Genome-Wide Association Study Identifies the First Germline Genetic Variant Associated With Erdheim-Chester Disease.

OBJECTIVE: Erdheim-Chester disease (ECD) is rare histiocytosis with a wide range of clinical manifestations. Somatic mutations are key to the pathogenesis of the disease; however, the relationship between germline genetic variants and ECD has not been examined so far. The present study aims to explore the inherited genetic component of ECD by performing the first genome-wide association study. METHODS: After quality controls, a cohort of 255 patients with ECD and 7,471 healthy donors was included in this study. Afterward, a logistic regression followed by in silico functional annotation was performed. RESULTS: A signal at the 18q12.3 genomic region was identified as a new susceptibility locus for ECD (P = 2.75 × 10-11 ; Odds Ratio = 2.09). This association was annotated to the SETBP1 gene, which is involved in clonal haematopoiesis. Functional annotation of this region and of the identified suggestive signals revealed additional genes that could be potentially involved in the pathogenesis of the disease. CONCLUSION: Overall, this work demonstrates that germline genetic variants can impact on the development of ECD and suggests new pathways with a potential pathogenic role.

Risk factors associated with development of colitis in horses post-exploratory laparotomy.

BACKGROUND: Diagnosis of colitis has been shown to impact morbidity and mortality in hospitalised horses. There are no studies to date that describe the incidence of infectious colitis after exploratory laparotomy. OBJECTIVES: To investigate risk factors associated with the development of colitis and infectious colitis post-exploratory laparotomy. STUDY DESIGN: Retrospective case-control. METHODS: Medical records of equids admitted from 2011 to 2020 were reviewed. The primary outcome was a diagnosis of colitis following exploratory laparotomy. Bivariable associations between colitis and risk factors were assessed using the 2-sample t-test and Fisher's exact test. All risk factors were subjected to a backward elimination variable reduction algorithm within a logistic regression framework (p-value set to 0.05). Odds ratios and 95% confidence intervals were computed for the final model. RESULTS: A total of 504 equids were included in the study. Forty-two patients (8.3%) were diagnosed with postoperative colitis. Five patients were diagnosed with Salmonella spp. and two with Clostridioides difficile. The odds of postoperative colitis were higher among patients that had pelvic flexure enterotomy (OR = 3.7, 95% CI = 1.7-7.9, p = 0.001), postoperative leukopenia or leukocytosis (OR = 21.2, 95% CI = 9.7-46.7, p < 0.001), or plasma lactate 2.0-4.0 mmol/L (OR = 3.0, 95% CI = 1.3-6.7, p < 0.008). Patients diagnosed with colitis had a longer median length of hospitalisation (9 days; range 2-21) compared with patients without colitis (7 days; range 2-25). Patients with colitis had a survival to discharge rate similar to patients without colitis (95% compared to 93%). MAIN LIMITATIONS: Risk factors for infectious colitis could not be determined due to variation in testing protocols in this retrospective study and the low number of positive cases. CONCLUSIONS: Colitis as a postoperative complication does not negatively impact survival to discharge but is associated with longer hospitalisation. Pelvic flexure enterotomy, postoperative leukopenia or leukocytosis, and increased plasma lactate were identified as significant risk factors associated with colitis.

INTRODUCTION/CONTEXTE: Il a été démontré qu'un diagnostic de colite a un impact sur la morbidité et la mortalité des chevaux hospitalisés. Il n'y a aucune étude décrivant l'incidence de colites infectieuses suivant une laparotomie exploratrice. OBJECTIFS: Investiguer les facteurs de risque associés au développement de colites et de colites infectieuses en période post-opératoire suivant une laparotomie exploratrice. TYPE D'ÉTUDE: Étude de type rétrospective avec cas témoins. MÉTHODES: Les dossiers médicaux de chevaux admis entre 2011 et 2020 ont été utilisés. La résultante primaire était un diagnostic de colite suivant une laparotomie exploratrice. Les analyses bivariées entre colites et facteurs de risque ont été évalués par le biais d'un test de Fisher exact et un test de T à deux échantillons. Tous les facteurs de risque ont été sujet à un algorithme de réduction par élimination régressive des variables dans le cadre d'une régression logistique (valeur de p à 0.05). Les probabilités (odds ratio) et les intervalles de confiance à 95% ont été inclus dans le modèle final. RÉSULTATS: Au total, 504 chevaux ont été inclus dans l'étude. Quarante-deux patients (8.3%) ont reçu un diagnostic de colite post-opératoire. Cinq patients ont reçu un diagnostic de Salmonella spp. et deux, de Clostridioides difficile. Les chances de colites post-opératoires étaient plus élevées chez les patients ayant subi une entérotomie de la courbure pelvienne (OR = 3.7, 95% CI = 1.7-7.9, p = 0.0008), ayant souffert d'une leucopénie ou leucocytose (OR = 21.2, 95% CI = 9.7-46.7, p < 0.0001), ou ayant eu une valeur de lactate plasmatique de 2.0-4.0 mmol/L (OR = 3.0, 95% CI = 1.3-6.7, p < 0.0084). Les patients diagnostiqués avec une colite ont eu une durée d'hospitalisation médiane supérieure (9 jours; étendu 2-21) comparativement aux patients sans colite (7 jours; étendu 2-25). Il n'y avait pas de différence entre les patients avec et ceux sans colite, en ce qui a trait au taux de survie de congé hospitalier (95% comparé à 93%). LIMITES PRINCIPALES: Les facteurs de risque pour les colites infectieuses n'ont pas pu être identifié en raison de variations des protocoles de tests employés dans cette étude rétrospective et du faible nombre de cas positifs. CONCLUSIONS: Les colites en tant que complication post-opératoire n'ont pas d'impact négatif sur le taux de survie hospitaliser mais sont associées à une période d'hospitalisation de plus longue durée. Une entérotomie de la courbure pelvienne, une leucopénie ou leucocytose post-opératoire et une valeur élevée de plasma sanguin ont été identifiés comme facteurs de risque associés au développement de colite.

Model ensembles of ecosystem services fill global certainty and capacity gaps.

Sustaining ecosystem services (ES) critical to human well-being is hindered by many practitioners lacking access to ES models ("the capacity gap") or knowledge of the accuracy of available models ("the certainty gap"), especially in the world's poorer regions. We developed ensembles of multiple models at an unprecedented global scale for five ES of high policy relevance. Ensembles were 2 to 14% more accurate than individual models. Ensemble accuracy was not correlated with proxies for research capacity, indicating that accuracy is distributed equitably across the globe and that countries less able to research ES suffer no accuracy penalty. By making these ES ensembles and associated accuracy estimates freely available, we provide globally consistent ES information that can support policy and decision-making in regions with low data availability or low capacity for implementing complex ES models. Thus, we hope to reduce the capacity and certainty gaps impeding local- to global-scale movement toward ES sustainability.

Role of dry watercourses of an arid watershed in carbon and nitrogen processing along an agricultural impact gradient.

In the Mediterranean arid region such as Southeast (SE) Spain, a considerable part of the fluvial network runs permanently dry. Here, many dry watercourses are embedded in catchments where agriculture has brought changes in carbon (C) and nitrogen (N) availability due to native riparian vegetation removal and the establishment of intensive agriculture. Despite their increasing scientific recognition and vulnerability, our knowledge about dry riverbeds biogeochemistry and environmental drivers is still limited, moreover for developing proper management plans at the whole catchment scale. We examined CO2 and N2O emissions in five riverbeds in SE Spain of variable agricultural impact under dry and simulated rewetted conditions. Sediment denitrifying capacity upon rewetting was also assessed. We found that, regardless of agricultural impact, all riverbeds can emit CO2 under dry and wet conditions. Emissions of N2O were only observed in our study when a long-term rewetting driving saturated sediments was conducted. Besides, most biogeochemical capabilities were enhanced in summer, reflecting the sensitiveness of microbial activity to temperature. Biogeochemical processing variation across rivers appeared to be more controlled by availability of sediment organic C, rather than by agriculturally derived nitrate. We found that the studied dry riverbeds, agriculturally affected or not, may be active sources of CO2 and contribute to transitory N2O emissions during rewetting phenomena, potentially through denitrification. We propose that management plans aiming to support ecosystem biogeochemistry through organic C from native vegetation rather than agricultural exudates would help to reduce anthropogenic greenhouse gases emissions and excess of nutrients in the watershed and to control the nitrate inputs to coastal ecosystems.

FLT3 functional low-frequency variant rs76428106-C is associated with susceptibility to systemic sclerosis.

OBJECTIVES: rs76428106-C, a low frequency polymorphism that affects the splicing of the FLT3 gene, has recently been associated with several seropositive autoimmune diseases. Here, we aimed to evaluate the potential implication of rs76428106-C in the susceptibility to systemic sclerosis (SSc). METHODS: We analysed a total of 26 598 European ancestry individuals, 9063 SSc and 17 535 healthy controls, to test the association between FLT3 rs76428106-C and SSc and its different subphenotypes. Genotype data of rs76428106 were obtained by imputation of already available genome-wide association study data and analysed by logistic regression analysis. RESULTS: In accordance with that observed in other autoimmune disorders, the FLT3 rs76428106-C allele was significantly increased [P-value = 2.03 × 10-3, odds ratio (OR) = 1.34] in SSc patients compared with healthy controls. A similar risk effect was found when the main SSc clinical and serological subgroups were compared with controls. When comparing SSc patients with and without digital ulcers (DU), the rs76428106-C frequency was significantly increased in DU-positive SSc patients in comparison with DU-negative patients (P-value = 0.036, OR = 2.16). CONCLUSION: This study is the first to report an association between rs76428176-C and SSc. Our results support the role of FLT3 as a relevant gene in seropositive immune-mediated diseases and a potential biomarker for SSc microangiopathy.

Online Databases of Genome Editing in Cardiovascular and Metabolic Diseases.

Metabolic and cardiovascular diseases are world-concerning pathologies that affect an important percentage of the population. Nowadays, advances in the genetic background of these diseases allow new approaches to models and therapies, as well as different gene edition trials. Furthermore, technological improvements in gene editing go along with the development of new online and biocomputational tools that provide us alternative ways to explore pathologies. In this chapter, historical gene editing methods are discussed but focusing on CRISPR-Cas system in detail and also online resources available to perform these types of experiments. Here, the different strategies for gene editing and their online tools are gathered, putting the light on its application in the study and treatment of cardiovascular and metabolic diseases.

Incisional complications after skin closure with n-butyl cyanoacrylate or stainless-steel skin staples in horses undergoing colic surgery.

OBJECTIVE: To compare the prevalence of incisional complications after skin closure with n-butyl cyanoacrylate (NBC) or stainless-steel skin staples (SS) after ventral midline celiotomy for colic surgery in the horse. STUDY DESIGN: Retrospective study (2014-2018). ANIMALS: Two hundred eighteen horses. METHODS: Medical records of horses that underwent exploratory celiotomy for colic were included when the skin was closed with NBC or SS and the horse survived ≥15 days after surgery. Records and a follow-up questionnaire were used to determine in-hospital and posthospital discharge incisional complications. Associations between variables were assessed by using bivariable and multivariable analysis. RESULTS: The cutaneous incision was closed with SS in 113 of 218 (51.8%) horses and with NBC in 105 of 218 (48.2%) horses. Follow-up information was available in 166 of 218 horses. Five horses with incisional complications prior to discharge but without follow-up were included in the overall analysis. Incisional complications were recorded in 17.5% (30/171) of horses, including 19.1% (17/89) of closures with SS and 15.9% (12/82) of closures with NBC (P = .54). Complications occurred before discharge in 14 of 218 (6.4%) horses and after discharge in 16 of 166 (9.6%) horses. Four horses with in-hospital incisional complications (surgical site infection) developed a second complication after discharge (hernia). Packed cell volume was a risk factor for in-hospital incisional complications (P = .04), and in-hospital incisional complications were associated with posthospital discharge incisional complications (P = .01). CONCLUSION: Occurrence of incisional complications did not differ between NBC and SS. CLINICAL SIGNIFICANCE: N-butyl cyanoacrylate is a suitable alternative to SS to close the cutaneous incision for ventral midline celiotomy for colic surgery in the horse.

Ensembles of ecosystem service models can improve accuracy and indicate uncertainty.

Many ecosystem services (ES) models exist to support sustainable development decisions. However, most ES studies use only a single modelling framework and, because of a lack of validation data, rarely assess model accuracy for the study area. In line with other research themes which have high model uncertainty, such as climate change, ensembles of ES models may better serve decision-makers by providing more robust and accurate estimates, as well as provide indications of uncertainty when validation data are not available. To illustrate the benefits of an ensemble approach, we highlight the variation between alternative models, demonstrating that there are large geographic regions where decisions based on individual models are not robust. We test if ensembles are more accurate by comparing the ensemble accuracy of multiple models for six ES against validation data across sub-Saharan Africa with the accuracy of individual models. We find that ensembles are better predictors of ES, being 5.0-6.1% more accurate than individual models. We also find that the uncertainty (i.e. variation among constituent models) of the model ensemble is negatively correlated with accuracy and so can be used as a proxy for accuracy when validation is not possible (e.g. in data-deficient areas or when developing scenarios). Since ensembles are more robust, accurate and convey uncertainty, we recommend that ensemble modelling should be more widely implemented within ES science to better support policy choices and implementation.

Identification of conservation and restoration priority areas in the Danube River based on the multi-functionality of river-floodplain systems.

Large river-floodplain systems are hotspots of biodiversity and ecosystem services but are also used for multiple human activities, making them one of the most threatened ecosystems worldwide. There is wide evidence that reconnecting river channels with their floodplains is an effective measure to increase their multi-functionality, i.e., ecological integrity, habitats for multiple species and the multiple functions and services of river-floodplain systems, although, the selection of promising sites for restoration projects can be a demanding task. In the case of the Danube River in Europe, planning and implementation of restoration projects is substantially hampered by the complexity and heterogeneity of the environmental problems, lack of data and strong differences in socio-economic conditions as well as inconsistencies in legislation related to river management. We take a quantitative approach based on best-available data to assess biodiversity using selected species and three ecosystem services (flood regulation, crop pollination, and recreation), focused on the navigable main stem of the Danube River and its floodplains. We spatially prioritize river-floodplain segments for conservation and restoration based on (1) multi-functionality related to biodiversity and ecosystem services, (2) availability of remaining semi-natural areas and (3) reversibility as it relates to multiple human activities (e.g. flood protection, hydropower and navigation). Our approach can thus serve as a strategic planning tool for the Danube and provide a method for similar analyses in other large river-floodplain systems.

Social equity shapes zone-selection: Balancing aquatic biodiversity conservation and ecosystem services delivery in the transboundary Danube River Basin.

Freshwater biodiversity is declining, despite national and international efforts to manage and protect freshwater ecosystems. Ecosystem-based management (EBM) has been proposed as an approach that could more efficiently and adaptively balance ecological and societal needs. However, this raises the question of how social and ecological objectives can be included in an integrated management plan. Here, we present a generic model-coupling framework tailored to address this question for freshwater ecosystems, using three components: biodiversity, ecosystem services (ESS), and a spatial prioritisation that aims to balance the spatial representation of biodiversity and ESS supply and demand. We illustrate this model-coupling approach within the Danube River Basin using the spatially explicit, potential distribution of (i) 85 fish species as a surrogate for biodiversity as modelled using hierarchical Bayesian models, and (ii) four estimated ESS layers produced by the Artificial Intelligence for Ecosystem Services (ARIES) platform (with ESS supply defined as carbon storage and flood regulation, and demand specified as recreation and water use). These are then used for (iii) a joint spatial prioritisation of biodiversity and ESS employing Marxan with Zones, laying out the spatial representation of multiple management zones. Given the transboundary setting of the Danube River Basin, we also run comparative analyses including the country-level purchasing power parity (PPP)-adjusted gross domestic product (GDP) and each country's percent cover of the total basin area as potential cost factors, illustrating a scheme for balancing the share of establishing specific zones among countries. We demonstrate how emphasizing various biodiversity or ESS targets in an EBM model-coupling framework can be used to cost-effectively test various spatially explicit management options across a multi-national case study. We further discuss possible limitations, future developments, and requirements for effectively managing a balance between biodiversity and ESS supply and demand in freshwater ecosystems.

Ecosystem-based management planning across aquatic realms at the Ria de Aveiro Natura 2000 territory.

Ria de Aveiro represents a coastal territory, in which its natural capital, mostly classified under a Natura 2000 network of protected areas, is of paramount importance for the regional and national economy, supporting harbour activities and maritime traffic, agriculture, commercial fisheries, aquaculture, manufacturing, tourism, sports and recreational activities. Current and foreseen changes connected to human activities, namely land and water uses and potential conflicts, in frame of environmental policies, sustainable economic development and human well-being require the implementation of ecosystem-based management (EBM) planning processes considering the connectivity across marine, transitional, freshwater, and terrestrial domains. The main objective is to elaborate on the co-development of the EBM planning process across the three water domains, all characterized by high biodiversity and by the wide range of services provided by ecosystems and their abiotic components, for the mitigation of impacts from the management plan under implementation. The approach used follows a stepwise procedure in frame of resilience principles, considering the analysis of the relationship between the social and ecological components and on how these can be connected through risk assessment and a spatial multi-criteria analysis based on the delivery of ecosystem services. Stakeholders' perception matched the ecosystem services provisioning risk assessment and supported the planning EBM response that consist in saltmarshes and seagrasses meadows restoration programs. Compliance of the proposed measures is achievable regarding policies (policy targets and policy instruments) and feasibility (scientific and technological knowledge and financial resources). The EBM response can support the Vouga estuary management plan and regional smart specialization (RIS3 Centro).

Towards globally customizable ecosystem service models.

Scientists, stakeholders and decision makers face trade-offs between adopting simple or complex approaches when modeling ecosystem services (ES). Complex approaches may be time- and data-intensive, making them more challenging to implement and difficult to scale, but can produce more accurate and locally specific results. In contrast, simple approaches allow for faster assessments but may sacrifice accuracy and credibility. The ARtificial Intelligence for Ecosystem Services (ARIES) modeling platform has endeavored to provide a spectrum of simple to complex ES models that are readily accessible to a broad range of users. In this paper, we describe a series of five "Tier 1" ES models that users can run anywhere in the world with no user input, while offering the option to easily customize models with context-specific data and parameters. This approach enables rapid ES quantification, as models are automatically adapted to the application context. We provide examples of customized ES assessments at three locations on different continents and demonstrate the use of ARIES' spatial multi-criteria analysis module, which enables spatial prioritization of ES for different beneficiary groups. The models described here use publicly available global- and continental-scale data as defaults. Advanced users can modify data input requirements, model parameters or entire model structures to capitalize on high-resolution data and context-specific model formulations. Data and methods contributed by the research community become part of a growing knowledge base, enabling faster and better ES assessment for users worldwide. By engaging with the ES modeling community to further develop and customize these models based on user needs, spatiotemporal contexts, and scale(s) of analysis, we aim to cover the full arc from simple to complex assessments, minimizing the additional cost to the user when increased complexity and accuracy are needed.

Participatory coastal management through elicitation of ecosystem service preferences and modelling driven by "coastal squeeze".

The Baixo Vouga Lagunar (BVL) is part of Ria de Aveiro coastal lagoon in Portugal, which is classified as a Special Protection Area under the European Habitats and Birds Directives. This part of the system, corresponding to the confluence of the Vouga River with the lagoon, is very important culturally and socioeconomically for the local communities, taking place several human activities, especially agriculture. To prevent salt water intrusion from the Ria de Aveiro into agriculture fields, a floodbank was initiated in the 90's. In frame of ongoing changes in Ria de Aveiro hydrodynamics, the existing floodbank will be now extended, introducing further changes in the ecological dynamics of the BVL and its adjacent area. As a consequence, the water level in the floodbank downstream side is expected to rise, increasing the submersion period in tidal wetlands, and leading to coastal squeeze. The aim of this study is to apply an ecosystem based-management approach to mitigate the impacts on biodiversity resulting from the management plan. To do so, we have modelled the implications of the changes in several hydrological and environmental variables on four saltmarsh species and habitats distribution, as well as on their associated ecosystem services, both upstream and downstream of the floodbank. The ecosystem services of interest were prioritized by stakeholders' elicitation, which were then used as an input to a spatial multi-criteria analysis aimed to find the best management actions to compensate for the unintended loss of biodiversity and ecosystem services in the BVL. According to our results, the main areas to be preserved in the BVL were the traditional agricultural mosaic fields; the freshwater courses and the subtidal estuarine channels. By combining ecology with the analysis of social preferences, this study shows how co-developed solutions can support adaptive management and the conservation of coastal ecosystems.

Cost-effective restoration and conservation planning in Green and Blue Infrastructure designs. A case study on the Intercontinental Biosphere Reserve of the Mediterranean: Andalusia (Spain) - Morocco.

Green and Blue Infrastructure (GBI) is a network designed and planned to deliver a wide range of ecosystem services and to protect biodiversity. Existing GBI designs lacked a systematic method to allocate restoration zones. This study proposes a novel approach for systematically selecting cost-effective areas for restoration on the basis of biodiversity, ecosystem services, and ecosystem condition to give an optimal spatial design of GBI. The approach was tested at a regional scale, in a transboundary setting encompassing the Intercontinental Biosphere Reserve of the Mediterranean in Andalusia (Spain) - Morocco (IBRM), across three aquatic ecosystems: freshwater, coastal and marine. We applied Marxan with Zones to stakeholder-defined scenarios of GBI in the IBRM. Specifically, we aimed to identify management zones within the GBl that addressed different conservation, restoration and exploitation objectives. Although almost all conservation targets were achieved, our results highlighted that the proportion of conservation features (i.e., biodiversity, ecosystem services) that would be compromised in the GBl, and the proportion of provisioning services that would be lost due to conservation (i.e., incidental representation) are potentially large, indicating that the probability of conflicts between conservation and exploitation goals in the area is high. The implementation of restoration zones improved connectivity across the GBI, and also achieved European and global policy targets. Our approach may help guide future applications of GBI to implement the flexible conservation management that aquatic environments require, considering many areas at different spatial scales, across multiple ecosystems, and in transboundary contexts.

Competitive ability, stress tolerance and plant interactions along stress gradients.

Exceptions to the generality of the stress-gradient hypothesis (SGH) may be reconciled by considering species-specific traits and stress tolerance strategies. Studies have tested stress tolerance and competitive ability in mediating interaction outcomes, but few have incorporated this to predict how species interactions shift between competition and facilitation along stress gradients. We used field surveys, salt tolerance and competition experiments to develop a predictive model interspecific interaction shifts across salinity stress gradients. Field survey and greenhouse tolerance tests revealed tradeoffs between stress tolerance and competitive ability. Modeling showed that along salinity gradients, (1) plant interactions shifted from competition to facilitation at high salinities within the physiological limits of salt-intolerant plants, (2) facilitation collapsed when salinity stress exceeded the physiological tolerance of salt-intolerant plants, and (3) neighbor removal experiments overestimate interspecific facilitation by including intraspecific effects. A community-level field experiment, suggested that (1) species interactions are competitive in benign and, facilitative in harsh condition, but fuzzy under medium environmental stress due to niche differences of species and weak stress amelioration, and (2) the SGH works on strong but not weak stress gradients, so SGH confusion arises when it is applied across questionable stress gradients. Our study clarifies how species interactions vary along stress gradients. Moving forward, focusing on SGH applications rather than exceptions on weak or nonexistent gradients would be most productive.