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Background SCD is a group of autosomal recessive red blood cell (RBC) disorders caused by a single point mutation in the β-globin gene, resulting in the production of hemoglobin S. Hemoglobin S polymerizes within RBCs under certain conditions, leading to the distortion of the RBC membrane and generation of dense and sickle RBCs. These pathologic RBCs contribute to microvascular occlusions in patients with SCD, which present as acute painful episodes called VOEs. Despite the majority of VOEs being managed at home, they remain the most common reason for emergency department (ED) visits and hospitalization among patients with SCD, with > 70% of ED visits and > 90% of hospital admissions for SCD being related to VOEs (Ballas et al. Am J Hematol 2005; Lanzkron et al. Am J Hematol 2010). One of the most severe complications of VOEs is acute chest syndrome, which is a leading cause of mortality among patients with VOEs (Vichinsky et al. N Engl J Med 2000; Bartolucci et al. eBioMedicine 2016). In the absence of targeted therapies for the management of VOEs in patients with SCD, treatment is currently limited to pain management, blood exchange transfusion (with the risk of complications), and other supportive care, representing a significant unmet medical need. Activation of the complement pathway has been described in patients with SCD at baseline, in acute pain crises, and in patients with delayed hemolytic transfusion reaction. Accumulating nonclinical data have suggested a multimodal role for complement dysregulation in the pathophysiology of SCD including vaso-occlusion, hemolysis, inflammation, thrombogenicity, endothelial activation, and end-organ damage (Roumenina et al. Am J Hematol 2020). Crovalimab is a novel, engineered, anti-complement C5 monoclonal antibody. In a Phase I/II study (Röth et al. Blood 2020) in patients with paroxysmal nocturnal hemoglobinuria, a complement-mediated disorder, crovalimab demonstrated rapid and sustained complement inhibition with promising efficacy and safety. Study Design and Methods CROSSWALK-a (NCT04912869) is a randomized, double-blind, placebo-controlled, Phase Ib study evaluating the safety of crovalimab for the management of acute uncomplicated VOEs in patients with SCD. Patients aged ≥ 12 years to ≤ 55 years, weighing ≥ 40 kg, and with a confirmed diagnosis of SCD homozygous hemoglobin S (HbSS) or sickle cell β 0 thalassemia (HbSβ 0) are eligible for the study (Figure). Patients must present with an acute uncomplicated VOE, requiring hospitalization and treatment with parenteral opioid analgesics. Vaccinations against Neisseria meningitidis, Hemophilus influenzae type B, and Streptococcus pneumoniae must be up to date. Eligible patients will be randomized 2:1 to receive either a single intravenous weight-based tiered dose of crovalimab or placebo. Patients in both study arms will continue to undergo pain management and receive other supportive care for their VOE and may also continue to receive ongoing concurrent SCD-directed therapies. Patients will be followed during the hospitalization until discharge and will continue to be followed post-discharge during an observational period. The maximum total study duration for an individual patient will be 12 weeks, which includes the hospitalization and observational periods. The primary objective is to evaluate the incidence and severity of adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0, incidence and severity of infusion-related reactions and hypersensitivity, and change from baseline in targeted vital signs and clinical laboratory test results. Efficacy, pharmacokinetics, pharmacodynamics, immunogenicity, and exploratory biomarker endpoints will also be evaluated. Figure 1 Figure 1. Disclosures Bartolucci: F. Hoffmann-La Roche Ltd: Consultancy; Bluebird: Consultancy, Research Funding; Emmaus: Consultancy; Hemanext: Consultancy; Jazz Pharma: Other: Lecture fees; AGIOS: Consultancy; GBT: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; INNOVHEM: Other: Co-founder; Fabre Foundation: Research Funding; Addmedica: Consultancy, Other: Lecture fees, Research Funding. Ataga: Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees. Callaghan: Alnylum: Current equity holder in publicly-traded company; Roche/Genentech: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy; Pfizer: Consultancy; Global Blood Therapeutics: Consultancy, Speakers Bureau; uniQure: Consultancy; Spark: Consultancy; Biomarin: Consultancy; Kedrion: Consultancy; Hema Biologics: Consultancy; Forma: Consultancy; Chesei: Consultancy; Agios Pharmaceuticals: Current Employment. De Franceschi: F. Hoffmann-La Roche Ltd: Consultancy. Minniti: F. Hoffmann-La Roche: Consultancy; Bluebird Bio: Other: Endpoint adjudicator; Forma: Consultancy; GBT: Consultancy; Novo Nordisk: Consultancy; CSL Behring: Other: Endpoint adjudicator; Novartis: Consultancy; Chiesi: Consultancy. Alexandrou: F. Hoffmann-La Roche Ltd: Consultancy, Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company. Imbs: F. Hoffmann-La Roche Ltd: Consultancy; Certara Inc.: Current Employment. Fox: Parexel International: Current Employment; Genentech, Inc.: Current Employment. Patel: Genentech, Inc.: Current Employment. Sostelly: F. Hoffmann-La Roche Ltd: Current Employment.

Current research indicates that more than half of patients with traumatic spinal cord injury (tSCI) experience delays in transfer and receive surgery >24 h post-injury. The objectives of this study were to determine the geographic distribution of tSCI in Canada relative to specialized treatment facilities, to assess clinical and logistical factors at play for indirect admissions to those facilities, and to explore differences in current time to admission and simulated scenarios in an attempt to assess the potential impact of changes to triage protocols. This study included data from 876 patients with tSCI enrolled in the prospectively collected acute Rick Hansen Spinal Cord Injury Registry (RHSCIR) between January 1, 2010 and December 31, 2013 for whom there were data on the location of their injury. Patients transported directly to a RHSCIR acute facility were more likely to reach the facility within 1 h of injury, whereas those transported indirectly were more likely to arrive 7 h later. Considering the injuries occurring within 40 km of a RHSCIR acute facility (n = 323), 249 patients (77%) were directly and 74 (23%) were indirectly admitted. In the multivariate regression analysis, only older age and longer road distance remained significantly associated with being indirectly admitted to a RHSCIR facility. Compared with the current status, the median time to admission decreased by 20% (3.5 h) in the 100% direct admission scenario, and increased by 102% (8.9 h) in the 100% indirect admission scenario.

It is important for conservationists to be able to assess the risks that climate change poses to species, in order to inform decision making. Using standardised and repeatable methods, we present a national-scale assessment of the risks of range loss and opportunities for range expansion that climate change could pose for over 3000 plants and animals. Species were selected by their occurrence in England, the primary focus of the study, but climate change impacts were assessed across Great Britain, widening their geographical relevance. A basic risk assessment that compared projected future changes in potential range with recently observed changes classified 21% of species as being at high risk and 6% at medium risk of range loss under a B1 climate change scenario. A greater number of species were classified as having a medium (16%) or high (38%) opportunity to potentially expand their distribution. A more comprehensive assessment, incorporating additional ecological information, including potentially confounding and exacerbating factors (e.g. dispersal, habitat availability and other constraints), was applied to 402 species, of which 35% were at risk of range loss and 42% may expand their range extent. This study covers a temperate region with a significant proportion of species at their poleward range limit; the balance of risks and opportunities from climate change may be different elsewhere. The outcome of both risk assessments varied between taxonomic groups, with bryophytes and vascular plants containing the greatest proportion of species at risk from climate change. Upland habitats contained more species at risk than other habitats. Whilst the overall pattern was clear, confidence was generally low for individual assessments, with the exception of well-studied taxa such as birds. In response to climate change, nature conservation needs to plan for changing species distributions and an uncertain future.

Citizen scientists are increasingly engaged in gathering biodiversity information, but trade-offs are often required between public engagement goals and reliable data collection. We compared population estimates for 18 widespread butterfly species derived from the first 4 years (2011–2014) of a short-duration citizen science project (Big Butterfly Count [BBC]) with those from long-running, standardized monitoring data collected by experienced observers (U.K. Butterfly Monitoring Scheme [UKBMS]). BBC data are gathered during an annual 3-week period, whereas UKBMS sampling takes place over 6 months each year. An initial comparison with UKBMS data restricted to the 3-week BBC period revealed that species population changes were significantly correlated between the 2 sources. The short-duration sampling season rendered BBC counts susceptible to bias caused by interannual phenological variation in the timing of species’ flight periods. The BBC counts were positively related to butterfly phenology and sampling effort. Annual estimates of species abundance and population trends predicted from models including BBC data and weather covariates as a proxy for phenology correlated significantly with those derived from UKBMS data. Overall, citizen science data obtained using a simple sampling protocol produced comparable estimates of butterfly species abundance to data collected through standardized monitoring methods. Although caution is urged in extrapolating from this U.K. study of a small number of common, conspicuous insects, we found that mass-participation citizen science can simultaneously contribute to public engagement and biodiversity monitoring. Mass-participation citizen science is not an adequate replacement for standardized biodiversity monitoring but may extend and complement it (e.g., through sampling different land-use types), as well as serving to reconnect an increasingly urban human population with nature.

1. Abundance data are the foundation for many ecological and conservation projects, but are only available for a few taxonomic groups. In contrast, distribution records (georeferenced presence records) are more widely available. Here we examine whether year-to-year changes in numbers of distribution records, collated over a large spatial scale, can provide a measure of species' population variability, and hence act as a metric of abundance changes. 2. We used 33 British butterfly species to test this possibility, using distribution and abundance data (transect counts) from 1976 to 2012. 3. Comparing across species, we found a strong correlation between mean year-to-year changes in total number of distribution records and mean year-to-year changes in abundance (N = 33 species; r2 = 0.66). This suggests that annual distribution data can be used to identify species with low versus high population variability. 4. For individual species, there was considerable variation in the strength of relationships between year-to-year changes in total number of distribution records and abundance. Between-year changes in abundance can be identified from distribution records most accurately for species whose populations are most variable (i.e. have high annual variation in numbers of records). 5. We conclude that year-to-year changes in distribution records can indicate overall population variability within a taxon, and are a reasonable proxy for year-to-year changes in abundance for some types of species. This finding opens up more opportunities to inform ecological and conservation studies about population variability, based on the wealth of citizen science distribution records that are available for other taxa.

Background Optimal surgical management for flexion-distraction cervical spine injuries remains controversial with current guidelines recommending anterior, posterior, and circumferential approaches. Here, we determined the incidence of and examined risk factors for clinical and radiographic failure in patients with 1-segment cervical distraction injuries having undergone anterior surgical fixation. Methods A retrospective review of 57 consecutive patients undergoing anterior fixation for subaxial flexion-distraction cervical injuries between 2008 and 2012 at our institution was performed. The primary outcome was the number of patients requiring additional surgical stabilization and/or radiographic failure. Data collected included age, gender, mechanism and level of injury, facet pattern injury, and vertebral end plate fracture. Results A total of 6 patients failed clinically and/or radiographically (11%). Four patients (7%) required additional posterior fixation. Although 2 other patients identified met radiographic failure criteria, at follow-up they had fused radiographically, were stable clinically, and no further treatment was pursued. Progressive kyphosis and translation were found to be significantly correlated with need for revision ( P P = 0.02, respectively). No differences were identified for all other clinical and radiologic factors assessed, including unilateral or bilateral facet injury, facet fracture, and end plate fracture. Conclusion This study contributes to the growing body of evidence supporting anterior fixation alone for flexion-distraction injuries. Findings suggest that current measurements of radiographic failure including segmental translation and kyphosis may predict radiographic failure and need for further surgical stabilization in some patients. Future follow-up studies assessing for independent risk factors for anterior approach failure with a validated predictive scoring model should be considered.

The British Thyroid Association recommended in new guidelines on thyroid cancer treatment [Kwak et al. (Korean J Radiol 14:110-117, 2013)] that ultrasound grading of thyroid nodules should be incorporated into MDT management. A retrospective study was carried out to determine that the impact of US grading has had on MDT decision making in practice. The design used in the study is a retrospective review of case notes. The study was carried out in the hub hospital for thyroid cancer in the North west London Cancer network. We included consecutive patients referred to the regional thyroid multidisciplinary meeting between August 2014 and May 2015 for investigation of thyroid nodules. Data were collected on patient demographics, co-morbidity, thy grading, ultrasound grading, surgery, post-operative histology, and radioactive iodine treatment details. Accuracy of cytology and ultrasound in diagnosing malignancy was correlated to definitive histology. 99 patients with thyroid nodules were included in the study. 97% of patients had at least one fine needle aspiration and 75% had ultrasound grading. Thy3f (Bethesda IV) nodules were more likely to be carcinoma if associated with a U4 grade rather than U3 (67 vs 18%, p = 0.028). Ultrasound grading has recently been introduced to the standard practice in investigation of thyroid nodules. Further assessment of the accuracy of ultrasound grading in clinical practice may allow us to risk-stratify thy3a/thy3f (Bethesda III/IV) lesions and personalise treatment.

Here, we determine annual estimates of occupancy and species trends for 5,293 UK bryophytes, lichens, and invertebrates, providing national scale information on UK biodiversity change for 31 taxonomic groups for the time period 1970 to 2015. The dataset was produced through the application of a Bayesian occupancy modelling framework to species occurrence records supplied by 29 national recording schemes or societies (n = 24,118,549 records). In the UK, annual measures of species status from fine scale data (e.g. 1 × 1 km) had previously been limited to a few taxa for which structured monitoring data are available, mainly birds, butterflies, bats and a subset of moth species. By using an occupancy modelling framework designed for use with relatively low recording intensity data, we have been able to estimate species trends and generate annual estimates of occupancy for taxa where annual trend estimates and status were previously limited or unknown at this scale. These data broaden our knowledge of UK biodiversity and can be used to investigate variation in and drivers of biodiversity change., Measurement(s)Occupancy • Species • biodiversity assessment objectiveTechnology Type(s)occupancy modelling • biological records • TrendsFactor Type(s)speciesSample Characteristic - OrganismLichens • Invertebrates • BryophytesSample Characteristic - LocationUnited Kingdom Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.9977426

Introduction/Background We have shown that Epigallocatechin-3-gallate (EGCG) targets the human papillomavirus (HPV)-encoded E6 and E7 oncoproteins for degradation, resulting in epithelial cell growth inhibition in in vitro models. Recent clinical trials indicated that Veregen®, a topical ointment containing 55–72 mg of EGCG, is a safe and effective treatment for vulval warts, benign lesions caused by low-risk HPV strains. Based on our findings, we undertook a phase II randomised control trial (RCT) to evaluate if Veregen® is also effective in the treatment of usual-type vulvar intraepithelial neoplasia (uVIN), a pre-malignant lesion associated with high-risk HPV infection. Methodology Eligible patients were randomised to receive either Veregen® or placebo ointment (applied 3 times daily for 16 weeks), and were followed up at 2, 4, 8, 16, 32 and 52 weeks. Outcome measures, recorded at 16 and 32 weeks, were histological (HR) and clinical (CR) response (measured by ≥30% reduction in the sum of the longest diameter of all lesions when compared to baseline) and toxicity. The primary outcome, HR, required a difference in the number of responders ≥3 in favour of Veregen® to detect a difference of 20% between groups (10% for placebo and 30% for Veregen®), as per Jung’s design with type I, II errors ≤0.15. Results 26 patients were randomised, all 13 patients who received Veregen® showed either complete (n=5) or partial (n=8) CR. In placebo group, 3 patients had complete CR, 2 had partial CR and 6 had stable disease. Patients in the Veregen® group showed significant improvement in CR as compared to the placebo group (P=0.0026). There was no evidence of difference in HR and toxicity reported in both groups. Conclusion This study indicates that Veregen® application is safe and leads to at least a partial clinical resolution of uVIN lesions, thus warranting a phase III multi-centre RCT. Disclosure The study is funded by the National Institute for Health Research via the Research for Patient Benefit programme and Medigene AG supplied Veregen® and placebo.

In 2016 there were 5250 brain cancer deaths in the UK. Standard treatment is surgical resection followed by chemo-radiotherapy. In most cases of diffuse glioma, complete tumour resection is not feasible. Many chemotherapy drugs have untested penetration through the blood brain barrier, potentially leading to sub-therapeutic concentrations in the tumour. There is need to refine current treatment strategies in relation to the understanding of tumour biology, and rapidly introduce and evaluate novel therapeutic approaches and agents through delivering rigorous clinical trials. The TESSA JOWELL BRAIN MATRIX Study will evaluate the feasibility of delivering precision medicine for brain cancer patients within the NHS. A multicentre, platform feasibility study of 1200 patients with diffuse glioma will build on the 100,000 genome project to develop and evaluate an infrastructure to collect and integrate: 1) real time comprehensive integrated molecular analysis, including whole genome sequencing and epigenetic classification; 2) serial sampling and annotation of tumours; 3) collection of matched clinical data; 4) assessment of patient quality of life; 5) centralised radiological review and response assessment as per RANO criteria. Once developed this will allow rapid introduction of therapeutic trials to specific patient groups. Secondary objectives include: understanding the association between extent of resection and molecular stratification to refine the role of surgery; optimisation and harmonisation of protocols to best collect, manage and store tissue, clinical data, and radiological images in order to provide a resource for researchers, both within and outside of the study. Improve patient recruitment by identifying and removing recruitment barriers and improve the information and consent processes for patients. Promote the development of a national network with expertise in brain cancer. Enrolment of the first patient is expected in late 2019. For further information, please contact the Brain Matrix Trial Office BrainMatrix@trials.bham.ac.uk.

An appreciation of how some species are becoming more common despite unprecedented anthropogenic pressures could offer key insights for mitigating the global biodiversity crisis. Research to date has largely focused on declining species, while species that are becoming more common have received relatively little attention. Macro-moths in Great Britain are well-studied and species-rich, making them an ideal group for addressing this knowledge gap. Here, we examine changes in 51 successful species between 1968 and 2016 using 4.5 million occurrence records and a systematic monitoring dataset. We employ 3D graphical analysis to visualise long-term multidimensional trends in prevalence (abundance and range) and use vector autoregression models to test whether past values of local abundance are useful for predicting changes in the extent of occurrence. The responses of Anthropocene winners are heterogeneous, suggesting multiple drivers are responsible. Changes in range and local abundance frequently occur intermittently through time, demonstrating the value of long-term, continuous monitoring. There is significant diversity among the winners themselves, which include widespread generalists, habitat specialists, and recent colonists. We offer brief discussion of possible causal factors and the wider ecosystem implications of these trends.

1. Wildfires drive global biodiversity patterns and affect plant–pollinator interactions, and are expected to become more frequent and severe under climate change. Post‐fire plant communities often have increased floral abundance and diversity, but the effects of wildfires on the ecological process of pollination are poorly understood. Nocturnal moths are globally important pollinators, but no previous study has examined the effects of wildfire on nocturnal pollination interactions. 2. We investigated the effects of wildfire on nocturnal pollen‐transport networks. We analysed the abundance and species richness of moths and flowers, and the structure of these networks, at three burned and three unburned sites in Portugal for two years, starting eight months after a large fire. 3. Nocturnal pollen‐transport networks had lower complexity and robustness following the fire than at nearby unburned sites. Overall, 70% of individual moths carried pollen, and moths were found to be transporting pollen from 83% of the flower species present. Burned sites had significantly more abundant flowers, but less abundant and species‐rich moths. Individual moths transported more pollen in summer at burned sites, but less in winter; however, total pollen transport by the moth assemblage at burned sites was just 20% of that at unburned sites. Interaction turnover between burned and unburned networks was high. 4. Negative effects of fire upon moths will likely permeate to other taxa through loss of mutualisms. Therefore, if wildfires become more frequent under climate change, community resilience may be eroded. Understanding the responses of ecological networks to wildfire can inform management that promotes resilience and facilitates whole‐ecosystem conservation.

A large array of species distribution model (SDM) approaches has been developed for explaining and predicting the occurrences of individual species or species assemblages. Given the wealth of existing models, it is unclear which models perform best for interpolation or extrapolation of existing data sets, particularly when one is concerned with species assemblages. We compared the predictive performance of 33 variants of 15 widely applied and recently emerged SDMs in the context of multispecies data, including both joint SDMs that model multiple species together, and stacked SDMs that model each species individually combining the predictions afterward. We offer a comprehensive evaluation of these SDM approaches by examining their performance in predicting withheld empirical validation data of different sizes representing five different taxonomic groups, and for prediction tasks related to both interpolation and extrapolation. We measure predictive performance by 12 measures of accuracy, discrimination power, calibration, and precision of predictions, for the biological levels of species occurrence, species richness, and community composition. Our results show large variation among the models in their predictive performance, especially for communities comprising many species that are rare. The results do not reveal any major trade-offs among measures of model performance; the same models performed generally well in terms of accuracy, discrimination, and calibration, and for the biological levels of individual species, species richness, and community composition. In contrast, the models that gave the most precise predictions were not well calibrated, suggesting that poorly performing models can make overconfident predictions. However, none of the models performed well for all prediction tasks. As a general strategy, we therefore propose that researchers fit a small set of models showing complementary performance, and then apply a cross-validation procedure involving separate data to establish which of these models performs best for the goal of the study., This work was funded by the Research Foundation of the University of Helsinki (A. Norberg), the Academy of Finland (CoE grant 284601 and grant 309581 to O. Ovaskainen, grant 308651 to N. Abrego, grant 1275606 to A. Lehikoinen), the Research Council of Norway (CoE grant 223257), the Jane and Aatos Erkko Foundation, and the Ministry of Science, Innovation and Universities (grant CGL2015‐68438‐P to M. B. Araújo).

Background Sorafenib is the current standard of care for patients with advanced hepatocellular carcinoma (aHCC) and has been shown to improve survival by about 3 months compared to placebo. However, survival varies widely from under three months to over two years. The aim of this study was to build a statistical model that allows personalised survival prediction following sorafenib treatment. Methods We had access to 1130 patients undergoing sorafenib treatment for aHCC as part of the control arm for two phase III randomised clinical trials (RCTs). A multivariable model was built that predicts survival based on baseline clinical features. The statistical approach permits both group-level risk stratification and individual-level survival prediction at any given time point. The model was calibrated, and its discrimination assessed through Harrell’s c-index and Royston-Sauerbrei’s R2D. Results The variables influencing overall survival were vascular invasion, age, ECOG score, AFP, albumin, creatinine, AST, extra-hepatic spread and aetiology. The model-predicted survival very similar to that observed. The Harrell’s c-indices for training and validation sets were 0.72 and 0.70, respectively indicating good prediction. Conclusions Our model (‘PROSASH’) predicts patient survival using baseline clinical features. However, it will require further validation in a routine clinical practice setting.

Objective Cancer initiation and progression has been linked to aberrant expression of the DNA methyltransferases (DNMT), the enzymes which establish and maintain DNA methylation patterns throughout the genome. In this study, we investigated if DNMT expression in vulvar squamous cell carcinomas (VSCC) was related to clinical outcome. Methods DNMT1, DNMT3A and DNMT3B expression was measured in a subset of cases drawn from a cohort of consecutive women treated for primary VSCC at the Pan Birmingham Gynaecological Cancer Centre between 2001 and 2008. Univariable and multivariable competing risk modelling was performed to identify whether DNMT expression was associated with local disease recurrence or disease morbidity. Results Over-expression of DNMT3A in the invasive component of the tumour was seen in 44% of tumours and was associated with an increased risk of local vulvar recurrence (LVR) (HR=4.51, p=0.012). This risk was found to increase further after adjustment for disease stage (HR=6.00, p=0.003) and groin node metastasis (HR=4.81, p=0.008). Over-expression of DNMT3B was associated with an increased risk of LVR (HR=5.69 p=0.03), however this ceased to be significant after adjustment for groin node metastasis. In a subset analysis, over-expression of DNMT3A was found to be significantly more common in VSCCs that stained negative for CDKN2A. Conclusions These observations are consistent with the possibility that epigenetic changes contribute to vulvar neoplasia and DNMT3A over-expression may be useful in predicting local disease recurrence.

In this study, we investigated if the presence of histologically abnormal epithelium adjacent to the primary tumour influenced the frequency, timing, and topography of local vulvar recurrences (LVR) following treatment for squamous cell carcinoma of the vulva (VSCC).The study population comprised a cohort of 201 consecutive cases with incident VSCC. LVR were categorised as local relapses (LR) if they occurred2cm from the tumour margins, and as second field tumours (SFT) when ≥2cm from these margins. Univariable and multivariable competing risk modelling was performed to identify the prognostic factors associated with local disease recurrence.The characterization of the epithelium adjacent to the invasive component was possible for 199 (99.0%) patients. Of these, 171 (85.9%) were found to have intraepithelial abnormalities found adjacent to the surgical specimen. Multivariable analyses revealed that, following adjustment, Lichen Sclerosis (LS) was associated with an increase in the incidence of LVR, LR and SFT (SHRs: 3.4, 2.7 and 4.4, respectively). Although the incidence of LR and SFT in women with LS associated VSCC was similar, the peak incidence of SFT occurred more than two years before that of LR.Women with VSCC arising in a field of LS may continue to have an increased risk of developing LR and SFT for many years after resection of their primary tumour. Our study suggests that these women should be followed up more regularly so that LVR can be detected earlier; unless a more robust surveillance programme or chemopreventative treatments become available.

Grounded in extensive ethnographic and archival research on the Indonesian island of Bali, More Than Words challenges conventional understandings of textuality and writing as they pertain to the religious traditions of Southeast Asia. Through a nuanced study of Balinese script as employed in rites of healing, sorcery and self-defence, this book explores the aims and desires embodied in the production and use of palm-leaf manuscripts, amulets and other inscribed objects. Balinese often attribute both life and independent volition to manuscripts and copperplate inscriptions, presenting them with elaborate offerings. Commonly addressed with personal honorifics, these script-bearing objects may become partners with humans and other sentient beings in relations of exchange and mutual obligation. The question is how such practices of ‘the living letter’ may be related to more recently emergent conceptions of writing—which take Balinese letters to be a symbol of cultural heritage, and a neutral medium for the transmission of textual meaning. One of the book’s central aims is to theorize the coexistence of these seemingly contradictory sensibilities, with an eye to its wider significance for the history and practice of religion in Southeast Asia and beyond.

Citizen science is a powerful way to undertake monitoring of biodiversity, both for detecting rare events (e.g. invasive species, animal and plant health issues or presence of rare species) and assessing trends. However, in order to use citizen science effectively we need to understand better the patterns of people’s participation in projects considering variation in participation between citizen science approaches and individual variation in participation within a project. variation in participation between citizen science approaches and individual variation in participation within a project. Here, we particularly focus on the information content of the data collected through citizen science (although we recognise that citizen science has many other benefits, in addition to data collection). Firstly, we assessed participation in five projects for biodiversity monitoring in the UK, from mass participation to monitoring by volunteer experts, representing up to two thousand people per activity per year. We quantified the patterns of participation (in terms of retention of participants, spatial patterns of participation, and unevenness of contributions per participant - as in the 90:10 rule). We found that the data from mass participation projects were more strongly spatially correlated with human population density and retention of individuals was lower compared to projects targeted on those with existing interest in the subject. Secondly, we quantified the recording behaviour of recorders in a butterfly citizen science project. We developed this with four thousand users of a smartphone app designed for recording sightings of butterflies in the UK. The majority of these users were active for less than 10 days, a feature common to many citizen science projects. The users who engaged for longer produced most of the records for the project. We characterised their recording behaviour using 11 metrics that describe the variation in temporal and spatial recording behaviour as well as the data they recorded. Results showed that citizen scientists in this project fall on a continuum along 4 main axes describing their behaviour. We then used a 20-year butterfly dataset to assess the contribution of different types of recorders to the overall estimate of biodiversity trends and their precision. Overall, variation in participation, both between projects and between individuals within projects, contributes to variation in the information content (and hence the usefulness) of citizen science datasets. We show how different approaches can provide data to meet different needs for data users and how this understanding can be used to improve analyses of these data, allowing us to better design citizen science activities in the future.

[EN] Citizen science plays an increasingly important role in biodiversity research and conservation, enabling large volumes of data to be gathered across extensive spatial scales in a cost-effective manner. Open access increases the utility of such data, informing land-use decisions that may affect species persistence, enhancing transparency and encouraging proliferation of research applications. However, open access provision of recent, fine-scale spatial information on the locations of species may also prompt legitimate concerns among contributors regarding possible unintended negative conservation impacts, violations of privacy and commercial exploitation of volunteer-gathered data. Here we canvas the attitudes towards open access of contributors (104 regional co-ordinators and 510 recorders) of species occurrence records to two of the largest citizen science biodiversity recording schemes, the UK’s Butterflies for the New Millennium project and National Moth Recording Scheme. We find that while the majority of participants expressed support for open access in principle, most were more cautious in practice, preferring to limit the spatial resolution of records, particularly of threatened species, and restrict commercial reuse of data. In addition, citizen scientists’ opinions differed between UK countries, taxonomic groups and the level of involvement volunteers had in the schemes. In order to maintain successful and democratic citizen science schemes, organisers, funders and data users must understand and respect participants’ expectations and aspirations regarding open data while seeking to optimise data use for scientific and societal benefits.

Oral malignant melanoma (OMM) is the most common canine melanocytic neoplasm. Overlap between the somatic mutation profiles of canine OMM and human mucosal melanomas suggest a shared UV-independent molecular aetiology. In common with human mucosal melanomas, most canine OMM metastasise. There is no reliable means of predicting canine OMM metastasis, and systemic therapies for metastatic disease are largely palliative. Herein, we employed exon microarrays for comparative expression profiling of FFPE biopsies of 18 primary canine OMM that metastasised and 10 primary OMM that did not metastasise. Genes displaying metastasis-associated expression may be targets for anti-metastasis treatments, and biomarkers of OMM metastasis. Reduced expression of CXCL12 in the metastasising OMMs implies that the CXCR4/CXCL12 axis may be involved in OMM metastasis. Increased expression of APOBEC3A in the metastasising OMMs may indicate APOBEC3A-induced double-strand DNA breaks and pro-metastatic hypermutation. DNA double strand breakage triggers the DNA damage response network and two Fanconi anaemia DNA repair pathway members showed elevated expression in the metastasising OMMs. Cross-validation was employed to test a Linear Discriminant Analysis classifier based upon the RT-qPCR-measured expression levels of CXCL12, APOBEC3A and RPL29. Classification accuracies of 94% (metastasising OMMs) and 86% (non-metastasising OMMs) were estimated.

There has been significant progress in the treatment of metastatic melanoma, however the impact of new agents on patients with brain metastases remains poorly understood. We report outcomes using SRS for patients with melanoma brain metastases exposed to BRAF targeted agents and/or immunotherapy. METHODS Consecutive patients with metastatic melanoma and brain metastases undergoing SRS without routine whole brain radiotherapy were identified. Selection was restricted to patients having systemic therapy within the same centre. Follow-up included 3monthly MRI scans. All patients were treated using Cyberknife. The target volume was neuroradiology approved without an uncertainty margin. A review of electronic records and follow up imaging was undertaken. Survival data were summarized using Kaplan-Meier curves and compared via a logrank test. RESULTS 49 patients with 148 target metastases were identified. Median number of lesions was 2 (range 1–12), median dose 21Gy, median volume 0.31cc (range 0.01–6.71cc) and 94% had extracranial disease at 2 or more sites. Three patients did not have follow up MRI. One patient required long-term steroids, 1 had transient symptomatic swelling at 11months and 3 patients experienced bleeds (1 symptomatic- post-SRS treated lesion). 12-month local disease free survival was 71% (CI 53, 84). Distant brain progression occurred in 28 patients (57%), with a median time to progression of 8months (95% CI 5, 15). Distant brain progression was less frequent in patients with a single metastasis (p=0.03). Median overall survival (OS) was 11months (95% CI 8, 17). Median OS was 20months (95% CI 5, NR), 10months (95% CI 4, 12) and 11months (95% CI 3, NR) for patients with 1, 2–4 and ≥ 5 metastases respectively (p=0.07). CONCLUSION Beyond a single metastasis, the number of brain metastases did not correlate with OS. Patients with multiple brain metastases and active systemic disease may benefit from SRS however prospective evaluation is recommended.

This chapter develops the contrast between styles of writing – and of reasoning – by reflecting on the Balinese notion that written letters are ‘alive’. Starting from the pragmatic assumption that ‘life’ is what living things do, it examines the ‘uses and acts of aksara (letters)’ in the village community of Batan Nangka. Here we discover that life – at least in Balinese – is less a state than it is a set of relations. As with villages, granaries and human bodies, the written characters of the Balinese alphabet are forged and perdure through their ongoing participation in a complex of relationships—both internal to themselves and with others. This may begin with the linkage of their constituent elements, and subsequent affixation to other letters (e.g., in palm-leaf manuscripts). But it seems the life of letters, as with other living objects, is ultimately contingent on a form of solidarity grounded in reciprocal obligation.