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Agnès Varda and JR's 2017 documentary "Visages Villages" is an extended gesture toward a creative politics that privileges decentralized, communal, and constantly shifting authorial positions. The co-directors not only explore the French countryside in their creative endeavor, but also expand upon preconceived notions of what constitutes a creator and a creation. Using the writings of Gilles Deleuze and Félix Guattari as a theoretical framework, Varda and JR's interactions with space and place offer a radical and subversive transformation that necessarily multiples everything it touches. This multiplicity is enacted not only through a Deleuzean-Guattarian brand of corporeal movement, but through the consistent regeneration and recycling of individual texts and images, all of which coalesce into an endlessly transformative body of work that resists totalization even as it suggests that textual possibility. [ABSTRACT FROM AUTHOR]

Anaesthetic agents have various financial and environmental impacts. Climate change is one of the biggest threats to human health, and anaesthetic gases contribute to global heating by acting as greenhouse gases. The primary aim of this study was to quantify the financial and environmental impacts of anaesthesia maintenance agents used during surgery in an Australian university teaching hospital. The volume of desflurane, sevoflurane, isoflurane and propofol purchased by a university teaching hospital between 2010 and 2020 was analysed and described in terms of financial and environmental impact. Estimated carbon emissions and financial costs of each agent per annum were calculated using the volumes purchased for each agent. A model of ideal anaesthetic agent usage was used to hypothesise the financial and environmental impact of replacing desflurane (the most environmentally damaging and expensive agent) with alternative agents. Using 2019 as an example year at our health service, replacing desflurane with low flow sevoflurane would save greenhouse gas emissions equivalent to driving over 1.4 million kilometres in an average petrol car. Removing desflurane from machines at our institution could save an estimated A$14,630 per annum through reduced machine testing alone. Our findings and calculations indicate that reducing the use of desflurane would have both financial and environmental benefits for healthcare. [ABSTRACT FROM AUTHOR]

Healthcare contributes to environmental harm. Trainee-led Research and Audit in Anaesthesia for Sustainable Healthcare (TRA2SH) is an Australasian network focused on sustainable anaesthesia practice. TRA2SH hypothesised that trainee-led audits alongside education presented on a scheduled national day, called Operation Clean Up, can improve engagement with sustainability initiatives. This paper aims to describe the first two years of Operation Clean Up in terms of goals, achievements and data collected so far. Environmental themes for Operation Clean Up were chosen based on available evidence (life cycle analyses and observational studies). The first Operation Clean Up (OCU 2020) focused on reducing the unnecessary use of single-use disposable absorbent pads (known as 'blueys' in Australia, 'greenies' in New Zealand). OCU 2021 included: refuse desflurane, reduce bluey use, reuse drug trays, and recycle paper and cardboard. TRA2SH provided an information pack to trainees who presented educational material to their department and fed back procurement figures to quantify each item. Descriptive statistics were used to analyse de-identified pooled data submitted to a centralised database. Eight departments submitted data for OCU 2020 and six provided follow-up data. Bluey use was reduced from a median of 37 to 34 blueys per ten surgical encounters. Fifteen departments submitted pre-campaign data for OCU 2021 with follow-up data to be collected during OCU 2022. Baseline data showed a median bluey use of 31 per ten surgical encounters. Volatile-related emissions were calculated; desflurane's proportion was 70% of these emissions yet was 11% of volatile procurement. Two participating departments removed desflurane from their formulary following OCU 2021. Operation Clean Up is a practical model for implementing sustainability initiatives using trainees as eco-leaders. [ABSTRACT FROM AUTHOR]

Self-harm is a common phenomenon amongst young people, often used to regulate emotional distress. Over the last decade harm reduction approaches to self-harm have been introduced as a means to minimize risk and reinforce alternative coping strategies. However, there is a stark absence of research into the perceived usefulness of such techniques amongst adolescents, and previous studies have highlighted ethical concerns about advocating 'safer' forms of self-harm. This study aimed to investigate the perceived usefulness of harm reduction techniques for adolescents who self-harm. We purposively recruited current clients of a British early intervention program supporting young people in managing self-harm. We conducted semi-structured interviews and analyzed transcripts using thematic analysis. Eleven interviews with service users aged 14–15 years identified three main themes: (1) Controlling the uncontrollable; (2) Barriers to practising safer self-harm; and (3) Developing a broad repertoire of harm reduction techniques. Participants expressed mixed views regarding the usefulness of such approaches. Some described greater competence and empowerment in self-harm management, whilst others described the utility of harm reduction methods as either short-lived or situation-specific, with the potential for misuse of anatomical knowledge to cause further harm to high-risk adolescents. The findings from our sample suggest harm reduction techniques have a place in self-harm management for some individuals, but their usage should be monitored and offered alongside alternative strategies and therapeutic support. Our study highlights the need for further research on who would benefit from these techniques and how they can be implemented successfully. Harm reduction can help people who self–harm manage distress and maintain autonomy People who self-harm have a broad repertoire of harm reduction techniques Harm reduction can help reduce long-term damage and frequency of self-harm [ABSTRACT FROM AUTHOR]

The endothelium is an attractive drug target and an important site of adverse drug reactions. Endothelial dysfunction is strongly associated with inflammation and contributes to drug-induced cardiovascular toxicity. Endothelial cells in the circulation are exposed to haemodynamic forces including shear stress. Including shear stress may improve future endothelial cell drug discovery or toxicity screening. Piezo-1 is required for endothelial cells to respond to shear stress. In this study, we investigated whether a small molecule activator of Piezo-1, Yoda-1, can mimic the effect of laminar flow-induced shear stress on endothelial cell inflammation, and endothelial cytotoxicity in response to the chemotherapy agent, doxorubicin. First, we tested whether Yoda-1 could mimic the effects of shear stress of expression of the endothelial adhesion molecules, ICAM-1 and VCAM-1. Human umbilical vein endothelial cells (HUVEC) were cultured in static conditions (with or without Yoda-1) or under laminar flow-induced shear stress (5 dyn/cm2). Yoda-1 and laminar flow had similar anti-inflammatory effects, reducing the ability of TNF-α to induce ICAM-1 and VCAM-1 expression. We then tested whether Yoda-1 could mimic the effect of shear stress on doxorubicin-induced cytotoxicity. Both laminar flow and Yoda-1 treatment of static cultures increased the cytotoxicity of doxorubicin. These findings show that Piezo-1 activation with Yoda-1 in static culture leads to an endothelial cell phenotype that mimics endothelial cells under laminar flow. Pharmacological activation of Piezo-1 may be a useful approach to mimic constant shear stress in static cultures, which may improve endothelial drug discovery and toxicity testing. [ABSTRACT FROM AUTHOR]

Plant growth in nitrogen (N)-limited, unfertilised terrestrial ecosystems should respond to additional N inputs from atmospheric deposition (Ndep). We investigated this for sites in Great Britain (GB) by compiling 796 estimates of net primary productivity (NPP) from measured biomass production over the period 1932–2014, although the great majority were for 1990 onwards. The sites were largely vegetated with shrubs, grass and bracken, and had a wide range of Ndep (0.5–3.3 gN m−2 a−1 in 2000). The measured NPP estimates were compared with calculated values from the biogeochemical ecosystem model N14CP, which predicts that NPP depends strongly upon Ndep. The measured and modelled average total NPP values (gC m−2 a−1) from all data were 387 (standard deviation, SD = 193) and 377 (SD = 72) respectively. Measured and modelled averages for vegetation classes followed the sequence: broadleaved trees ~ needle-leaved trees > herbs (rough grassland + bracken) ~ shrubs. After averaging measured values for sites in individual model grid cells (5 km × 5 km) with 10 or more replicates, the measured and modelled NPP values were correlated (n = 26, r2 = 0.22, p = 0.011), with a slope close to unity. Significant linear relationships were found between measured ln NPP and cumulative Ndep for both herbs (n = 298, p = 0.021) and shrubs (n = 473, p = 0.006), with slopes comparable to those predicted with the model. The results suggest that semi-natural NPP in GB depends positively upon Ndep, in a manner that agrees quantitatively with N14CP predictions. Calculations with the model, using modelled temporal variation in Ndep, indicate that fertilisation by Ndep caused average increases in semi-natural NPP over the period 1800 to 2010 of 30% for shrubs, 71% for herbs, and 91% for broadleaved trees. Combined with previous published results for forests, our findings suggest a general and widespread vegetation response to fertilisation by Ndep. [ABSTRACT FROM AUTHOR]

Background: The anaplastic lymphoma kinase (ALK) treatment landscape is crowded following recent ALK inhibitor approvals, and updated information on real-world treatment patterns in advanced non-small-cell lung cancer (aNSCLC) with ALK rearrangement (ALK+) is needed.Methods: This retrospective US cohort study used Flatiron Health's longitudinal electronic health record (EHR)-derived database. Patients (≥ 18 years old) diagnosed with stage IIIB/IV aNSCLC, with documented ALK rearrangement and ≥2 visits after January 1, 2011 were followed until February 28, 2016. Patients enrolled on a clinical trial or exposed to ALK inhibitors other than crizotinib or ceritinib were excluded. Treatment patterns, time and type of biomarker testing, and overall survival (OS) were analyzed.Results: Median age (n = 300) was 62.5 years; 55% female; 48% non-smokers; 8.7% central nervous system (CNS) metastases at diagnosis. Overall, 73% and 86% received their first ALK biomarker test before/at diagnosis, or before/during first-line treatment, respectively. In total, 90.0%, 78.1%, and 74.7% received first-, second-, and third-line therapy, respectively. Most patients received ALK-targeted treatment; 62% received crizotinib, of which 21% reported a dose reduction. Progression was the most common reason for crizotinib (78%) and ceritinib (41%) discontinuation. Median OS was 29.4 months (95% CI =24.7-39.6) overall; 27.1 months (95% CI =22.0-35.0) in patients with CNS metastases, and 36.9 months (95% CI =25.1-not reached) without.Conclusions: Despite widespread crizotinib use in patients with ALK+ aNSCLC, a high proportion of patients progressed. Ongoing analyses of EHR-derived cohorts are valuable in assessing real-world testing rates and therapeutic use of ALK inhibitors. [ABSTRACT FROM AUTHOR]

Background The efficacy of bevacizumab (BEV) in elderly patients with glioblastoma remains unclear. We evaluated the effect of BEV on survival in this patient population using the Survival, Epidemiology, and End Results (SEER)-Medicare database. Methods This retrospective, cohort study analyzed SEER-Medicare data for patients (aged ≥66 years) diagnosed with glioblastoma from 2006 to 2011. Two cohorts were constructed: one comprised patients who had received BEV (BEV cohort); the other comprised patients who had received any anticancer treatment other than BEV (NBEV cohort). The primary analysis used a multivariate Cox proportional hazards model to compare overall survival in the BEV and NBEV cohorts with initiation of BEV as a time-dependent variable, adjusting for potential confounders (age, gender, Charlson comorbidity index, region, race, radiotherapy after initial surgery, and diagnosis of coronary artery disease). Sensitivity analyses were conducted using landmark survival, propensity score modeling, and the impact of poor Karnofsky Performance Status. Results We identified 2603 patients (BEV, n = 597; NBEV, n = 2006). In the BEV cohort, most patients were Caucasian males and were younger with fewer comorbidities and more initial resections. In the primary analysis, the BEV cohort showed a lower risk of death compared with the NBEV cohort (hazard ratio, 0.80; 95% confidence interval, 0.72–0.89; P <.01). The survival benefit of BEV appeared independent of the number of temozolomide cycles or frontline treatment with radiotherapy and temozolomide. Conclusion BEV exposure was associated with a lower risk of death, providing evidence that there might be a potential benefit of BEV in elderly patients with glioblastoma. [ABSTRACT FROM AUTHOR]

HMGB1 and HMGB2 are DNA-interacting proteins but can also have extracellular actions during inflammation. Despite their relatively high homology, they may have distinct roles, making it essential to be able to differentiate between the two. Here we examine the specificity of five commercially-available anti-HMGB1 antibodies. By Western blotting of recombinant proteins and HMGB1−/− mouse embryonic fibroblasts, we identified only one HMGB1 antibody that, under our experimental conditions, did not also detect HMGB2. Selecting specific antibodies for HMGB1 and HMGB2 allowed identification of distinct HMGB1 and HMGB2 subcellular pools in primary neutrophils. [ABSTRACT FROM AUTHOR]

This paper contributes with a pragmatic evaluation framework for explainable Machine Learning (ML) models for clinical decision support. The study revealed a more nuanced role for ML explanation models, when these are pragmatically embedded in the clinical context. Despite the general positive attitude of healthcare professionals (HCPs) towards explanations as a safety and trust mechanism, for a significant set of participants there were negative effects associated with confirmation bias, accentuating model over-reliance and increased effort to interact with the model. Also, contradicting one of its main intended functions, standard explanatory models showed limited ability to support a critical understanding of the limitations of the model. However, we found new significant positive effects which repositions the role of explanations within a clinical context: these include reduction of automation bias, addressing ambiguous clinical cases (cases where HCPs were not certain about their decision) and support of less experienced HCPs in the acquisition of new domain knowledge. [ABSTRACT FROM AUTHOR]

Background: Climate change is one of the greatest threats to public health in this century. The UK is one of six countries that has enshrined in law a commitment to become net zero by 2050. However, there is a lack of guidance and structure for local government in the UK, which has responsibility for public health, to reach this goal and help their communities mitigate and adapt to the health and health inequality impacts of climate change. This study aimed to identify common barriers and facilitators related to addressing the health and health inequality impacts of climate change in local governments. Methods: Using Normalisation Process Theory, we developed a two-round survey for people working in local authorities to identify the barriers and facilitators to including the health and health inequality impact of climate change in their climate action plans. The survey was delivered online via Qualtrics software. In the first-round respondents were able to express their views on barriers and facilitators and in the second round they ranked common themes identified from the first round. Two hundred and fifty people working in local government were invited to take part and n = 28 (11.2%) completed the first round of the survey and n = 14 completed the second round. Thematic analysis was used in Round 1 to identify common themes and weighted rankings were used to assess key barriers and facilitators in Round 2. Results: Key facilitators were the need to save money on energy, and successful partnership working already in place including across local government, with local communities and external stakeholders. Key barriers were insufficient staff, resources and lack of support from management/leaders, and lack of local evidence. Conclusion: To mitigate and adapt to the health impacts of climate change, local government must nurture a culture of innovation and collaboration to ensure that different departments work together This means not just working with external partners, but also collaborating and co-producing with communities to achieve health equity and mitigate the debilitating effect of climate change on public health. [ABSTRACT FROM AUTHOR]

Most patients with advanced non-small cell lung cancer (NSCLC) have a poor prognosis and receive limited benefit from conventional treatments, especially in later lines of therapy. In recent years, several novel therapies have been approved for second- and third-line treatment of advanced NSCLC. In light of these approvals, it is valuable to understand the uptake of these new treatments in routine clinical practice and their impact on patient care. A systematic literature search was conducted in multiple scientific databases to identify observational cohort studies published between January 2010 and March 2017 that described second- or third-line treatment patterns and clinical outcomes in patients with advanced NSCLC. A qualitative data synthesis was performed because a meta-analysis was not possible due to the heterogeneity of the study populations. A total of 12 different study cohorts in 15 articles were identified. In these cohorts, single-agent chemotherapy was the most commonly administered treatment in both the second- and third-line settings. In the 5 studies that described survival from the time of second-line treatment initiation, median overall survival ranged from 4.6 months (95% CI, 3.8–5.7) to 12.8 months (95% CI, 10.7–14.5). There was limited information on the use of biomarker-directed therapy in these patient populations. This systematic literature review offers insights into the adoption of novel therapies into routine clinical practice for second- and third-line treatment of patients with advanced NSCLC. This information provides a valuable real-world context for the impact of recently approved treatments for advanced NSCLC. [ABSTRACT FROM AUTHOR]

Multiple sclerosis is an autoimmune disease of the central nervous system. Genome wide association studies have identified over 100 common variants associated with multiple sclerosis, the majority of which implicate immunologically relevant genes, particularly those involved in T-cell development. SNP rs13204742 at the THEMIS/PTPRK locus is one such variant. Here, we have demonstrated mutually exclusive use of exon 1 and 2 amongst 16 novel THEMIS isoforms. We also show inverse correlation between THEMIS expression in human CD4+ T-cells and dosage of the multiple sclerosis risk allele at rs13204742, driven by reduced expression of exon 1- containing isoforms. In silico analysis suggests that this may be due to cell-specific, allele-dependent binding of the transcription factors FoxP3 and/or E47. Research exploring the functional implications of GWAS variants is important for gaining an understanding of disease pathogenesis, with the ultimate aim of identifying new therapeutic targets. [ABSTRACT FROM AUTHOR]

We investigate manipulation of the Borda voting rule, as well as two elimination style voting rules, Nanson's and Baldwin's voting rules, which are based on Borda voting. We argue that these rules have a number of desirable computational properties. For unweighted Borda voting, we prove that it is NP-hard for a coalition of two manipulators to compute a manipulation. This resolves a long-standing open problem in the computational complexity of manipulating common voting rules. We prove that manipulation of Baldwin's and Nanson's rules is computationally more difficult than manipulation of Borda, as it is NP-hard for a single manipulator to compute a manipulation. In addition, for Baldwin's and Nanson's rules with weighted votes, we prove that it is NP-hard for a coalition of manipulators to compute a manipulation with a small number of candidates. Because of these NP-hardness results, we compute manipulations using heuristic algorithms that attempt to minimise the number of manipulators. We propose several new heuristic methods. Experiments show that these methods significantly outperform the previously best known heuristic method for the Borda rule. Our results suggest that, whilst computing a manipulation of the Borda rule is NP-hard, computational complexity may provide only a weak barrier against manipulation in practice. In contrast to the Borda rule, our experiments with Baldwin's and Nanson's rules demonstrate that both of them are often more difficult to manipulate in practice. These results suggest that elimination style voting rules deserve further study. [ABSTRACT FROM AUTHOR]

When model-checking reports that a property holds on a model, vacuity detection increases user confidence in this result by checking that the property is satisfied in the intended way. While vacuity detection is effective, it is a relatively expensive technique requiring many additional model-checking runs. We address the problem of efficient vacuity detection for Bounded Model Checking (BMC) of linear temporal logic properties, presenting three partial vacuity detection methods based on the efficient analysis of the resolution proof produced by a successful BMC run. In particular, we define a characteristic of resolution proofs— peripherality—and prove that if a variable is a source of vacuity, then there exists a resolution proof in which this variable is peripheral. Our vacuity detection tool, VaqTree, uses these methods to detect vacuous variables, decreasing the total number of model-checking runs required to detect all sources of vacuity. [ABSTRACT FROM AUTHOR]

Understanding how agricultural practices alter biogeochemical cycles is vital for maintaining land productivity, food security, and other ecosystem services such as carbon sequestration. However, these are complex, highly coupled long-term processes that are difficult to observe or explore through empirical science alone. Models are required that capture the main anthropogenic disturbances, whilst operating across regions and long timescales, simulating both natural and agricultural environments, and shifts among these. Many biogeochemical models neglect agriculture or interactions between carbon and nutrient cycles, which is surprising given the scale of intervention in nitrogen and phosphorus cycles introduced by agriculture. This gap is addressed here, using a plant-soil model that simulates integrated soil carbon, nitrogen and phosphorus (CNP) cycling across natural, semi-natural and agricultural environments. The model is rigorously tested both spatially and temporally using data from long-term agricultural experiments across temperate environments. The model proved capable of reproducing the magnitude of and trends in soil nutrient stocks, and yield responses to nutrient addition. The model has potential to simulate anthropogenic effects on biogeochemical cycles across northern Europe, for long timescales (centuries) without site-specific calibration, using easily accessible input data. The results demonstrate that weatherable P from parent material has a considerable effect on modern pools of soil C and N, despite significant perturbation of nutrient cycling from agricultural practices, highlighting the need to integrate both geological and agricultural processes to understand effects of land-use change on food security, C storage and nutrient sustainability. The results suggest that an important process or source of P is currently missing in our understanding of agricultural biogeochemical cycles. The model could not explain how yields were sustained in plots with low P fertiliser addition. We suggest that plant access to organic P is a key uncertainty warranting further research, particularly given sustainability concerns surrounding rock sources of P fertiliser. Unlabelled Image • A C-N-P model simulating transition from natural to agricultural land-use • The model is compared with data from long-term experimental plots in Europe. • Agriculture causes significant changes to nutrient cycling. • Modern C and N stocks remain strongly influenced by initial weatherable P. • Results indicate a missing process or source of P in current understanding. [ABSTRACT FROM AUTHOR]

As any model of real-world phenomena, soil erosion models must be tested against empirical evidence to have their performance evaluated. This is critical to develop knowledge and confidence in model predictions. However, evaluating soil erosion models is complicated due to the uncertainties involved in the estimation of model parameters and measurements of system responses. Here, we undertake a term co-occurrence analysis to investigate how model evaluation is approached in soil erosion research. The analysis illustrates how model testing is often neglected, and how model evaluation topics are segregated from current research interests. We perform a meta-analysis of model performance to understand the mechanisms that influence model predictive accuracy. Results indicate that different models do not systematically outperform each other, and that calibration seems to be the main mechanism of model improvement. We review how soil erosion models have been evaluated at different temporal and spatial scales, focusing on the methods, assumptions, and data used for model testing. We discuss the implications of uncertainty and equifinality in soil erosion models, and implement a case study of uncertainty assessment that enables models to be tested as hypotheses. A comment on the way forward for the evaluation of erosion models is presented, discussing philosophical aspects of hypothesis testing in environmental modelling. We refute the notion that soil erosion models can be validated, and emphasize the necessity of defining fit-for-purpose tests, based on multiple sources of data, that allow for a broad investigation of model usefulness and consistency. [ABSTRACT FROM AUTHOR]

• Mental health and neurodevelopmental disorders are common in childhood epilepsy. • Timely detection and intervention for these comorbidities is critical. • We reviewed and evaluated mental health PROMs designed for paediatric epilepsy. • There were few validated PROMs for mental health outcomes in this population. • Development and validation of childhood epilepsy mental health PROMs is needed. Children and young people with epilepsy are at higher risk of mental health disorders and atypical neurodevelopmental outcomes compared to the general population. It is essential to detect such comorbidities early in children with epilepsy and provide appropriate interventions, to improve clinical outcomes. We aimed to identify and evaluate the measurement properties of Patient-Reported Outcome Measures (PROMs) that have been validated specifically to measure mental health and neurodevelopmental outcomes in children and/or young people with epilepsy. We searched Embase, Medline, and PsycINFO in May 2023 for relevant studies. Mental health was defined as psychological symptoms (e.g., anxiety, depression, psychosis) and/or behavioural difficulties (e.g., conduct disorders). Neurodevelopmental outcomes included neurodevelopmental disorder traits such as attention-deficit hyperactivity disorder (ADHD) and autistic spectrum disorders. We assessed methodological quality using Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) guidance. Twelve papers were identified that psychometrically evaluated 13 relevant PROMs (two epilepsy-specific, eleven generic). The appraisal of the PROMs was limited by the availability of only one or two published articles for each, and incomplete psychometric evaluations in some cases. The tool demonstrating the strongest evidence was The Neurological Disorders Depression Inventory-Epilepsy for Youth. The ADHD Rating Scale-IV and The Paediatric Symptom Checklist -17 demonstrated good evidence in favour of at least two measurement properties. This review identified only a small number of mental health and neurodevelopmental PROMs evaluated specifically in paediatric epilepsy. There is a need for further validation of mental health and neurodevelopmental PROMs in children with epilepsy. [ABSTRACT FROM AUTHOR]

Background: A Guide for Healthcare Professionals (HCP Guide) and patient alert card (PAC) for atezolizumab as additional risk minimization measures for physicians were distributed to raise awareness and help in the detection and management of immune-related adverse drug reactions. Objectives: The main objective of this study was to assess the receipt, knowledge, and behaviors of physicians regarding the atezolizumab HCP Guide and PAC. Methods: A multi-country, one-wave, observational, cross-sectional, web-based, self-reported physician survey was conducted to assess the level of knowledge of key messages related to immune-related adverse drug reactions summarized in the atezolizumab HCP Guide and PAC among physicians (oncologists, pulmonologists, and urologists) prescribing atezolizumab in six European countries (Denmark, Germany, Italy, Spain, Sweden, and the UK). Responses regarding the receipt, understanding and use of the materials, and knowledge and behavior related to the HCP Guide and PAC are presented as percentages and continuous scores scaled out of 100 points, with corresponding 95% confidence intervals (CIs). Results: Among 313 physicians (255 oncologists, 30 pulmonologists, and 28 urologists), 77.4% received the HCP Guide and 74.2% the PAC. The HCP Guide was read by 71.3% of the 267 physicians who received the materials, and the mean usage score was 69.5 (95% CI 66.0–72.9), and 57.1% of physicians had scores ≥ 70. The HCP Guide was completely understood by 85.4% of physicians who had read it. Mean knowledge scores were 63.9 (95% CI 62.1–65.7) and 39.4% of physicians had correct knowledge scores ≥ 70. Mean knowledge scores were 66.8 (95% CI 64.9–68.7) for receipt of both the HCP Guide and PAC, 59.4 (95% CI 55.5–63.4) for one of the materials, and 60.8 (95% CI 55.4–66.2) for having received none of the materials. Mean behavior scores were 78.9 (95% CI 76.8–81.0), and 74.8% of physicians had behavior scores ≥ 70. The mean behavior score was 79.0 (95% CI 76.5–81.5) for those who received both the HCP Guide and PAC, 76.9 (95% CI 72.2–81.5) for receipt of one of the materials, and 81.5 (95% CI 75.0–88.0) for those who received none of the materials. Conclusions: The study assessed the effectiveness of the atezolizumab additional risk minimization educational materials among physicians in six European countries, using process indicators. The educational materials reached over 70% of target physicians, 57.1% of whom reported using them. Knowledge and behavior related to immune-related adverse drug reactions for atezolizumab were no better in those who received the additional risk minimization educational materials. The results support the safe use of atezolizumab by these physician groups and contributed to the European Medicines Agency permitting removal of the HCP Guide. [ABSTRACT FROM AUTHOR]

Globally pervasive increases in atmospheric CO2 and nitrogen (N) deposition could have substantial effects on plant communities, either directly or mediated by their interactions with soil nutrient limitation. While the direct consequences of N enrichment on plant communities are well documented, potential interactions with rising CO2 and globally widespread phosphorus (P) limitation remain poorly understood. We investigated the consequences of simultaneous elevated CO2 (eCO2) and N and P additions on grassland biodiversity, community and functional composition in P‐limited grasslands. We exposed soil‐turf monoliths from limestone and acidic grasslands that have received >25 years of N additions (3.5 and 14 g m−2 year−1) and 11 (limestone) or 25 (acidic) years of P additions (3.5 g m−2 year−1) to eCO2 (600 ppm) for 3 years. Across both grasslands, eCO2, N and P additions significantly changed community composition. Limestone communities were more responsive to eCO2 and saw significant functional shifts resulting from eCO2–nutrient interactions. Here, legume cover tripled in response to combined eCO2 and P additions, and combined eCO2 and N treatments shifted functional dominance from grasses to sedges. We suggest that eCO2 may disproportionately benefit P acquisition by sedges by subsidising the carbon cost of locally intense root exudation at the expense of co‐occurring grasses. In contrast, the functional composition of the acidic grassland was insensitive to eCO2 and its interactions with nutrient additions. Greater diversity of P‐acquisition strategies in the limestone grassland, combined with a more functionally even and diverse community, may contribute to the stronger responses compared to the acidic grassland. Our work suggests we may see large changes in the composition and biodiversity of P‐limited grasslands in response to eCO2 and its interactions with nutrient loading, particularly where these contain a high diversity of P‐acquisition strategies or developmentally young soils with sufficient bioavailable mineral P. [ABSTRACT FROM AUTHOR]

To meet the increasing global demand for food, feed, fibre and other plant‐derived products, a steep increase in crop productivity is a scientifically and technically challenging imperative. The CropBooster‐P project, a response to the H2020 call 'Future proofing our plants', is developing a roadmap for plant research to improve crops critical for the future of European agriculture by increasing crop yield, nutritional quality, value for non‐food applications and sustainability. However, if we want to efficiently improve crop production in Europe and prioritize methods for crop trait improvement in the coming years, we need to take into account future socio‐economic, technological and global developments, including numerous policy and socio‐economic challenges and constraints. Based on a wide range of possible global trends and key uncertainties, we developed four extreme future learning scenarios that depict complementary future developments. Here, we elaborate on how the scenarios could inform and direct future plant research, and we aim to highlight the crop improvement approaches that could be the most promising or appropriate within each of these four future world scenarios. Moreover, we discuss some key plant technology options that would need to be developed further to meet the needs of multiple future learning scenarios, such as improving methods for breeding and genetic engineering. In addition, other diverse platforms of food production may offer unrealized potential, such as underutilized terrestrial and aquatic species as alternative sources of nutrition and biomass production. We demonstrate that although several methods or traits could facilitate a more efficient crop production system in some of the scenarios, others may offer great potential in all four of the future learning scenarios. Altogether, this indicates that depending on which future we are heading toward, distinct plant research fields should be given priority if we are to meet our food, feed and non‐food biomass production needs in the coming decades. [ABSTRACT FROM AUTHOR]

Soil health is one of the key factors in determining the sustainability of global agricultural systems and the stability of natural ecosystems. Microbial decomposition activity plays an important role in soil health; and gaining spatiotemporal insights into this attribute is critical for understanding soil function as well as for managing soils to ensure agricultural supply, stem biodiversity loss, and mitigate climate change. Here, a novel in situ electronic soil decomposition sensor that relies on the degradation of a printed conductive composite trace utilizing the biopolymer poly(3‐hydroxybutyrate‐co‐3‐hydroxyvalerate) as a binder is presented. This material responds selectively to microbially active environments with a continuously varying resistive signal that can be readily instrumented with low‐cost electronics to enable wide spatial distribution. In soil, a correlation between sensor response and intensity of microbial decomposition activity is observed and quantified by comparison with respiration rates over 14 days, showing that devices respond predictably to both static conditions and perturbations in general decomposition activity. [ABSTRACT FROM AUTHOR]

The world needs more than double its current agricultural productivity by 2050 to produce enough food and feed, as well as to provide feedstock for the bioeconomy. These future increases will not only need to be sustainable but without comprommising the nutritional quality, and ideally also need to decrease greenhouse gas emissions and increase carbon sequestration to help mitigate the consequences of global climate change. These challenges could be tackled by developing and integrating new future‐proof crops into our food system. The H2020 CropBooster‐P project sets out plant‐centered breeding approaches guided by a broad socio‐economic and societal support. First, the potential approaches for breeding crops with sustainably increased yields adapted to the future climate of Europe are identified. These crop‐breeding options are subsequently prioritized and their adoption considered by experts across the agri‐food system and the wider public, taking into account environmental, economic and other technical criteria. In this way, a specific research agenda to future‐proof our crops was developed, supported by an eventual implementation plan. [ABSTRACT FROM AUTHOR]

Crop breeding is one of the main tools which can assist in future‐proofing food systems for more sustainable outcomes. In order to ensure priorities are aligned with the needs and wants of food system actors, it is essential to engage with key stakeholders to understand preferences on plant breeding solutions. This study presents results from a series of online focus groups conducted with agricultural production related stakeholders (i.e. farmers and farmer representatives, policymakers and NGOs) regarding the potential for crop improvement to future‐proof European food systems. Stakeholders shared concern around climate change and environmental impacts (particularly drought and heat stress), and general agreement about the need to develop resilient crops which combine multiple positive attributes, while reducing trade‐offs and negative externalities. Stakeholders also prioritized plant breeding solutions for areas where they felt they had little agency, and existing alternative solutions, such as improving input use efficiency, or altering diets to be considered where these are available. This highlights the need for the crop breeding community to focus its attentions on the 'most hard to fix' issues, where in‐field measures are currently not offering viable solutions, to maximize acceptance and adoption by agricultural production stakeholders. It also highlights that consideration of trade‐offs, within plant and within a broader agri‐food context, must be integrated into crop breeding research and development, with trade‐off analysis an explicit component of breeding research. Understanding broader agri‐food system knock‐on effects of plant innovation is a non‐trivial challenge requiring interdisciplinary research and close partnerships with food system stakeholders. [ABSTRACT FROM AUTHOR]

The global demand for providing nutritious, sustainable, and safe diets for a 10 billion population by 2050 while preserving affordability, reducing environmental impacts, and adapting to climate change will require accelerating the transition to sustainable agri‐food systems. A plausible way to help tackle these challenges is by developing new plant varieties that have improved crop yield, plant nutritional quality, and sustainability (or resilience) traits. However, stakeholders, consumers, and citizens' concerns and appreciation of future‐proofing crops and the acceptability of new plant breeding strategies are not well‐established. These groups are actors in the agri‐food systems, and their views, values, needs, and expectations are crucial in helping to co‐design fair, ethical, acceptable, sustainable, and socially desirable policies on new plant breeding techniques (NPBTs) and the transition to sustainable agri‐food systems. In this study, we engaged with consumer experts and societal stakeholders to consider their perceptions, expectations, and acceptability of improving crops and NPBTs for future‐proofing the agri‐food systems. Our analysis points to a need for governments to take a proactive role in regulating NPBTs, ensure openness and transparency in breeding new crop varieties, and inform consumers about the effects of these breeding programmes and the risks and benefits of the new crop varieties developed. Consumer experts and societal stakeholders considered these strategies necessary to instil confidence in society about NPBTs and accelerate the transition to sustainable agri‐food systems. [ABSTRACT FROM AUTHOR]

Food system resilience has multiple dimensions. We draw on food system and resilience concepts and review resilience framings of different communities. We present four questions to frame food system resilience (Resilience of what? Resilience to what? Resilience from whose perspective? Resilience for how long?) and three approaches to enhancing resilience (robustness, recovery, and reorientation—the three "Rs"). We focus on enhancing resilience of food system outcomes and argue this will require food system actors adapting their activities, noting that activities do not change spontaneously but in response to a change in drivers: an opportunity or a threat. However, operationalizing resilience enhancement involves normative choices and will result in decisions having to be negotiated about trade-offs among food system outcomes for different stakeholders. New approaches to including different food system actors' perceptions and goals are needed to build food systems that are better positioned to address challenges of the future. [ABSTRACT FROM AUTHOR]

The clinical profiles and outcomes of patients with neurotrophic tropomyosin receptor kinase fusion-positive (NTRK+) solid tumors receiving standard of care other than tropomyosin receptor kinase inhibitor (TRKi) targeted therapy have not been well documented. Here, we describe the clinical characteristics of patients with NTRK+ tumors treated in clinical practice using information from a United States electronic health record-derived clinicogenomic database. We also compared survival outcomes in NTRK+ patients and matched NTRK fusion-negative (NTRK–) patients and investigated the clinical prognostic value of NTRK fusions. NTRK positivity was defined by the presence of a fusion or rearrangement involving NTRK1/2/3, determined using NGS (Foundation Medicine, Inc.). NTRK+ patients (n = 28) were diagnosed with locally advanced/metastatic solid tumors between January 1, 2011 and December 31, 2019 and had received no TRKis (e.g., entrectinib or larotrectinib) during their patient journey. The unselected NTRK−population comprised 24,903 patients, and the matched NTRK−cohort included 280 patients. NTRK+ patients tended to be younger, were more commonly not smokers, and had a shorter time from advanced diagnosis to first NGS report, compared with unselected NTRK−patients; however, these differences were not significant. Median overall survival (OS) from advanced/metastatic diagnosis was 10.2 months (95% CI, 7.2–14.1) for the NTRK+ cohort versus 10.4 months (95% CI, 6.7–14.3) for the matched NTRK−cohort; hazard ratio for death in NTRK+ versus matched NTRK−patients was 1.6 (95% CI, 1.0–2.5; P = 0.05). Genomic co-alterations were rare in the NTRK+ cohort (only two of 28 patients had a co-alteration). Overall, while hazard ratios suggest NTRK fusions may be a negative prognostic factor of survival, there are no significant indications of any favorable impact of NTRK fusions on patient outcomes. TRKis, with their high response rate and good tolerability, are likely to improve outcomes for patients compared with existing standard-of-care treatments. [ABSTRACT FROM AUTHOR]

It has been hypothesised that romantic partners are more similar than chance in relation to autistic traits. To test this theory, we recruited n = 105 heterosexual couples and examined within-couple correlations for autistic traits [measured using the Autism Spectrum Quotient (AQ)], empathizing [measured using the Empathy Quotient (EQ)], and systemizing [measured using the Systemizing Quotient-Revised (SQ-R)]. For a subsample that attended the lab (n = 58 couples), we also investigated theory of mind via facial expressions using the Reading the Mind in the Eyes Test (RMET) and attention to detail, a component within systemizing, using the Embedded Figures Task (EFT). Variable-centred analyses revealed positive within-couple correlations for all measures except EQ, although these effects were only statistically significant for unmarried couples and not for married/engaged couples. Follow-up analyses indicated that the observed couple similarity effects are likely consistent with people pairing with those more similar than chance (initial assortment) rather than becoming alike over time (convergence), and to seeking out self-resembling partners (active assortment) rather than pairing in this manner via social stratification processes (social homogamy). Additionally, a significant within-couple correlation for autistic traits was observed at the meta-analytic level. However, it should be noted that the meta-analytic effect size estimate was small (r = 0.153) and indicates that only ~ 2% of variance in a person's score on a phenotypic measure of autistic traits can be predicted by that of their partner. [ABSTRACT FROM AUTHOR]

PURPOSE: The molecular heterogeneity of metastatic colorectal cancer (mCRC) presents a therapeutic challenge, with few trials focused on patients with human epidermal growth factor receptor 2 amplification (HER2-Amp). Our limited understanding of real-world patterns and outcomes by HER2 status of treatment-refractory patients leaves treatment decisions with little contextual information. We conducted a retrospective cohort study to describe the natural disease history of patients with refractory mCRC using an electronic health record–derived database with oncogenomic information. METHODS: We included patients with stage IV or recurrent mCRC diagnosed from January 2011 through December 2019 from a deidentified clinicogenomic database. Patients with ≥ 2 documented clinic visits, ≥ 2 lines of therapy (LOT) after mCRC diagnosis, and comprehensive genomic profiling were eligible. Patient records defined by treatment-refractory LOT were allocated to the HER2-Amp or HER2 wild-type (WT) cohort on the basis of comprehensive genomic profiling. Index date was defined as the start of any treatment-refractory LOT (≥ 2 LOT; patients could contribute multiple records). Descriptive statistics included demographic and clinical characteristics, treatments, laboratory values, and biomarkers. Overall survival (OS) was calculated as time (in months) from the index date until death from any cause and analyzed using Kaplan-Meier methodology. Sensitivity analyses were conducted to test the robustness of the primary findings. RESULTS: A total of 576 patients were included (1,339 records); 63 (158 records) were HER2-Amp, and 513 (1,181 records) were HER2-WT. Demographics, clinical characteristics, biomarkers, and laboratory values were comparable between HER2 cohorts. OS was similar, with an unadjusted median OS of 11.2 months (95% CI, 8.6 to 15.1) and 9.9 months (95% CI, 8.3 to 10.9) across LOT for HER2-Amp and HER2-WT cohorts, respectively. CONCLUSION: This study showed considerable treatment heterogeneity and poor outcomes among patients with treatment-refractory mCRC, emphasizing a substantial unmet therapeutic need. Real-world data study shows considerable treatment heterogeneity and poor outcomes among patients with treatment-refractory HER2-amplified and HER2 wild-type metastatic colorectal cancer, emphasizing a substantial unmet therapeutic need. [ABSTRACT FROM AUTHOR]

Memory B cells (MBCs) can provide a recall response able to supplement waning antibodies (Abs) with an affinity-matured response better able to neutralize variant viruses. We studied a cohort of elderly care home residents and younger staff (median age of 87 years and 56 years, respectively), who had survived COVID-19 outbreaks with only mild or asymptomatic infection. The cohort was selected because of its high proportion of individuals who had lost neutralizing antibodies (nAbs), thus allowing us to specifically investigate the reserve immunity from SARS-CoV-2-specific MBCs in this setting. Class-switched spike and receptor-binding domain (RBD) tetramer-binding MBCs persisted 5 months after mild or asymptomatic SARS-CoV-2 infection, irrespective of age. The majority of spike- and RBD-specific MBCs had a classical phenotype, but we found that activated MBCs, indicating possible ongoing antigenic stimulation or inflammation, were expanded in the elderly group. Spike- and RBD-specific MBCs remained detectable in the majority of individuals who had lost nAbs, although at lower frequencies and with a reduced IgG/IgA isotype ratio. Functional spike-, S1 subunit of the spike protein- (S1-), and RBD-specific recall was also detectable by enzyme-linked immune absorbent spot (ELISPOT) assay in some individuals who had lost nAbs, but was significantly impaired in the elderly. Our findings demonstrate that a reserve of SARS-CoV-2-specific MBCs persists beyond the loss of nAbs but highlight the need for careful monitoring of functional defects in spike- and RBD-specific B cell immunity in the elderly. [ABSTRACT FROM AUTHOR]

The adoptive transfer of regulatory T-cells (Tregs) is a promising therapeutic approach in transplantation and autoimmunity. However, because large cell numbers are needed to achieve a therapeutic effect, in vitro expansion is required. By comparing their function, phenotype and transcriptomic profile against ex vivo Tregs, we demonstrate that expanded human Tregs switch their metabolism to aerobic glycolysis and show enhanced suppressive function through hypoxia-inducible factor 1-alpha (HIF1A) driven acquisition of CD73 expression. In conjunction with CD39, CD73 expression enables expanded Tregs to convert ATP to immunosuppressive adenosine. We conclude that for maximum therapeutic benefit, Treg expansion protocols should be optimised for CD39/CD73 co-expression. Jarvis et al demonstrate that expanded human Tregs switch their metabolism to aerobic glycolysis and show enhanced suppressive function through hypoxia-inducible factor 1-alpha (HIF1A)-driven acquisition of CD73 expression, which along with CD39, enables expanded Tregs to convert ATP to immunosuppressive adenosine. Given this, the data suggests that Treg expansion protocols should be optimised for CD39/CD73 co-expression to enhance therapeutic potential. [ABSTRACT FROM AUTHOR]

Urban agriculture (UA), the growing of fruits and vegetables in urban and peri-urban areas, may improve food security and access, public health and dietary quality on both a broad and personal scale. However, there is little research on the relationship between UA and diet, and potential mediating factors are also unclear. This study aimed to investigate if proximity to and engagement with UA is associated with better diet quality, and what accounts for this relationship. UK-based adults (N = 583, 69% Female) completed measures of proximity to and engagement with UA, perceived access to fruits and vegetables, health and ethical food choice motivations, connection with nature, psychological distress and dietary quality in an online survey. Participants were recruited from UA-related groups and the general public. Proposed relationships were analysed using a structural equation model. Greater proximity to and engagement with UA was associated with greater perceived access to fruits and vegetables, more health-related food choice motivations, more ethical-related food choice, feeling more connected with nature, and, surprisingly greater psychological distress. Furthermore, proximity to and engagement with UA was indirectly associated with better diet quality via health-, and ethical-related, food choice motivations. While the direct pathway between proximity to and engagement with UA and diet quality was not significant, UA is associated with better diet quality, partly via healthier and ethical food choice motivations. Upscaling UA may have benefits for dietary quality via these factors, and more research is needed to test causal relationships and understand these complex interactions. [ABSTRACT FROM AUTHOR]

Evaluating distributed soil erosion models is challenging because of the uncertainty in models and measurements of system responses. Here, we present an approach to evaluate soil erosion and sediment delivery models, which incorporates sediment source fingerprinting and sediment-rating curve uncertainty into model testing. We applied the Generalized Likelihood Uncertainty Estimation (GLUE) methodology to the Sediment Delivery Distributed model (SEDD) for a large catchment in Southeast Brazil. The model was not rejected, as 23.4% of model realizations were considered behavioral. Fingerprinting results and SEDD simulations showed a partial agreement regarding the identification of the main sediment sources in the catchment. However, grid-based estimates of soil erosion and sediment delivery rates were highly uncertain, which restricted the model's usefulness for quantifying sediment dynamics. Although our results are case-specific, similar levels of error might be expected in erosion models elsewhere. The representation of such errors should be standard practice. • GLUE was applied to an erosion and sediment delivery model. • Models were conditioned according to sediment load measurements. • Behavioral simulations were tested against sediment fingerprinting apportionments. • Forcing and testing data were highly uncertain, as well as model outputs. • Better observational data is needed to reject non-behavioral models. [ABSTRACT FROM AUTHOR]

PURPOSE: Liver metastases are associated with poor outcomes in patients with advanced non–small-cell lung cancer (aNSCLC). Nevertheless, the vasculature in the liver microenvironment may be conducive to the use of antiangiogenesis inhibitors to potentially improve outcomes. Limited real-world clinical and economic data are currently available for this patient subpopulation. METHODS: Two retrospective cohort analyses were conducted using data from an electronic health record (n = 14,209) and a claims database (n = 9,017). Patients with aNSCLC with and without liver metastases were identified in each database. Patients with baseline liver metastases in the electronic health record database were further categorized into two subgroups—those who had or had not received bevacizumab-containing regimens. Multivariable Cox proportional hazards regression models were used to adjust for baseline characteristics to evaluate the effect of treatment of bevacizumab. RESULTS: Liver metastases were associated with significantly poorer survival (median overall survival, 6.3 months v 10.1 months) and higher costs and health care resource utilization—total per-patient-per-month costs of $27,589 versus $19,607. Cost differences were primarily driven by inpatient costs, including a two-fold increase in hospitalizations and a 1.7-fold higher mean length of stay. Treatment with bevacizumab was associated with improved survival. Whereas overall survival improved in patients with and without baseline liver metastases who received bevacizumab, the relative survival benefit was greater in patients with liver metastases (hazard ratio, 0.63 [95% CI, 0.50 to 0.81] v hazard ratio, 0.80 [95% CI, 0.74 to 0.86]). CONCLUSION: Patients with aNSCLC with liver metastases have poorer survival and a higher cost and health care resource utilization burden. Bevacizumab was associated with a survival benefit in patients with aNSCLC with liver metastases. [ABSTRACT FROM AUTHOR]

This paper describes an agricultural model (Roth-CNP) that estimates carbon (C), nitrogen (N) and phosphorus (P) pools, pool changes, their balance and the nutrient fluxes exported from arable and grassland systems in the UK during 1800–2010. The Roth-CNP model was developed as part of an Integrated Model (IM) to simulate C, N and P cycling for the whole of UK, by loosely coupling terrestrial, hydrological and hydro-chemical models. The model was calibrated and tested using long term experiment (LTE) data from Broadbalk (1843) and Park Grass (1856) at Rothamsted. We estimated C, N and P balance and their fluxes exported from arable and grassland systems on a 5 km × 5 km grid across the whole of UK by using the area of arable of crops and livestock numbers in each grid and their management. The model estimated crop and grass yields, soil organic carbon (SOC) stocks and nutrient fluxes in the form of NH 4 -N, NO 3 -N and PO 4 -P. The simulated crop yields were compared to that reported by national agricultural statistics for the historical to the current period. Overall, arable land in the UK have lost SOC by −0.18, −0.25 and −0.08 Mg C ha −1 y −1 whereas land under improved grassland SOC stock has increased by 0.20, 0.47 and 0.24 Mg C ha −1 y −1 during 1800–1950, 1950–1970 and 1970–2010 simulated in this study. Simulated N loss (by leaching, runoff, soil erosion and denitrification) increased both under arable (−15, −18 and −53 kg N ha −1 y −1 ) and grass (−18, −22 and −36 kg N ha −1 y −1 ) during different time periods. Simulated P surplus increased from 2.6, 10.8 and 18.1 kg P ha −1 y −1 under arable and 2.8, 11.3 and 3.6 kg P ha −1 y −1 under grass lands 1800–1950, 1950–1970 and 1970–2010. [ABSTRACT FROM AUTHOR]

Water erosion negatively affects soil fertility, soil structure, and water availability to plants. Moreover, off-site erosion effects contribute to the sedimentation and eutrophication of water courses. The Grande River is one of the main tributaries of the Paraná River, and an important source of hydroelectric power in Brazil. The Upper Grande River Basin covers an area of 15,705 km 2 , mostly occupied by rangelands. Shallow and little permeable Cambisols are the predominant soil class in the basin, which, combined with the intensive and highly concentrated summer rainfall, characterize an erosion-prone scenario. The aim of this study was to model the soil losses and the sediment yield in the Upper Grande River Basin. It also sought to quantify the sediment delivery to the two main hydroelectric power plant reservoirs in the basin: Camargos/Itutinga and Funil. Geographical Information Systems (GIS) were used to apply the Revised Universal Soil Loss Equation (RUSLE) and the Sediment Delivery Distributed model (SEDD) in the study area. The models were calibrated using sediment transport data obtained from a river gauging station located in a subwatershed. RUSLE predictions estimated that the average soil losses in the Upper Grande River Basin were of 22.35 t ha − 1 yr − 1 , and that bare soils, eucalypt and agriculture suffered the highest erosion rates among the identified land use classes. The average specific sediment yield in the basin was of 1.93 t ha − 1 yr − 1 . According to the model calibration, the specific sediment yield predictions showed an error of 0.01 t ha − 1 yr − 1 , or 0.6%. Agriculture and eucalypt forests, which compose approximately 10% of the study area, contribute to more than 40% of the sediment yield in the basin. The model predictions estimated that 1.45 million t yr − 1 of sediments are delivered to the Camargos/Itutinga power plant reservoir, whereas the Funil power plant reservoir receives a sediment input of 1.68 million t yr − 1 . Although model calibration yielded small errors in relation to the observed sediment measurements, the relative lack of available data has impaired a more thorough validation of the employed models. Nevertheless, the results indicate that the RUSLE/SEDD approach may be useful for analyzing sediment transport in Brazilian watersheds, where limited input data is available. [ABSTRACT FROM AUTHOR]

Abstract: Proteins are chains of simple molecules called amino acids. The three-dimensional shape of a protein and its amino acid composition define its biological function. Over millions of years, living organisms have evolved a large catalog of proteins. By exploring the space of possible amino acid sequences, protein engineering aims at similarly designing tailored proteins with specific desirable properties. In Computational Protein Design (CPD), the challenge of identifying a protein that performs a given task is defined as the combinatorial optimization of a complex energy function over amino acid sequences. In this paper, we introduce the CPD problem and some of the main approaches that have been used by structural biologists to solve it, with an emphasis on the exact method embodied in the dead-end algorithm . The CPD problem is a specific form of binary Cost Function Network (CFN, aka Weighted CSP). We show how DEE algorithms can be incorporated and suitably modified to be maintained during search, at reasonable computational cost. We then evaluate the efficiency of CFN algorithms as implemented in our solver toulbar2, on a set of real CPD instances built in collaboration with structural biologists. The CPD problem can be easily reduced to 0/1 Linear Programming, 0/1 Quadratic Programming, 0/1 Quadratic Optimization, Weighted Partial MaxSAT and Graphical Model optimization problems. We compare toulbar2 with these different approaches using a variety of solvers. We observe tremendous differences in the difficulty that each approach has on these instances. Overall, the CFN approach shows the best efficiency on these problems, improving by several orders of magnitude against the exact approach. The introduction of dead-end elimination before or during search allows to further improve these results. [Copyright &y& Elsevier]

The association between lymphopenia and autoimmunity is recognized, but the underlying mechanisms are poorly understood and have not been studied systematically in humans. People with multiple sclerosis treated with the lymphocyte-depleting monoclonal antibody alemtuzumab offer a unique opportunity to study this phenomenon; one in three people develops clinical autoimmunity, and one in three people develops asymptomatic autoantibodies after treatment. Here, we show that T-cell recovery after alemtuzumab is driven by homeostatic proliferation, leading to the generation of chronically activated (CD28-CD57+), highly proliferative (Ki67+), oligoclonal, memory-like CD4 and CD8 T cells (CCR7-CD45RA- or CCR7-CD45RA+) capable of producing proinflammatory cytokines. Individuals who develop autoimmunity after treatment are no more lymphopenic than their nonautoimmune counterparts, but they show reduced thymopoiesis and generate a more restricted T-cell repertoire. Taken together, these findings demonstrate that homeostatic proliferation drives lymphopeniaassociated autoimmunity in humans. [ABSTRACT FROM AUTHOR]

The increasing pressure humans place on the land has led to the acceleration of soil erosion, to an extent where human-induced erosion of the soil is expected to outpace the production of new soil by more than an order of magnitude. Given that the thickness of the pedosphere is a first order control on soil functions, with thicker soils having a greater capacity for water, carbon and nutrient storage, the continued thinning of non-renewable soil profiles and the associated consequences on their productivity and health is arguably one of the most significant threats to soil sustainability. Despite the fact that the future long-term security of soils depends on mitigating soil erosion rates down to (and below) the rates of soil formation, our knowledge of the latter is surprisingly meagre. Recent developments in cosmogenic radionuclide analysis have catalysed greater investment in the derivation of soil formation data, and yet there still exists no isotopically-constrained study of soil formation in arable contexts. Arable soils are often the loci for accelerated erosion but in the absence of comparative soil formation data, the magnitude of the threat this accelerated erosion places on arable soils is unknown. Future policy to ensure their long-term security, and the delivery of multiple ecosystem services, demands greater work in quantifying soil formation in these contexts. Our research is the first in the world to respond to this call and here we present the first soil formation rates under arable soils. Saprolite was extracted at the soil-bedrock interface down a catena sequence at Rufford Forest Farm (Nottinghamshire, UK) and processed through cosmogenic radionuclide analysis. Further samples from a catena sequence in a woodland near Quatt (Shropshire, UK) were also processed. We will present our isotopically constrained rates with reference to the relationship between soil formation and soil depth and in the context of the worldwide soil formation rate inventory. [ABSTRACT FROM AUTHOR]