Phase II trial of domatinostat (4SC-202) in combination with avelumab in patients with previously treated advanced mismatch repair proficient oesophagogastric and colorectal adenocarcinoma: EMERGE.

BACKGROUND: Most oesophagogastric adenocarcinomas (OGAs) and colorectal cancers (CRCs) are mismatch repair proficient (MMRp), responding poorly to immune checkpoint inhibition. We evaluated the safety and efficacy of domatinostat (histone deacetylase inhibitor) plus avelumab (anti-PD-L1 antibody) in patients with previously treated inoperable, advanced/metastatic MMRp OGA and CRC. PATIENTS AND METHODS: Eligible patients were evaluated in a multicentre, open-label dose escalation/dose expansion phase II trial. In the escalation phase, patients received escalating doses of domatinostat [100 mg once daily (OD), 200 mg OD, 200 mg twice daily (BD)] orally for 14 days followed by continuous dosing plus avelumab 10 mg/kg administered intravenously 2-weekly (2qw) to determine the recommended phase II dose (RP2D). The trial expansion phase evaluated the best objective response rate (ORR) during 6 months by RECIST version 1.1 using a Simon two-stage optimal design with 2/9 and 1/10 responses required to proceed to stage 2 in the OGA and CRC cohorts, respectively. RESULTS: Patients (n = 40) were registered between February 2019 and October 2021. Patients in the dose escalation phase (n = 12) were evaluated to confirm the RP2D of domatinostat 200 mg BD plus avelumab 10 mg/kg. No dose-limiting toxicities were observed. Twenty-one patients were treated at the RP2D, 19 (9 OGA and 10 CRC) were assessable for the best ORR; 2 patients with CRC did not receive combination treatment and were not assessable for the primary endpoint analysis. Six patients were evaluated in the dose escalation and expansion phases. In the OGA cohort, the best ORR was 22.2% (95% one-sided confidence interval lower bound 4.1) and the median duration of disease control was 11.3 months (range 9.9-12.7 months). No responses were observed in the CRC cohort. No treatment-related grade 3-4 adverse events were reported at the RP2D. CONCLUSIONS: Responses in the OGA cohort met the criteria to expand to stage 2 of recruitment with an acceptable safety profile. There was insufficient signal in the CRC cohort to progress to stage 2. TRIAL REGISTRATION: NCT03812796 (registered 23rd January 2019).

Diminished criminal responsibility: A multinational comparative review.

This article reviews the legal frameworks of diminished criminal responsibility in eighteen civil law jurisdictions across the globe-Brazil, Chile, China, the Czech Republic, Finland, France, Germany, Greece, Italy, Japan, Luxembourg, Poland, Portugal, Russia, Spain, Switzerland, Taiwan, and Turkey. Specifically, it reports the legal standards and main features of partial responsibility, associated penalty reductions, and potential dispositions following a partial responsibility finding. It also surveys empirical data on the prevalence of diminished responsibility as compared to criminal nonresponsibility. This article, which reflects contemporary penal codes and draws from both English and non-English sources, is the only known existing source to compile these partial responsibility standards or to delineate their precise sentencing consequences. It is also the only known source in English to describe Portugal's and Chile's treatment of diminished responsibility. Providing a comparative overview of graduated responsibility in nearly twenty countries invites global discussion on whether and how society should recognize partial responsibility, as well as the punitive and therapeutic consequences that should attend this finding.

The structural components of the Azotobacter vinelandii iron-only nitrogenase, AnfDKG, form a protein complex within the plant mitochondrial matrix.

A long-held goal of synthetic biology has been the transfer of a bacterial nitrogen-fixation pathway into plants to reduce the use of chemical fertiliser on crops such as rice, wheat and maize. There are three classes of bacterial nitrogenase, named after their metal requirements, containing either a MoFe-, VFe- or FeFe-cofactor, that converts N2 gas to ammonia. Relative to the Mo-nitrogenase the Fe-nitrogenase is not as efficient for catalysis but has less complex genetic and metallocluster requirements, features that may be preferable for engineering into crops. Here we report the successful targeting of bacterial Fe-nitrogenase proteins, AnfD, AnfK, AnfG and AnfH, to plant mitochondria. When expressed as a single protein AnfD was mostly insoluble in plant mitochondria, but coexpression of AnfD with AnfK improved its solubility. Using affinity-based purification of mitochondrially expressed AnfK or AnfG we were able to demonstrate a strong interaction of AnfD with AnfK and a weaker interaction of AnfG with AnfDK. This work establishes that the structural components of the Fe-nitrogenase can be engineered into plant mitochondria and form a complex, which will be a requirement for function. This report outlines the first use of Fe-nitrogenase proteins within a plant as a preliminary step towards engineering an alternative nitrogenase into crops.

A survey of liver ablation amongst UK interventional radiologists.

AIM: To characterise training for, and conduct of, image-guided liver tumour ablation amongst UK interventional radiologists. MATERIALS AND METHODS: A web-based survey of British Society of Interventional Radiology members was carried out between 31 August to 1 October 2022. Twenty-eight questions were designed, covering four domains: (1) respondent background, (2) training, (3) current practice, and (4) operator technique. RESULTS: One hundred and six responses were received, with an 87% completion rate and an approximate response rate of 13% of society members. All UK regions were represented, with the majority from London (22/105, 21%). Seventy-two out of 98 (73%) were either extremely or very interested in learning about liver ablation during training, although levels of exposure varied widely, and 37/103 (36%) had no exposure. Performed numbers of cases also varied widely, between 1-10 cases and >100 cases per operator annually. All (53/53) used microwave energy, and most routinely used general anaesthesia (47/53, 89%). Most 33/53 (62%) did not have stereotactic navigation system, and 25/51(49%) always, 18/51 (35%) never, and 8/51(16%) sometimes gave contrast medium (mean 40, SD 32%) after procedures. Fusion software to judge ablation completeness was never used by 86% (43/55), sometimes used by 9% (5/55), and always used by 13% (7/55) of respondents. CONCLUSION: Although there are high levels of interest in image-guided liver ablation amongst UK interventional radiologists, training arrangements, operator experience, and procedural technique vary widely. As image-guided liver ablation evolves, there is a growing need to standardise training and techniques, and develop the evidence base to ensure high-quality oncological outcomes.

Biting the hand that feeds: Anthropogenic drivers interactively make mosquitoes thrive.

Anthropogenic stressors on the environment are increasing at unprecedented rates and include urbanization, nutrient pollution, water management, altered land use and climate change. Their effects on disease vectors are poorly understood. A series of full factorial experiments investigated how key human induced abiotic pressures, and interactions between these, affect population parameters of the cosmopolitan disease vector, Culex pipiens s.l. Selected pressures include eutrophication, salinity, mean temperature, and temperature fluctuation. Data were collected for each individual pressure and for potential interactions between eutrophication, salinization and temperature. All experiments assessed survival, time to pupation, time to emergence, sex-ratio and ovipositioning behavior. The results show that stressors affect vector survival, may speed up development and alter female to male ratio, although large differences between stressors exist to quite different extents. While positive effects of increasing levels of eutrophication on survival were consistent, negative effects of salinity on survival were only apparent at higher temperatures, thus indicating a strong interaction effect between salinization and temperature. Temperature had no independent effect on larval survival. Overall, increasing eutrophication and temperatures, and the fluctuations thereof, lowered development rate, time to pupation and time to emergence while increasing levels of salinity increased development time. Higher levels of eutrophication positively impacted egg-laying behavior; the reverse was found for salinity while no effects of temperature on egg-laying behavior were observed. Results suggest large and positive impacts of anthropogenically induced habitat alterations on mosquito population dynamics. Many of these effects are exacerbated by increasing temperatures and fluctuations therein. In a world where eutrophication and salinization are increasingly abundant, mosquitoes are likely important benefactors. Ultimately, this study illustrates the importance of including multiple and combined stressors in predictive models as well as in prevention and mitigation strategies, particularly because they resonate with possible, but yet underdeveloped action plans.

Percutaneous cryoablation for desmoid fibromatosis: initial experience at a UK centre.

AIM: To report the first UK experience of cryoablation in desmoid fibromatosis (DF) with particular focus on technique, safety, and efficacy. MATERIALS AND METHODS: Patients were selected at multidisciplinary tumour board meetings at a specialist cancer hospital. Radiation dose, procedure duration, and number of cryoprobes were compared for small versus large tumours (>10 cm long axis). Response at magnetic resonance imaging (MRI) was evaluated using different criteria, and percentage agreement with clinical response as assessed in oncology clinic calculated. RESULTS: Thirteen procedures were performed in 10 patients (eight women, median age 51 years, IQR 42-69 years) between February 2019 and August 2021. Procedures for large tumours had higher radiation dose (2,012 ± 1,012 versus 1,076 ± 519 mGy·cm, p=0.048) used more cryoprobes (13 ± 7 versus 4 ± 2, p=0.009), and were more likely to have residual unablated tumour (38 ± 37% versus 7.5 ± 10%, p=0.045). Adverse events were minor apart from one transient radial nerve palsy. Eight of 10 patients had symptomatic benefit at clinical follow-up (median 353 days, IQR 86-796 days), and three started systemic therapy mean 393 days later. All patients who had complete ablation demonstrated symptomatic response, with no instances of repeat treatment, recurrence, or need for systemic therapy during the study period. All progression occurred outside ablation zones. CONCLUSION: Cryoablation for symptomatic DF is a reproducible technique with low, transient toxicity, where one or two treatments can achieve a meaningful response. Where possible, the ablation ice ball should fully cover DF tumours.

Extreme emotional disturbance: Legal frameworks and considerations for forensic evaluation.

A significant minority of jurisdictions in the United States offer extreme emotional disturbance (EED) as a partial defense to murder. The form of this defense, as established by statute and case law, varies widely among jurisdictions. Empirical research on EED is scant with little guidance to forensic mental health professionals on how to approach and conceptualize potential EED cases. This paper addresses these issues by being the first known published work to (1) set forth a contemporary map of the varying definitions and scope of EED across the United States, (2) translate legal terminology into constructs accessible to forensic evaluators, and (3) provide legal and clinical analyses of sample EED cases to highlight key differences in the form of the defense and the admissibility of evidence between jurisdictions.

Mitogen-activated protein kinases contribute to temperature-induced cardiac remodelling in rainbow trout (Oncorhynchus mykiss).

Rainbow trout (Oncorhynchus mykiss) live in environments where water temperatures range between 4 °C and 20 °C. Laboratory studies demonstrate that cold and warm acclimations of male trout can have oppositional effects on cardiac hypertrophy and the collagen content of the heart. The cellular mechanisms behind temperature-induced cardiac remodelling are unclear, as is why this response differs between male and female fish. Studies with cultured trout cardiac fibroblasts suggests that collagen deposition is regulated, at least in part, by mitogen-activated protein kinase (MAPK) cell signalling pathways. We, therefore, hypothesized that temperature-dependent cardiac remodelling is regulated by these signalling pathways. To test this, male and female trout were acclimated to 18 °C (warm) in the summer and to 4 °C (cold) in the winter and the activation of MAPK pathways in the hearts were characterized and compared to that of control fish maintained at 12 °C. In addition, cardiac collagen content, cardiac morphology and the expression of gene transcripts for matrix metalloproteinases (MMP) -9, MMP-2, tissue inhibitor of matrix metalloproteinases and collagen 1α were characterized. p38 MAPK phosphorylation increased in the hearts of female fish with cold acclimation and the phosphorylation of extracellular signal-regulated kinase increased in the hearts of male fish with warm acclimation. However, there was no effect of thermal acclimation on cardiac morphology or collagen content in either male or female fish. These results indicate that thermal acclimation has transient and sex-specific effects on the phosphorylation of MAPKs but also how variable the response of the trout heart is to thermal acclimation.

Wastewater effluents cause microbial community shifts and change trophic status.

Widespread wastewater pollution is one of the greatest challenges threatening the sustainable management of rivers globally. Understanding microbial responses to gradients in environmental stressors, such as wastewater pollution, is crucial to identify thresholds of community change and to develop management strategies that protect ecosystem integrity. This study used multiple lines of empirical evidence, including a novel combination of microbial ecotoxicology methods in the laboratory and field to link pressure-stressor-response relationships. Specifically, community-based whole effluent toxicity (WET) testing and environmental genomics were integrated to determine real-world community interactions, shifts and functional change in response to wastewater pollution. Here we show that wastewater effluents above moderate (>10%) concentrations caused consistent significant shifts in bacterial community structure and function. These thresholds of community shifts were also linked to changes in the trophic state of receiving waters in terms of nutrient concentrations. Differences in the community responses along the effluent concentration gradient were primarily driven by two globally relevant bacterial indicator taxa, namely Malikia spp. (Burkholderiales) and hgcI_clade (Frankiales). Species replacement occurred above moderate effluent concentrations with abundances of Malikia spp. increasing, while abundances of hgcI_clade decreased. The responses of Malikia spp. and hgcI_clade matched gene patterns associated with globally important nitrogen cycling pathways, such as denitrification and nitrogen fixation, which linked the core individual taxa to putative function and ecosystem processes, rarely achieved in previous studies. This study has identified potential indicators of change in trophic status and the functional consequences of wastewater pollution. These findings have immediate implications for both the management of environmental stressors and protection of aquatic ecosystems.

Making seawalls multifunctional: The positive effects of seeded bivalves and habitat structure on species diversity and filtration rates.

The marine environment is being increasingly modified by the construction of artificial structures, the impacts of which may be mitigated through eco-engineering. To date, eco-engineering has predominantly aimed to increase biodiversity, but enhancing other ecological functions is arguably of equal importance for artificial structures. Here, we manipulated complexity through habitat structure (flat, and 2.5 cm, 5 cm deep vertical and 5 cm deep horizontal crevices) and seeding with the native oyster (Saccostrea glomerata, unseeded and seeded) on concrete tiles (0.25 m × 0.25 m) affixed to seawalls to investigate whether complexity (both orientation and depth of crevices) influences particle removal rates by suspension feeders and colonisation by different functional groups, and whether there are any ecological trade-offs between these functions. After 12 months, complex seeded tiles generally supported a greater abundance of suspension feeding taxa and had higher particle removal rates than flat tiles or unseeded tiles. The richness and diversity of taxa also increased with complexity. The effect of seeding was, however, generally weaker on tiles with complex habitat structure. However, the orientation of habitat complexity and the depth of the crevices did not influence particle removal rates or colonising taxa. Colonisation by non-native taxa was low compared to total taxa richness. We did not detect negative ecological trade-offs between increased particle removal rates and diversity and abundance of key functional groups. Our results suggest that the addition of complexity to marine artificial structures could potentially be used to enhance both biodiversity and particle removal rates. Consequently, complexity should be incorporated into future eco-engineering projects to provide a range of ecological functions in urbanised estuaries.

Authenticity and the Potability of Coconut Water - a Critical Review.

BACKGROUND: The content of the endosperm of the coconut (Cocos nucifera L.) contains "coconut water". This practically sterile liquid which is prized for its delicate, albeit labile, flavor when fresh, has had a recent dramatic increase in global demand. The organoleptic superiority of water from young coconuts means that degree of maturity at harvesting is the most influential factor in yield and composition. OBJECTIVE: To provide a guide to establishing the authenticity and the potability of samples of coconut water. METHOD: Review and evaluate the literature on the factors that determine the composition and stability of coconut water. RESULTS: Data is presented on the variances in natural composition, maturity, processing-induced compositional changes, adulterations, product recalls, classical and instrumental methods of analysis and on the available composition standards of coconut water. CONCLUSIONS: Advice is provided for official food analysts, and others, on prudent approaches as how to ascertain the authenticity and potability, or otherwise, of coconut water samples.

A novel real-world ecotoxicological dataset of pelagic microbial community responses to wastewater.

Real-world observational datasets that record and quantify pressure-stressor-response linkages between effluent discharges and natural aquatic systems are rare. With global wastewater volumes increasing at unprecedented rates, it is urgent that the present dataset is available to provide the necessary information about microbial community structure and functioning. Field studies were performed at two time-points in the Austral summer. Single-species and microbial community whole effluent toxicity (WET) testing was performed at a complete range of effluent concentrations and two salinities, with accompanying environmental data to provide new insights into nutrient and organic matter cycling, and to identify ecotoxicological tipping points. The two salinity regimes were chosen to investigate future scenarios based on a predicted salinity increase at the study site, typical of coastal regions with rising sea levels globally. Flow cytometry, amplicon sequencing of 16S and 18S rRNA genes and micro-fluidic quantitative polymerase-chain reactions (MFQPCR) were used to determine chlorophyll-a and total bacterial cell numbers and size, as well as taxonomic and functional diversity of pelagic microbial communities. This strong pilot dataset could be replicated in other regions globally and would be of high value to scientists and engineers to support the next advances in microbial ecotoxicology, environmental biomonitoring and estuarine water quality modelling.

Daily intake of non-fried potato does not affect markers of glycaemia and is associated with better diet quality compared with refined grains: a randomised, crossover study in healthy adults.

Epidemiological studies suggest that consumption of potatoes is associated with increased risk of cardiometabolic diseases. However, few clinical trials have empirically tested this. The aim of this single-blind, randomised, crossover study was to evaluate the effect of daily potato consumption, compared with refined grains, on risk factors for cardiometabolic diseases. It was hypothesised that no difference in cardiometabolic endpoints would be detected between conditions, but diet quality would improve with potato consumption. Healthy participants on self-selected diets received one potato-based side dish or one refined grain-based side dish daily, for 4 weeks, separated by a minimum 2-week break. Dishes were isoenergetic, carbohydrate-matched and prepared without excess saturated fat or Na. Participants were instructed to consume the side dish with a meal in place of carbohydrates habitually consumed. Lipids/lipoproteins, markers of glycaemic control, blood pressure, weight and pulse wave velocity were measured at baseline and condition endpoints. Diet quality was calculated, based on 24-h recalls, using the Healthy Eating Index (HEI)-2015. Fifty adults (female n 34; age 40 (sd 13) years; BMI 24·5 (sd 3·6) kg/m2) completed the present study. No between-condition differences were detected for fasting plasma glucose (-0·05 mmol/l, 95 % CI -0·14, 0·04; P = 0·15), the primary outcome or any other outcomes. Compared with refined grains, the HEI-2015 score (3·5, 95 % CI 0·6, 6·4; P = 0·01), K (547 mg, 95 % CI 331, 764, P < 0·001) and fibre (2·4 g, 95 % CI 0·6, 4·2, P = 0·01) were higher following the potato condition. Consuming non-fried potatoes resulted in higher diet quality, K and fibre intake, without adversely affecting cardiometabolic risk.

Twin-beam sub-shot-noise raster-scanning microscope.

By exploiting the quantised nature of light, we demonstrate a sub-shot-noise scanning optical transmittance microscope. Our microscope demonstrates, with micron scale resolution, a factor of improvement in precision of 1.76(9) in transmittance estimation gained per probe photon relative to the theoretical model, a shot-noise-limited source of light, in an equivalent single-pass classical version of the same experiment using the same number of photons detected with a 90% efficient detector. This would allow us to observe photosensitive samples with nearly twice the precision, without sacrificing image resolution or increasing optical power to improve signal-to-noise ratio. Our setup uses correlated twin-beams produced by parametric down-conversion, and a hybrid detection scheme comprising photon-counting-based feed-forward and a highly efficient CCD camera.

TuLIP (Tunnelled Line Intraluminal Plasty): An Alternative Technique for Salvaging Haemodialysis Catheter Patency in Fibrin Sheath Formation.

BACKGROUND: Renal patients with a tunnelled haemodialysis line are at risk of fibrin 'sheath' formation which can lead to occlusion. Dysfunctional lines are best treated by catheter exchange with a new subcutaneous tunnel; however, there is a risk of scarring, venous stenosis, potential loss of valuable access as well as the risk of infection. METHOD: We report a retrospective review of our experience using tunnelled line intraluminal plasty (TuLIP) in 11 patients over 16 months with fibrin sheath formation on pre-existing tunnelled haemodialysis catheters. RESULT: All patients responded well to treatment with median line patency post TuLIP reaching 112 days. CONCLUSION: TuLIP may have a role in extending catheter lifespan and delaying more invasive intervention.

After decades of stressor research in urban estuarine ecosystems the focus is still on single stressors: A systematic literature review and meta-analysis.

Natural systems are threatened by a variety of anthropogenic stressors and so understanding the interactive threats posed by multiple stressors is essential. In this study we focused on urban stressors that are ubiquitous to urban estuarine systems worldwide: elevated nutrients, toxic chemical contaminants, built infrastructure and non-indigenous species (NIS). We investigated structural (abundance, diversity and species richness) and functional endpoints (productivity, primary production (chlorophyll-a) and metabolism) commonly used to determine responses to these selected stressors. Through a systematic review of global literature, we found 579 studies of our selected stressors; 93% measured responses to a single stressor, with few assessing the effects of multiple stressors (7%). Structural endpoints were commonly used to measure the effects of stressors (49% of the total 579 studies). Whereas, functional endpoints were rarely assessed alone (10%) but rather in combination with structural endpoints (41%). Elevated nutrients followed by NIS were the most studied single stressors (43% and 16% of the 541 single stressor studies), while elevated nutrients and toxic contaminants were overwhelmingly the most common stressor combination (79% of the 38 multiple stressor studies); with NIS and built infrastructure representing major gaps in multi-stressor research. In the meta-analysis, structural endpoints tended to decrease, while functional endpoints increased and/or decreased in response to different types of organisms or groups. We predicted an antagonistic effect of elevated nutrients and toxic contaminants based on the opposing enriching versus toxic effects of this stressor combination. Of note, biodiversity was the only endpoint that revealed such an antagonistic response. Our results highlight the continuing paucity of multiple stressor studies and provide evidence for opposing patterns in the responses to single and interacting stressors depending on the measured endpoint. The latter is of significant consequence to understanding relevant impacts of stressors in coastal monitoring and management.

Gender and cultural bias in student evaluations: Why representation matters.

Gendered and racial inequalities persist in even the most progressive of workplaces. There is increasing evidence to suggest that all aspects of employment, from hiring to performance evaluation to promotion, are affected by gender and cultural background. In higher education, bias in performance evaluation has been posited as one of the reasons why few women make it to the upper echelons of the academic hierarchy. With unprecedented access to institution-wide student survey data from a large public university in Australia, we investigated the role of conscious or unconscious bias in terms of gender and cultural background. We found potential bias against women and teachers with non-English speaking backgrounds. Our findings suggest that bias may decrease with better representation of minority groups in the university workforce. Our findings have implications for society beyond the academy, as over 40% of the Australian population now go to university, and graduates may carry these biases with them into the workforce.

An ecological halo surrounding a large offshore artificial reef: Sediments, infauna, and fish foraging.

Artificial reefs are deployed in coastal systems to meet a range of social objectives and infrastructure requirements, such as recreational diving and fisheries enhancement. Such reefs are typically deployed on soft sediments and yet we know little of their effect on the biophysical characteristics of the surrounding benthos. This study investigated the composition of benthic infauna, sediment characteristics, and demersal fish foraging activity surrounding a large, steel, designed offshore artificial reef (OAR), measuring 12 m × 16 m x 12 m (height x length x width) and weighing approximately 42 tonnes. Using a gradient approach we established four transects with sediment sampling sites located 15, 30, 60, 120 and 240 m from the OAR. Taxon richness of infauna was lower close to the OAR (15, 30 m), and abundances of total infauna elevated at 15 m, driven largely by two families of polychaete (Onuphidae and Spionidae). Sediment characteristics (grain size, total organic carbon, metals) did not vary with distance from the OAR. Using unbaited videos we established that fish foraging activity on the soft sediments was enhanced close to the OAR (15 m), with a 5-10 fold increase in total foraging time that was largely accounted for by the activity of four benthivorous fish species (blue morwong Nemadactylus douglasii, the silver trevally Pseudocaranx georgianus, and goatfishes Upeneichthys vlamingii and U. lineatus). Fish foraging may cause changes in the composition of benthic infauna due to disturbance and selective predation. The effective benthic 'ecological halo' or 'footprint' of the OAR was 15 times the area of the actual reef. We demonstrate that a single large OAR can influence the surrounding benthic invertebrate and vertebrate communities, but that the effects are highly localised.

Combining role-play with interactive simulation to motivate informed climate action: Evidence from the World Climate simulation.

Climate change communication efforts grounded in the information deficit model have largely failed to close the gap between scientific and public understanding of the risks posed by climate change. In response, simulations have been proposed to enable people to learn for themselves about this complex and politically charged topic. Here we assess the impact of a widely-used simulation, World Climate, which combines a socially and emotionally engaging role-play with interactive exploration of climate change science through the C-ROADS climate simulation model. Participants take on the roles of delegates to the UN climate negotiations and are challenged to create an agreement that meets international climate goals. Their decisions are entered into C-ROADS, which provides immediate feedback about expected global climate impacts, enabling them to learn about climate change while experiencing the social dynamics of negotiations. We assess the impact of World Climate by analyzing pre- and post-survey results from >2,000 participants in 39 sessions in eight nations. We find statistically significant gains in three areas: (i) knowledge of climate change causes, dynamics and impacts; (ii) affective engagement including greater feelings of urgency and hope; and (iii) a desire to learn and do more about climate change. Contrary to the deficit model, gains in urgency were associated with gains in participants' desire to learn more and intent to act, while gains in climate knowledge were not. Gains were just as strong among American participants who oppose government regulation of free markets-a political ideology that has been linked to climate change denial in the US-suggesting the simulation's potential to reach across political divides. The results indicate that World Climate offers a climate change communication tool that enables people to learn and feel for themselves, which together have the potential to motivate action informed by science.