the benefits of CP-ENS fortropical regions. This study examines CP-ENS forecasts produced by the UK Met Office overtropical East Africa, for 24 cases in the period April-May 2019. The CP-ENS, an ensemble withparametrized convection (Glob-ENS), and their deterministic counterparts are evaluated againstrainfall estimates derived from satellite observations (GPM-IMERG). The CP configurations havethe best representation of the diurnal cycle, although heavy rainfall amounts are overestimatedcompared to observations. Pairwise comparisons between the different configurations reveal thatthe CP-ENS is generally the most skilful forecast for both 3-h and 24-h accumulations of heavyrainfall (97th percentile), followed by the CP deterministic forecast. More precisely, probabilisticforecasts of heavy rainfall, verified using a neighbourhood approach, show that the CP-ENS isskilful at scales greater than 100 km, significantly better than the Glob-ENS, although not as goodas found in the mid-latitudes. Skill decreases with lead time and varies diurnally, especially forCP forecasts. The CP-ENS is under-spread both in terms of forecasting the locations of heavyrainfall and in terms of domain-averaged rainfall. This study demonstrates potential benefits inusing CP-ENS for operational forecasting of heavy rainfall over tropical Africa and gives specificsuggestions for further research and development, including probabilistic forecast guidance.

BACKGROUND AND AIMS: In February 2020, the Organ Procurement and Transplantation Network replaced donor service area-based allocation of livers with acuity circles, a system based on three homogeneous circles around each donor hospital. This system has been criticized for neglecting to consider varying population density and proximity to coast and national borders. APPROACH AND RESULTS: Using Scientific Registry of Transplant Recipients data from July 2013 to June 2017, we designed heterogeneous circles to reduce both circle size and variation in liver supply/demand ratios across transplant centers. We weighted liver demand by Model for End-Stage Liver Disease (MELD)/Pediatric End-Stage Liver Disease (PELD) because higher MELD/PELD candidates are more likely to be transplanted. Transplant centers in the West had the largest circles; transplant centers in the Midwest and South had the smallest circles. Supply/demand ratios ranged from 0.471 to 0.655 livers per MELD-weighted incident candidate. Our heterogeneous circles had lower variation in supply/demand ratios than homogeneous circles of any radius between 150 and 1,000 nautical miles (nm). Homogeneous circles of 500 nm, the largest circle used in the acuity circles allocation system, had a variance in supply/demand ratios 16 times higher than our heterogeneous circles (0.0156 vs. 0.0009) and a range of supply/demand ratios 2.3 times higher than our heterogeneous circles (0.421 vs. 0.184). Our heterogeneous circles had a median (interquartile range) radius of only 326 (275–470) nm but reduced disparities in supply/demand ratios significantly by accounting for population density, national borders, and geographic variation of supply and demand. CONCLUSIONS: Large homogeneous circles create logistical burdens on transplant centers that do not need them, whereas small homogeneous circles increase geographic disparity. Using carefully designed heterogeneous circles can reduce geographic disparity in liver supply/demand ratios compared with homogeneous circles of radius ranging from 150 to 1,000 nm.

The BRG1/BRM associated factors (BAF) complex is a chromatin remodeling SWI/SNF which is mutated in 20% of cancers. This complex has many interchangeable subunits which may have oncogenic or tumor suppressor activity in a context-dependent manner. The BAF complex is mutated in 35-50% of metastatic prostate cancer (PC); however, its role in advanced disease is unclear. This review attempts to consolidate current knowledge of the BAF complex in PC and explore potential therapeutic approaches.This review covers the known roles of some BAF subunits, their alterations, and the models which best explain their mechanisms in driving PC. Following this, the authors provide their expert perspective on how this complex could be targeted in the future with a personalized medicine approach.Personalized medicine would allow for patient stratification to exploit synthetic lethal strategies in targeting a mutated BAF complex as shown experimentally in other cancers. BAF dependency can also be targeted in patients stratified for other molecular markers such as BRG1 targeting in phosphatase and tensin homolog (PTEN) deficient PC.

Impact of land surface processes on mesoscale convective initiation over Africa in ensemble model simulations: 3 Case studies using UKMO Unified ModelV S Semeena1, C Taylor1 and A Hartley21. UK Centre for Ecology and Hydrology, Wallingford, Oxfordshire, OX10 8BB, UK2. Met Office, FitzRoy Road, Exeter, Devon, EX1 3PB, UKThe populations of the developing world have a greater need for accurate weather predictions because national economies and personal livelihoods depend very heavily on weather-sensitive factors including agriculture, water resources and public health. Climate related risk is an obstacle in improving food security and rural livelihood in Africa. An effective system to provide reasonable forecast can have a great positive impact on the life quality in African continent. Thus predicting an event with accuracy is essential to provide early warning of heavy rainfall and floods that may lead to loss of life and property. Past studies have shown the importance of the land surface on the development of African convective storms. Here we are using 72 hour ensemble model simulations to evaluate the representation of land and its influence on convection in forecast models. Three episodes of heavy rainfall events are identified over western and eastern African region over late springtime of 2019 for this study. A heavy rainfall event is recorded over SW Mali on 25th April 2019 followed by the development of a convective system over northern Benin on 29th April 2019. The latter one develops into a mesoscale system on 30th April extending up to western Nigeria and this convective initiation in the afternoon and development into a larger system by late evening continues until 3rd May. Our eastern African case examines the daytime development of convective cells which develop over southern Sudan, and grow into a mesoscale system which crosses over to Congo by midnight. 17 ensemble members simulation of the UK Met Office Unified Model (UKMO-UM) that were run for a forecasting testbed within the African SWIFT (Science for Weather Information and Forecasting Techniques) is used to understand the role of land surface temperature (LST) and soil moisture (SM) in formation of mesoscale systems. Single-model ensemble simulations of the UM in global domain at 0.2813 X 0.1875 degree longitude, latitude resolution and the regional convection permitting (CP) model in 2 different horizontal resolutions – 8.8km and 4.4km – are performed. Results are compared with LST from Meteosat Second Generation (MSG) satellite data and precipitation data from Global Precipitation Measurements (GPM). Both global and regional models capture the main features though the convective initiation takes place much earlier in the models than in reality. We notice that the representation of rivers and wetlands in the global model affects the spatial patterns of surface fluxes, in turn introducing biases into the forecast. Further comparison of surface fluxes in the ensemble simulations of these case studies with observed LST and SM illustrate the importance of land initialisation for short term forecasts.

This study aimed to evaluate the prevalence of glucocorticoid-induced adrenal insufficiency in a cohort of patients with brain and skull base tumours and to identify factors which may predict its occurrence. Patients with brain or skull base tumours attending for a short synacthen test (SST) (adrenocorticotropin hormone (ACTH) stimulation test) at a single institution over a 3-year period were retrospectively identified. Baseline demographics and dexamethasone exposure were examined. Only patients with dexamethasone exposure were included in the final analysis looking at the primary end point of SST failure. Fisher’s exact test, Student’s t test, Mann-Whitney test and the Kendall’s tau-b test were used to evaluate the influence of age, gender, diagnosis and mean pituitary radiation dose on the primary endpoint. Receiver operating characteristic (ROC) curves were generated to explore the impact of duration and total exposure to dexamethasone on likelihood of SST failure. Thirty-one of 51 patients with previous dexamethasone exposure failed their first SST (61%). No significant relationship was demonstrated between age, gender, diagnosis or mean pituitary radiation dose and SST failure. Duration of and total exposure to dexamethasone were significantly associated with SST failure (p = 0.001 and p = 0.007, respectively). ROC curves generated values of 78 days and 171 mg days to give a sensitivity of 94 and 97%, respectively, to detect SST failure. Duration of dexamethasone use and total exposure predict for adrenal insufficiency in patients with brain and skull base tumours. Values derived from this study may be useful to identify patients at higher risk of adrenal suppression who require empirical hydrocortisone pending formal testing of the hypothalamic-pituitary-adrenal axis.

Aims Positron emission tomography/computed tomography (PET/CT) is used to restage head and neck cancer 3 months after chemoradiotherapy. The purpose of this study was to determine the negative predictive value (NPV) of a scan reported as having no abnormal uptake and the positive predictive values (PPV) for different maximum standardised uptake value (SUVmax) thresholds. Materials and methods Patients with squamous cell carcinoma of the oro-/hypopharynx/larynx ( n = 206) were included. SUVmax and subsequent locoregional recurrence were documented. Results The median SUVmax was 11.2 (range 4–33)/4.6 (range 2–30), respectively, in patients with/without definite primary site recurrence ( P = 0.004). The median SUVmax was 4.4 (range 2.6–15.6)/3.1 (range 2.1–4.6), respectively, in patients with/without definite nodal recurrence ( P = 0.003). The NPV for a scan reported as having no abnormal uptake was 92%. The PPV for the SUVmax thresholds 4, 6 and 8, respectively, were 53, 65 and 92% (primary site) and 93, 100 and 100% (nodes). Conclusions The NPV of PET/CT after chemoradiation is consistent with the literature and underlines the importance of PET/CT in restaging the primary site if salvage neck dissection is considered. The overall PPV of PET/CT remains low but is high for nodal SUVmax > 4. These data could be used to design risk-stratified follow-up schedules.

Although the number of studies discerning the impact of climate change on ecological systems continues to increase, there has been relatively little sharing of the lessons learnt when accumulating this evidence. At a recent workshop entitled ‘Using climate data in ecological research’ held at the UK Met Office, ecologists and climate scientists came together to discuss the robust analysis of climate data in ecology. The discussions identified three common pitfalls encountered by ecologists: 1) selection of inappropriate spatial resolutions for analysis; 2) improper use of publically available data or code; and 3) insufficient representation of the uncertainties behind the adopted approach. Here, we discuss how these pitfalls can be avoided, before suggesting ways that both ecology and climate science can move forward. Our main recommendation is that ecologists and climate scientists collaborate more closely, on grant proposals and scientific publications, and informally through online media and workshops. More sharing of data and code (e.g. via online repositories), lessons and guidance would help to reconcile differing approaches to the robust handling of data. We call on ecologists to think critically about which aspects of the climate are relevant to their study system, and to acknowledge and actively explore uncertainty in all types of climate data. And we call on climate scientists to make simple estimates of uncertainty available to the wider research community. Through steps such as these, we will improve our ability to robustly attribute observed ecological changes to climate or other factors, while providing the sort of influential, comprehensive analyses that efforts to mitigate and adapt to climate change so urgently require.

Anthropogenic climate change is already impacting ecological systems. Understanding how organisms respond to weather (short-term) and climate (long-term) variability, and the population and ecosystem-wide consequences of climate change, is a research priority. The appropriate use of information on past and potential future weather and climate conditions is crucial for such research, but uncertainties and biases in this information are seldom given full consideration, with important consequences for assessing the potential impacts of climate change on the conservation of biodiversity. Here, we highlight three important neglected issues pertaining to the major applications of weather and climate information in ecological and biogeographical studies. These are as follows: (1) the uncertainty associated with historical weather and climate information; (2) the selection of ensembles of simulated future climate conditions derived from general circulation models (GCM); and (3) the uncertainty and assumptions associated with downscaling GCM simulations to ecologically relevant spatial scales. Broadly, in order to improve the use of weather and climate information in ecological studies, we propose that ecologists must: (1) use weather and climate products that are appropriate for their intended purpose; (2) explore the consequences of uncertainty in these products for ecological conclusions; and (3) seek greater integration of ecological and climate research to create products that reflect both the requirements of ecologists and the limits of climatology. This will enable more effective research into the likely responses of ecological systems to future climate change.

Background The incidence of human papillomavirus (HPV)-positive oropharyngeal cancer, a disease affecting younger patients, is rapidly increasing. Cetuximab, an epidermal growth factor receptor inhibitor, has been proposed for treatment de-escalation in this setting to reduce the toxicity of standard cisplatin treatment, but no randomised evidence exists for the efficacy of this strategy. Methods We did an open-label randomised controlled phase 3 trial at 32 head and neck treatment centres in Ireland, the Netherlands, and the UK, in patients aged 18 years or older with HPV-positive low-risk oropharyngeal cancer (non-smokers or lifetime smokers with a smoking history of

BACKGROUND: Following stereotactic radiosurgery (SRS), brain metastases initially increase in size in up to a third of cases, suggesting treatment failure. Current imaging using structural MRI cannot differentiate between tumour recurrence and SRS-induced changes, creating difficulties with patient management. Combining multiparametric MRI techniques, which assess tissue physiological and metabolic information has shown promise for answering this clinical question. MATERIALS AND METHODS: Multiparametric MRI techniques including spectroscopy, diffusion and perfusion imaging were used for differentiation of radiation-induced necrosis and tumour recurrence after SRS for intracranial metastases in six cases. All patients presented with enlargement of the treated lesion, an increase in perilesional brain oedema, and aggravation or appearance of neurological signs and symptoms from 7–29 weeks after primary treatment. RESULTS: Multiparametric imaging helped to differentiate features of tumour progression (n=4) from radiation-induced necrosis (n=2). A low apparent diffusion coefficient (ADC) 2.1, high choline:creatine (Cho:Cr) ratio >1.8 suggested tumour recurrence. A high ADC >1000 x 10(–6) mm(2)/s, low rCBV ratio

Maps are a crucial asset in communicating climate science to a diverse audience, and there is a wealth of software available to analyse and visualise climate information. However, this availability makes it easy to create poor maps as users often lack an underlying cartographic knowledge. Unlike traditional cartography, where many known standards allow maps to be interpreted easily, there is no standard mapping approach used to represent uncertainty (in climate or other information). Consequently, a wide range of techniques have been applied for this purpose, and users may spend unnecessary time trying to understand the mapping approach rather than interpreting the information presented. Furthermore, communicating and visualising uncertainties in climate data and climate change projections, using for example ensemble based approaches, presents additional challenges for mapping that require careful consideration. The aim of this paper is to provide background information and guidance on suitable techniques for mapping climate variables, including uncertainty. We assess a range of existing and novel techniques for mapping variables and uncertainties, comparing "intrinsic" approaches that use colour in much the same way as conventional thematic maps with "extrinsic" approaches that incorporate additional geometry such as points or features. Using cartographic knowledge and lessons learned from mapping in different disciplines we propose the following 6 general mapping guidelines to develop a suitable mapping technique that represents both magnitude and uncertainty in climate data: – use a sensible sequential or diverging colour scheme; – use appropriate colour symbolism if it is applicable; – ensure the map is usable by colour blind people; – use a data classification scheme that does not misrepresent the data; – use a map projection that does not distort the data – attempt to be visually intuitive to understand. Using these guidelines, we suggest an approach to map climate variables with associated uncertainty, that can be easily replicated for a wide range of climate mapping applications. It is proposed this technique would provide a consistent approach suitable for mapping information for the Fifth Assessment Report of the Intergovernmental Panel on Climate Change (IPCC AR5).

Stereotactic radiosurgery (SRS) has become increasingly important in the management of brain metastases due to improving systemic disease control and rising incidence. Initial trials demonstrated SRS with whole-brain radiotherapy (WBRT) improved local control rates compared with WBRT alone. Concerns with WBRT associated neurocognitive toxicity have contributed to a greater use of SRS alone, including for patients with multiple metastases and following surgical resection. Molecular information, targeted agents, and immunotherapy have also altered the landscape for the management of brain metastases. This review summarises current and emerging data on the role of SRS in the management of brain metastases.

Integrating immunotherapy, proton therapy and biological dose escalation into the definitive chemoradiation of oropharyngeal cancer poses several challenges. Reliable and reproducible data must be obtained in a timely fashion. However, despite recent international radiotherapy contouring guidelines, controversy persists as to the applicability of such guidelines to all cases. Similarly, a lack of consensus exists concerning both the definition of the organ at risk for oral mucositis and the most appropriate endpoint to measure for this critical toxicity. Finally, the correlation between early markers of efficacy such as complete response on PET CT following treatment and subsequent survival needs elucidation for biological subsets of oropharyngeal cancer.

Metastases to the cervical lymph nodes from a occult primary (CUP) of head and neck squamous carcinomas has been increasing in presentation (HNSCC). Modern diagnostic workup, including clinical evaluation, conventional imaging, FDG-PET/CT and panendoscopy/tonsillectomy enables detection of the primary site in over half of all cases, and is associated with significantly improved survival rates. Recent studies have demonstrated the utility of novel molecular pathology and transoral surgical techniques in improving diagnosis and treatment. We present a new, evidence-based protocol incorporating these novel diagnostic modalities. It aims to identify the site of the primary tumor, and determine the stage of the disease, including extranodal extension. This information can personalise treatment recommendations, rationalise combinations of treatment modalities, and thereby potentially minimise toxicity and improving functional outcomes.

Aim We conduct the first assessment of likely future climate change impacts for biodiversity across the West African protected area (PA) network using climate projections that capture important climate regimes (e.g. West African Monsoon) and mesoscale processes that are often poorly simulated in general circulation models (GCMs). Location West Africa. Methods We use correlative species distribution models to relate species (amphibians, birds, mammals) distributions to modelled contemporary climates, and projected future distributions across the PA network. Climate data were simulated using a physically based regional climate model to dynamically downscale GCMs. GCMs were selected because they accurately reproduce important regional climate regimes and generate a range of regional climate change responses. We quantify uncertainty arising from projected climate change, modelling methodology and spatial dependency, and assess the spatial and temporal patterns of climate change impacts for biodiversity across the PA network. Results Substantial species turnover across the network is projected for all three taxonomic groups by 2100 (amphibians = 42.5% (median); birds = 35.2%; mammals = 37.9%), although uncertainty is high, particularly for amphibians and mammals, and, importantly, increases across the century. However, consistent patterns of impacts across taxa emerge by early to mid-century, suggesting high impacts across the Lower Guinea forest. Main conclusions Reducing (e.g. using appropriate climate projections) and quantifying uncertainty in climate change impact assessments helps clarify likely impacts. Consistent patterns of high biodiversity impacts emerge in the early and mid-century projections, while end-of-century projections are too uncertain for reliable assessments. We recommend that climate change adaptation should focus on earlier projections, where we have most confidence in species responses, rather than on end-of-century projections that are frequently used. In addition, our work suggests climate impact should consider a broad range of species, as we simulate divergent responses across taxonomic groups.

IntroductionThe use of metallic containing creams to prevent and treat radiodermatitis is controversial and lacking evidence base. We compare the dose effect of two metallic-based skin creams, which could be used for treating radiodermatitis, to a control.MethodologyUniversal containers of silver sulfadiazine cream, zinc oxide cream and aqueous cream were examined using a computed tomography scanner to assess their electron densities relative to water. Second, each cream was exposed to 100 kV and 6 MV photons. The relative doses were measured using an X-ray chamber.ResultsThe relative electron density measured was similar for the silver sulfadiazine and aqueous creams. Zinc oxide was 40% higher. The relative dose measurements showed that silver sulfadiazine behaved in a similar way to aqueous cream; however, zinc oxide cream exhibited a dose difference of 11·0% in kV photons and −4·1% in MV photons.ConclusionApplication of silver sulfadiazine appears unlikely to bring about significant changes in the dose distribution when compared with aqueous during MV or kV radiotherapy. While zinc oxide cream brought about more significant dose changes.