The impact of clinical genome sequencing in a global population with suspected rare genetic disease.

There is mounting evidence of the value of clinical genome sequencing (cGS) in individuals with suspected rare genetic disease (RGD), but cGS performance and impact on clinical care in a diverse population drawn from both high-income countries (HICs) and low- and middle-income countries (LMICs) has not been investigated. The iHope program, a philanthropic cGS initiative, established a network of 24 clinical sites in eight countries through which it provided cGS to individuals with signs or symptoms of an RGD and constrained access to molecular testing. A total of 1,004 individuals (median age, 6.5 years; 53.5% male) with diverse ancestral backgrounds (51.8% non-majority European) were assessed from June 2016 to September 2021. The diagnostic yield of cGS was 41.4% (416/1,004), with individuals from LMIC sites 1.7 times more likely to receive a positive test result compared to HIC sites (LMIC 56.5% [195/345] vs. HIC 33.5% [221/659], OR 2.6, 95% CI 1.9-3.4, p < 0.0001). A change in diagnostic evaluation occurred in 76.9% (514/668) of individuals. Change of management, inclusive of specialty referrals, imaging and testing, therapeutic interventions, and palliative care, was reported in 41.4% (285/694) of individuals, which increased to 69.2% (480/694) when genetic counseling and avoidance of additional testing were also included. Individuals from LMIC sites were as likely as their HIC counterparts to experience a change in diagnostic evaluation (OR 6.1, 95% CI 1.1-∞, p = 0.05) and change of management (OR 0.9, 95% CI 0.5-1.3, p = 0.49). Increased access to genomic testing may support diagnostic equity and the reduction of global health care disparities.

When resilience is not enough: 2022 extreme marine heatwave threatens climatic refugia for a habitat-forming Mediterranean octocoral.

Climate change is impacting ecosystems worldwide, and the Mediterranean Sea is no exception. Extreme climatic events, such as marine heat waves (MHWs), are increasing in frequency, extent and intensity during the last decades, which has been associated with an increase in mass mortality events for multiple species. Coralligenous assemblages, where the octocoral Paramuricea clavata lives, are strongly affected by MHWs. The Medes Islands Marine Reserve (NW Mediterranean) was considered a climate refugia for P. clavata, as their populations were showing some resilience to these changing conditions. In this study, we assessed the impacts of the MHWs that occurred between 2016 and 2022 in seven shallow populations of the octocoral P. clavata from a Mediterranean Marine Protected Area. The years that the mortality rates increased significantly were associated with the ones with strong MHWs, 2022 being the one with higher mortalities. In 2022, with 50 MHW days, the proportion of total affected colonies was almost 70%, with a proportion of the injured surface of almost 40%, reaching levels never attained in our study site since the monitoring was started. We also found spatial variability between the monitored populations. Whereas few of them showed low levels of mortality, others lost around 75% of their biomass. The significant impacts documented here raise concerns about the future of shallow P. clavata populations across the Mediterranean, suggesting that the resilience of this species may not be maintained to sustain these populations face the ongoing warming trends.

El canvi climatic està impactant els ecosistemes arreu del planeta, i el Mar Mediterrani no n'és una excepció. Els esdeveniments climàtics extrems, com ara les onades de calor marines, estan augmentant en freqüència, extensió i intensitat en les darreres dècades, i estan sent associades a un increment dels esdeveniments de mortalitat massiva de múltiples espècies. El coral·ligen, on hi viu l'octocorall Paramuricea clavata, està altament afectat per les onades de calor marines. La Reserva Marina de les Illes Medes (NO del Mediterrani) es considerava un refugi climàtic per aquesta espècie, degut a que les seves poblacions mostraven certa resiliència a les condicions canviants. En aquest estudi hem avaluat els impactes de les onades de calor marines succeïdes entre els anys 2016 i 2022 a set poblacions someres de l'octocorall P. clavata, en una Àrea Marina Protegida del Mediterrani. Els anys en els quals les taxes de mortalitat van incrementar significativament s'associen amb els anys amb fortes onades de calor marines, sent el 2022 l'any amb la mortalitat més elevada. Al 2022, amb 50 dies d'onada de calor, la proporció total de colònies afectades va ser prop del 70%, amb un percentatge de superfície afectada de gairebé el 40%, arribant a valors mai observats en el lloc d'estudi des de que es va iniciar el seguiment d'aquestes poblacions. També hem observat variabilitat espacial entre les poblacions mostrejades. Mentre que algunes d'elles han mostrat poca mortalitat, altres han perdut al voltant del 75% de la seva biomassa. Els impactes documentats en aquest estudi mostren un futur preocupant de les poblacions someres de P. clavata arreu del Mediterrani, i això suggereix que la resiliència d'aquesta espècie podria no ser suficient per mantenir les seves poblacions en l'escenari d'escalfament que es preveu.

The importance of equity in payments to encourage coexistence with large mammals.

Large mammals often impose significant costs such as livestock depredation or crop foraging on rural communities, and this can lead to the retaliatory killing of threatened wildlife populations. One conservation approach-payments to encourage coexistence (PEC)-aims to reduce these costs through financial mechanisms, such as compensation, insurance, revenue sharing, and conservation performance payments. Little is known about the equitability of PEC, however, despite its moral and instrumental importance, prevalence as a conservation approach, and the fact that other financial tools for conservation are often inequitable. We used examples from the literature to examine the capability of PEC-as currently perceived and implemented-to be inequitable. We recommend improving the equitability of current and future schemes through the cooperative design of schemes that promote compensatory equity and greater consideration of conservation performance payments and by changing the international model for funding PEC to reduce global coexistence inequalities. New and existing programs must address issues of equitability across scales to ensure that conservation efforts are not undermined by diminished social legitimacy.

Importancia de la equidad de pago para alentar la coexistencia con mamíferos mayores Resumen Con frecuencia, los grandes mamíferos acarrean costes importantes para las comunidades rurales, como resultado de la depredación del ganado o por daños a cultivos, lo que puede derivar en la caza de cierta fauna amenazada como represalia. Una de las posibles estrategias para la protección de esta fauna-los llamados 'pagos para alentar la coexistencia' (PEC por sus siglas en inglés)-busca reducir estos costes a través de mecanismos financieros como los seguros de compensación, el reparto de ingresos y el 'pago por resultados'. Actualmente se conoce muy poco sobre aspectos relacionados con la equidad en relación a los PECs, a pesar de la importancia moral e instrumental de este asunto, y de la prevalencia de estos instrumentos, especialmente considerando que otras herramientas financieras para la conservación suelen no ser equitativas. En este artículo usamos ejemplos de la literatura para examinar la (in)equidad potencial de los PECs - de acuerdo a como están siendo percibidos e implementados actualmente. En las conclusiones, recomendamos que los programas actuales y futuros sean mejorados mediante diseños cooperativos que promuevan la equidad compensatoria y una mayor consideración del pago por resultados de conservación. Así mismo, debe cambiarse modelo internacional de financiamiento de los PECs para reducir las desigualdades globales en cuanto a la coexistencia con grandes mamíferos. Tanto los programas nuevos como los ya existentes deben abordar los temas de equidad a todas las escalas para asegurar que los esfuerzos de conservación no se vean perjudicados por una legitimidad social disminuida.

Marine heatwaves drive recurrent mass mortalities in the Mediterranean Sea.

Climate change is causing an increase in the frequency and intensity of marine heatwaves (MHWs) and mass mortality events (MMEs) of marine organisms are one of their main ecological impacts. Here, we show that during the 2015-2019 period, the Mediterranean Sea has experienced exceptional thermal conditions resulting in the onset of five consecutive years of widespread MMEs across the basin. These MMEs affected thousands of kilometers of coastline from the surface to 45 m, across a range of marine habitats and taxa (50 taxa across 8 phyla). Significant relationships were found between the incidence of MMEs and the heat exposure associated with MHWs observed both at the surface and across depths. Our findings reveal that the Mediterranean Sea is experiencing an acceleration of the ecological impacts of MHWs which poses an unprecedented threat to its ecosystems' health and functioning. Overall, we show that increasing the resolution of empirical observation is critical to enhancing our ability to more effectively understand and manage the consequences of climate change.

How do information flows affect impact from environmental research? - An analysis of a science-policy network.

Evidence of the impact arising from environmental research is increasingly demanded. Exchanges between science providers and actors that use scientific knowledge to address environmental problems are recognized as a key component of the mechanisms through which impact occurs. Yet, the role of interactions between science and policy actors in delivering and shaping research impact is not well established. We aim to better understand how transfer of science in a science-policy network generates impact. Our approach relies on an exploratory social network analysis (SNA), applied to a network of organisations working on land and water management in a catchment in the UK. We analyse flows of scientific information across these organisations and how those contribute to impact, which we conceptualized as change in organisations at three levels: increased awareness, operational change and strategic change. We find that organisations occupying central positions in the network facilitate the transfer of science and influence the level of change achieved. We also find that the effectiveness of the flows of information and impact delivery depends on boundary organisations, in particular public regulatory bodies, that connect agents with others. Moreover, intended change reported by science providers does not often transform directly into change as reported by the receivers of the information. We conclude that both exchanges between researchers and research users and the role of boundary organisations are key to impact delivery and making change possible. This is valuable for understanding where improvements to information flows between organisations might enhance impact.

Are stakeholders ready to transform phosphorus use in food systems? A transdisciplinary study in a livestock intensive system.

Food systems worldwide are vulnerable to Phosphorus (P) supply disruptions and price fluctuations. Current P use is also highly inefficient, generating large surpluses and pollution. Global food security and aquatic ecosystems are in jeopardy if transformative action is not taken. This paper pivots from earlier (predominantly conceptual) work to develop and analyse a P transdisciplinary scenario process, assessing stakeholders potential for transformative thinking in P use in the food system. Northern Ireland, a highly livestock-intensive system, was used as case study for illustrating such process. The stakeholder engagement takes a normative stance in that it sets the explicit premise that the food system needs to be transformed and asks stakeholders to engage in a dialogue on how that transformation can be achieved. A Substance Flow Analysis of P flows and stocks was employed to construct visions for alternative futures and stimulate stakeholder discussions on system responses. These were analysed for their transformative potential using a triple-loop social learning framework. For the most part, stakeholder responses remained transitional or incremental, rather than being fundamentally transformative. The process did unveil some deeper levers that could be acted upon to move the system further along the spectrum of transformational change (e.g. changes in food markets, creation of new P markets, destocking, new types of land production and radical land use changes), providing clues of what an aspirational system could look like. Replicated and adapted elsewhere, this process can serve as diagnostics of current stakeholders thinking and potential, as well as for the identification of those deeper levers, opening up avenues to work upon for global scale transformation.

Do awareness-focussed approaches to mitigating diffuse pollution work? A case study using behavioural and water quality evidence.

Efforts to tackle diffuse water pollution from agriculture are increasingly focusing on improving farmers' awareness under the expectation that this would contribute to adoption of best management practices (BMPs) and, in turn, result in water quality improvements. To date, however, no study has explored the full awareness-behaviour-water quality pathway; with previous studies having mostly addressed the awareness-behaviour link relying on disciplinary approaches. Using an interdisciplinary approach, we investigate whether awareness-focussed approaches to mitigating diffuse water pollution from agriculture indeed result in water quality improvement, addressing the pathway in full. We worked with Dwr Cymru Welsh Water (a water and waste utility company in the UK) on a pesticide pollution intervention programme, referred to as "weed wiper trial". The main goal of the trial was to raise farmers' awareness regarding pesticide management practices and to promote uptake of BMPs to tackle the rising concentrations of the pesticide MCPA (2-methyl-4-chlorophenoxyacetic acid) in raw water in three catchments in Wales. Using factorial analysis of variance, we analysed MCPA concentrations from 2006 to 2019 in the three targeted catchments and in three control catchments. This was followed by semi-structured in-depth interviews with institutional stakeholders and farmers with varying degrees of exposure to the weed wiper trial. Results show that MCPA concentration for both targeted and control catchments had reduced after the implementation of the weed wiper trial. However, the decline was significantly larger (F(1) = 6.551, p < 0.05, n = 3077, Partial eta-squared (ηp2) = 0.002) for the targeted catchments (mean = 45.2%) compared to the control catchments (mean = 10.9%). Results from the stakeholder interviews indicate that improved awareness contributed to changes in farmers' behaviour and that these can be related to the water quality improvements reflected by the decline in MCPA concentration. Alongside awareness, other psychosocial, economic, agronomic factors, catchment and weather conditions also influenced farmer's ability to implement BMPs and thus overall water quality improvements.

Five pillars for stakeholder analyses in sustainability transformations: The global case of phosphorus.

Phosphorus is a critical agricultural nutrient and a major pollutant in waterbodies due to inefficient use. In the form of rock phosphate it is a finite global commodity vulnerable to price shocks and sourcing challenges. Transforming toward sustainable phosphorus management involves local to global stakeholders. Conventional readings of stakeholders may not reflect system complexity leaving it difficult to see stakeholder roles in transformations. We attempt to remedy this issue with a novel stakeholder analysis method based on five qualitative pillars: stakeholder agency, system roles, power and influence, alignment to the problem, and transformational potential. We argue that our approach suits case studies of individual stakeholders, stakeholder groups, and organisations with relationships to sustainability challenges.

Integrated cost-effectiveness analysis of agri-environmental measures for water quality.

This paper presents an application of integrated methodological approach for identifying cost-effective combinations of agri-environmental measures to achieve water quality targets. The methodological approach involves linking hydro-chemical modelling with economic costs of mitigation measures. The utility of the approach was explored for the River Dee catchment in North East Scotland, examining the cost-effectiveness of mitigation measures for nitrogen (N) and phosphorus (P) pollutants. In-stream nitrate concentration was modelled using the STREAM-N and phosphorus using INCA-P model. Both models were first run for baseline conditions and then their effectiveness for changes in land management was simulated. Costs were based on farm income foregone, capital and operational expenditures. The costs and effects data were integrated using 'Risk Solver Platform' optimization in excel to produce the most cost-effective combination of measures by which target nutrient reductions could be attained at a minimum economic cost. The analysis identified different combination of measures as most cost-effective for the two pollutants. An important aspect of this paper is integration of model-based effectiveness estimates with economic cost of measures for cost-effectiveness analysis of land and water management options. The methodological approach developed is not limited to the two pollutants and the selected agri-environmental measures considered in the paper; the approach can be adapted to the cost-effectiveness analysis of any catchment-scale environmental management options.

Estimating the heating of complex nanoparticle aggregates for magnetic hyperthermia.

Understanding and predicting the heat released by magnetic nanoparticles is central to magnetic hyperthermia treatment planning. In most cases, nanoparticles form aggregates when injected in living tissues, thereby altering their response to the applied alternating magnetic field and preventing the accurate prediction of the released heat. We performed a computational analysis to investigate the heat released by nanoparticle aggregates featuring different sizes and fractal geometry factors. By digitally mirroring aggregates seen in biological tissues, we found that the average heat released per particle stabilizes starting from moderately small aggregates, thereby facilitating making estimates for their larger counterparts. Additionally, we studied the heating performance of particle aggregates over a wide range of fractal parameters. We compared this result with the heat released by non-interacting nanoparticles to quantify the reduction of heating power after being instilled into tissues. This set of results can be used to estimate the expected heating in vivo based on the experimentally determined nanoparticle properties.

Oxidative Machinery of basidiomycetes as potential enhancers in lignocellulosic biorefineries: A lytic polysaccharide monooxygenases approach.

Basidiomycetes are renowned as highly effective decomposers of plant materials, due to their extensive array of oxidative enzymes, which enable them to efficiently break down complex lignocellulosic biomass structures. Among the oxidative machinery of industrially relevant basidiomycetes, the role of lytic polysaccharide monooxygenases (LPMO) in lignocellulosic biomass deconstruction is highlighted. So far, only a limited number of basidiomycetes LPMOs have been identified and heterologously expressed. These LPMOs have presented activity on cellulose and hemicellulose, as well as participation in the deconstruction of lignin. Expanding on this, the current review proposes both enzymatic and non-enzymatic mechanisms of LPMOs for biomass conversion, considering the significance of the Carbohydrate-Binding Modules and other C-terminal regions domains associated with their structure, which is involved in the deconstruction of lignocellulosic biomass.

A blood biomarker test for brain amyloid impacts the clinical evaluation of cognitive impairment.

OBJECTIVE: The objective of this study was to examine clinicians' patient selection and result interpretation of a clinically validated mass spectrometry test measuring amyloid beta and ApoE blood biomarkers combined with patient age (PrecivityAD® blood test) in symptomatic patients evaluated for Alzheimer's disease (AD) or other causes of cognitive decline. METHODS: The Quality Improvement and Clinical Utility PrecivityAD Clinician Survey (QUIP I, ClinicalTrials.gov Identifier: NCT05477056) was a prospective, single-arm cohort study among 366 patients evaluated by neurologists and other cognitive specialists. Participants underwent blood biomarker testing and received an amyloid probability score (APS), indicating the likelihood of a positive result on an amyloid positron emission tomography (PET) scan. The primary study outcomes were appropriateness of patient selection as well as result interpretation associated with PrecivityAD blood testing. RESULTS: A 95% (347/366) concordance rate was noted between clinicians' patient selection and the test's intended use criteria. In the final analysis including these 347 patients (median age 75 years, 56% women), prespecified test result categories incorporated 133 (38%) low APS, 162 (47%) high APS, and 52 (15%) intermediate APS patients. Clinicians' pretest and posttest AD diagnosis probability changed from 58% to 23% in low APS patients and 71% to 89% in high APS patients (p < 0.0001). Anti-AD drug therapy decreased by 46% in low APS patients (p < 0.0001) and increased by 57% in high APS patients (p < 0.0001). INTERPRETATION: These findings demonstrate the clinical utility of the PrecivityAD blood test in clinical care and may have added relevance as new AD therapies are introduced.

Application of a value-based equivalency method to assess environmental damage compensation under the European Environmental Liability Directive.

The Environmental Liability Directive (ELD) establishes a framework of liability based on the 'polluter-pays' principle to prevent and remedy environmental damage. The ELD requires the testing of appropriate equivalency methods to assess the scale of compensatory measures needed to offset damage. The aim of this paper is to contribute to fill the existing knowledge gap on the application of the value equivalency approach for damage compensation in this context. We analyze the toxic spill damaging the Doñana National Park (Spain) in 1998. The welfare losses associated with the resource damage are estimated using non-market valuation and compared to the value of the compensatory measures taken after the accident. Our results show that the in-kind compensation may have been insufficient to offset the welfare losses. We conclude that a more comprehensive knowledge of the human welfare effects caused by environmental damage is of substantial importance to determine compensatory remediation, as insufficient information in this respect can lead to erroneous decisions causing loss to society.

Individual particle heating of interacting magnetic nanoparticles at nonzero temperature.

Interaction phenomena have become a hot topic in nanotechnology due to their influence on the performance of magnetic nanostructures for biomedical applications. Hysteresis loops give a good account of the particles' magnetic behaviour, providing valuable clues on subsequent improvements. Nevertheless, the individual hysteresis loops of these systems are also influenced by any potential energy exchanged between the particles, and in contrast to non-interacting particles, are no longer a good measure for the local heat generated by each particle. As of today, there is no method capable of analysing the heat dissipation resulting from the nanoscale magnetisation dynamics in its full generality, i.e. in the presence of interactions and at nonzero temperature (allowing for thermally induced switching), and therefore the means of exploiting these dynamics remain hampered by a lack of understanding. In this work we address this problem by proposing and validating an equation that can be used to resolve the individual heat dissipation of interacting nanoparticles at nonzero temperature. After assessing this equation for different model systems, we have found that the proportion of heat dissipated in each individual particle tends to become more uniformly distributed for larger fields. Our results might have implications for magnetic particle hyperthermia where one of the most long-standing challenges is to achieve a homogeneous therapeutic temperature distribution in the target region during a treatment. Although tackling this issue involves a number of aspects related to the tissues involved, the injected nanoparticles, and the applied magnetic field, we believe that a more homogeneous heating of the particles inside the tumour will help to overcome this challenge.

Tunable blood oxygenation in the vascular anatomy of a semi-anthropomorphic photoacoustic breast phantom.

SIGNIFICANCE: Recovering accurate oxygenation estimations in the breast with quantitative photoacoustic tomography (QPAT) is not straightforward. Accurate light fluence models are required, but the unknown ground truth of the breast makes it difficult to validate them. Phantoms are often used for the validation, but most reported phantoms have a simple architecture. Fluence models developed in these simplistic objects are not accurate for application on the complex tissues of the breast. AIM: We present a sophisticated breast phantom platform for photoacoustic (PA) and ultrasound (US) imaging in general, and specifically for QPAT. The breast phantom is semi-anthropomorphic in distribution of optical and acoustic properties and contains wall-less channels with blood. APPROACH: 3D printing approaches are used to develop the solid 3D breast phantom from custom polyvinyl chloride plastisol formulations and additives for replicating the tissue optical and acoustic properties. A flow circuit was developed to flush the channels with bovine blood with a controlled oxygen saturation level. To showcase the phantom's functionality, PA measurements were performed on the phantom with two oxygenation levels. Image reconstructions with and without fluence compensation from Monte Carlo simulations were analyzed for the accuracy of oxygen saturation estimations. RESULTS: We present design aspects of the phantom, demonstrate how it is developed, and present its breast-like appearance in PA and US imaging. The oxygen saturations were estimated in two regions of interest with and without using the fluence models. The fluence compensation positively influenced the SO2 estimations in all cases and confirmed that highly accurate fluence models are required to minimize estimation errors. CONCLUSIONS: This phantom allows studies to be performed in PA in carefully controlled laboratory settings to validate approaches to recover both qualitative and quantitative features sought after in in-vivo studies. We believe that testing with phantoms of this complexity can streamline the transition of new PA technologies from the laboratory to studies in the clinic.

Effect of Whole-Genome Sequencing on the Clinical Management of Acutely Ill Infants With Suspected Genetic Disease: A Randomized Clinical Trial.

Importance: Whole-genome sequencing (WGS) shows promise as a first-line genetic test for acutely ill infants, but widespread adoption and implementation requires evidence of an effect on clinical management. Objective: To determine the effect of WGS on clinical management in a racially and ethnically diverse and geographically distributed population of acutely ill infants in the US. Design, Setting, and Participants: This randomized, time-delayed clinical trial enrolled participants from September 11, 2017, to April 30, 2019, with an observation period extending to July 2, 2019. The study was conducted at 5 US academic medical centers and affiliated children's hospitals. Participants included infants aged between 0 and 120 days who were admitted to an intensive care unit with a suspected genetic disease. Data were analyzed from January 14 to August 20, 2020. Interventions: Patients were randomized to receive clinical WGS results 15 days (early) or 60 days (delayed) after enrollment, with the observation period extending to 90 days. Usual care was continued throughout the study. Main Outcomes and Measures: The main outcome was the difference in the proportion of infants in the early and delayed groups who received a change of management (COM) 60 days after enrollment. Additional outcome measures included WGS diagnostic efficacy, within-group COM at 90 days, length of hospital stay, and mortality. Results: A total of 354 infants were randomized to the early (n = 176) or delayed (n = 178) arms. The mean participant age was 15 days (IQR, 7-32 days); 201 participants (56.8%) were boys; 19 (5.4%) were Asian; 47 (13.3%) were Black; 250 (70.6%) were White; and 38 (10.7%) were of other race. At 60 days, twice as many infants in the early group vs the delayed group received a COM (34 of 161 [21.1%; 95% CI, 15.1%-28.2%] vs 17 of 165 [10.3%; 95% CI, 6.1%-16.0%]; P = .009; odds ratio, 2.3; 95% CI, 1.22-4.32) and a molecular diagnosis (55 of 176 [31.0%; 95% CI, 24.5%-38.7%] vs 27 of 178 [15.0%; 95% CI, 10.2%-21.3%]; P < .001). At 90 days, the delayed group showed a doubling of COM (to 45 of 161 [28.0%; 95% CI, 21.2%-35.6%]) and diagnostic efficacy (to 56 of 178 [31.0%; 95% CI, 24.7%-38.8%]). The most frequent COMs across the observation window were subspecialty referrals (39 of 354; 11%), surgery or other invasive procedures (17 of 354; 4%), condition-specific medications (9 of 354; 2%), or other supportive alterations in medication (12 of 354; 3%). No differences in length of stay or survival were observed. Conclusions and Relevance: In this randomized clinical trial, for acutely ill infants in an intensive care unit, introduction of WGS was associated with a significant increase in focused clinical management compared with usual care. Access to first-line WGS may reduce health care disparities by enabling diagnostic equity. These data support WGS adoption and implementation in this population. Trail Registration: ClinicalTrials.gov Identifier: NCT03290469.

Towards resolving the phosphorus chaos created by food systems.

The chaotic distribution and dispersal of phosphorus (P) used in food systems (defined here as disorderly disruptions to the P cycle) is harming our environment beyond acceptable limits. An analysis of P stores and flows across Europe in 2005 showed that high fertiliser P inputs relative to productive outputs was driving low system P efficiency (38 % overall). Regional P imbalance (P surplus) and system P losses were highly correlated to total system P inputs and animal densities, causing unnecessary P accumulation in soils and rivers. Reducing regional P surpluses to zero increased system P efficiency (+ 16 %) and decreased total P losses by 35 %, but required a reduction in system P inputs of ca. 40 %, largely as fertiliser. We discuss transdisciplinary and transformative solutions that tackle the P chaos by collective stakeholder actions across the entire food value chain. Lowering system P demand and better regional governance of P resources appear necessary for more efficient and sustainable food systems.