Elimination et Choix Traduisant la Realité (ELECTRE), and Cross-Efficiency (CE)—to establish a ranking of countries that export cereals to the European Union, based on structural criteria related to the detection of potential associated risks . In addition, the analysis examines whether the wealth and institutional capacity of supplier countries influence their position in the ranking. The research was carried out biannually over the period from 2012–2016, allowing an assessment to be made of the possible stability of the markets. The results reveal that suppliers’ rankings based exclusively on aspects related to food risk differ from importers’ actual choices determined by micro/macroeconomic features . The rankings obtained by the three proposed methods are not the same, but present certain similarities, with the ability to discern countries according to their level of food risk. The proposed methodology can be applied to support sourcing strategies. In the future, food safety considerations could have increased influence in importing decisions, which would involve further difficulties for low-income countries.International trade in food knows no borders, hence the need for prevention systems to avoid the consumption of products that are harmful to health. This paper proposes the use of multicriteria risk prevention tools that consider the socioeconomic and institutional conditions of food exporters. We propose the use of three decision-making methods—Technique for Order Preference by Similarity to the Ideal Solution (TOPSIS),  The internationalization of the food trade has evolved in parallel with concerns about quality, prompting the development of techniques to assess and prevent the risk associated with the transmission of pathogens and address other safety issues. Agencies such as the Codex Alimentarius Commission (CAC), the United Nations Food and Agriculture Organization (FAO), and the World Health Organization (WHO), among others, have been collaborating for more than three decades in an effort to protect health and ensure good practices in the trade of food products . They alThe justification for this research is that there is an emerging need for a systematized approach to carrying out food risk assessment that takes into account the economic and policy conditions of exporters. Wood, V.R., et al., identified 200 indicators that influence the choice of the supplier country, making it possible to distinguish international target markets . The FAOAs far as international trade is concerned, some econometric studies have introduced policy and institutional variables for forecasting food incidents and alerts ,14,15,16In this paper, a multicriteria analysis tool is proposed to assist panels of experts of importing firms to select product suppliers according to their domestic institutional conditions. The framework is able to rank supplying countries according to different domestic markers based on their logistical complexity, state of food quality, level of development, environmental conditions, and reputation in terms of the history of previous safety notifications for their exports of a given food product. Our purpose is to provide a tool for risk prevention that improves the exchange of information between all stakeholders, advisors, managers, and even consumers ,18,19,20Elimination et Choix Traduisant la Realité (ELECTRE), and cross-efficiency (CE)—to establish a ranking of non-European Union countries supplying cereals to the European Union in 2012, 2014, and 2016. The study employs innovative discrimination criteria: instead of using micro/macroeconomic parameters to produce a ranking based on business trends, the applied criteria characterize the quality of the product and the potential food risk associated with the exporting country. In this way, it is possible to indicate suppliers whose products pose the least danger to consumer health. This research expands the current paradigm surrounding food risk, in which MCDM methods have been mainly applied to topics related to food safety, policies designed to improve microbial food safety, and identifying obstacles to food safety policies [This research paper proposes the use of three MCDM methods—Technique for Order Preference by Similarity to the Ideal Solution (TOPSIS), policies ,22,23.The use of multicriteria models to choose suppliers in the food sector has been studied in the literature ,25,26,27We take cereals as an interesting value chain to apply the proposed framework. Cereals are products of paramount relevance to human consumption, animal feed, and pet food. As with any food that can be processed for consumption, there is a need to ensure quality and safety throughout the supply chain. It is a product of great relevance in European trade, as shown by official United Nations statistics through Comtrade. Specifically, the value of cereal imports by the EU ($6523 million in 2016) exceeds other food imports, such as dairy products and eggs ($712 million), sugar ($2870 million), and meat ($6024 million). It is therefore a widely consumed product that a priori can seem to be without risk; nevertheless, its consumption in a bad state would seriously harm the health of the population.In summary, the paper makes a number of contributions to the literature: (1) It provides a systematized approach to risk assessment that integrates basic institutional conditions linked to the likelihood of potential risks in the country of origin; (2) The conditions are integrated into a multicriteria decision-making process valid for food importers; (3) The framework combines three methodologies to strengthen the conclusions obtained; (4) The methodology makes it possible to rank cereal suppliers based on several criteria  that can be used to inform the decision-making of food importers; and (5) The application provides an analysis of how the development and institutional capacity of cereal exporters determine their position in the ranking. This approach differs from the most common food safety techniques by anticipating, through signaling country risks, the problems that may arise.The rest of the paper is organized as follows: Over the past two decades, the EU has focused on developing and strengthening risk assessment in order to adapt guidelines to existing needs ,29. In pThe EU has developed controls on cereals; both European-grown and imported cereals are subject to strict regulatory standards, due to their high exposure to pollutants. Notifications at borders that are reported by the member state authorities to the Rapid Alert System for Food and Feed (RASFF) go some way toward ensuring that food is imported in perfect condition. While institutional conditions have been considered for the quantitative forecasting of RASFF notifications for fresh food products , nuts 1, and theMulticriteria decision-making (MCDM) methods are ideal tools for gaining a better understanding of decision-making processes, facilitating comparisons between alternatives. According to , the cenIn the literature, there is a lot of work aimed at establishing rankings of countries, suppliers, and/or indicators by means of MCDM methods, in order to facilitate the choices of decision-makers. However, little attention has been given to the social, political, and institutional conditions affecting food risk. Multicriteria decision-making has scarcely been used as a risk prevention tool in agricultural trade, and even less to weigh the socioeconomic and institutional conditions of the country of origin. The proposed decision-making framework in this paper is aimed at covering a less worked aspect which is of vital importance to ensuring the safety of the population, providing a tool for assessing the food risk and introducing exporter’s institutional variables into evaluations. The use of different methodologies reinforces the conclusions obtained, identifying supplier countries whose products are more likely to carry pathogens and addressing other issues that invalidate the safety of the product.MCDM methods cover a wide variety of approaches and can be classified into two broad categories: discrete MCDM, also known as multi-attribute decision-making (MADM), and continuous MCDM, or multiobjective optimization problems (MOOPs). The latter methods are associated with problems where the alternatives are not predetermined, with the aim of designing the best option, taking into account a set of quantifiable objectives; they include goal programming, multiple objective programming, and compromise solution methods . These pData envelopment analysis (DEA), on the other hand, can be used to solve problems with multiple inputs/outputs that characterize a set of observations, enabling a ranking of the observations, like the aforementioned MCDM models . DEA hasAs  pointed This study proposes the use of TOPSIS, ELECTRE, and CE, all of which have proven to be suitable for solving problems that require the calculation of a ranking for a set of alternatives. Furthermore, they are comparable when applied to the same sample of exporters and provide robustness to the conclusions obtained. A diagram with the stages of each method is shown in It is important that the alternatives are well defined and the criteria to be evaluated are correctly set. When implementing TOPSIS and ELECTRE, weights must be assigned to the criteria, depending on their importance in the final result. DEA, on the other hand, requires the identification of inputs/outputs that define the production function, allowing a reference frontier to be identified and the subsequent ranking of observations to be carried out ,78. TablComtrade data on the origin of imports in 2012 and 2016 indicate that Ukraine was the main European supplier of cereals, accounting for more than $2 billion worth in 2012, and slightly less in 2016 . Since 2The main EU suppliers remain fairly stable, with Canada, the USA, Russia, and Ukraine dominating in both 2012 and 2016 . The EU The empirical analysis focused on a sample of countries that constituted the main non-EU suppliers of cereals to the EU in 2012, 2014, and 2016. It was constructed using information on cereal imports provided by Comtrade (United Nations). Following the sample construction process, for each year under study, 30 suppliers were initially selected, representing around 97% of EU cereal imports. However, due to the criteria used for the ranking, the sample had to be reduced to 24, 22, and 25 observations for 2012, 2014, and 2016, respectively. The set of suppliers constitutes alternatives for the models used, while the criteria were determined by the following economic, environmental, and institutional conditions related to their level of food risk .The analysis of notifications was carried out using information published in the RASFF database. This is a platform that registers all products imported by European countries that either do not comply with EU regulations or simply offer reasonable grounds upon which to suspect a lack of compliance. The system is key to ensuring the cross-border monitoring of goods, and enables rapid reaction when public health risks due to alterations in food or feed consignments are detected in the food chain. The number of notifications reveals the perceived historical records by EU border controls on cereal suppliers’ safety. The information was extracted from the RASFF database, with the search being constrained to the years considered in the analysis, cereals as the only type of product, and the receipt of any type of safety notification.The Logistics Performance Index (LPI), published by the World Bank, provides information on the logistics of 160 countries ,87,88. TThe quality and safety index (Q&S) is one of the four pillars that make up the Global Food Security Index published by the Economist Intelligence Unit; the other three dimensions are affordability, availability, and natural resources and resilience. It comprehensively examines 113 countries, establishing a ranking based on 26 indicators. This study uses the Q&S dimension corresponding to the 2012–2016 period, which, in addition to nutritional issues, assesses aspects related to food safety.The Corruption Perceptions Index (CPI) classifies countries according to their perceived level of public sector corruption, as determined by expert assessment and opinion surveys. It is constructed on the basis of a combination of 13 surveys and evaluations from 12 independent institutions specializing in governance and business environment analysis.The Environmental Performance Index (EPI) is produced jointly by Yale University and Columbia University in collaboration with the World Economic Forum. It provides information at a national scale on how close countries are to achieving established environmental policy goals. It is divided into two pillars: environmental health and ecosystem vitality. In turn, these are divided into several categories. The present study uses the ecosystem vitality category, referring to the sustainability of agricultural resources for the considered 2012–2016 time period.The values of these last three indices lie between 0 and 100, with a score of 100 corresponding to countries that are less corrupt whose food products register a high level of quality and safety, and whose agricultural resources score highly in terms of the environment. The main statistics for the criteria explained above are detailed in Given the particular features of each criterion and the objective of this research, the aim is to maximize the LPI, Q&S, CPI, and EPI, and minimize the number of notifications. In the years analyzed, the first three criteria to be maximized appear to remain fairly stable, whereas greater variations are observed in EPI and notifications. The latter two register a drastic reduction, as can be seen when comparing the maximum values. However, while the fall in the number of notifications represents an improvement in the food risk of imported products, the EPI indicates the opposite, i.e., it reflects the poorer environmental performance of the countries assessed. Nevertheless, this value may be due to methodological changes in the evaluation of agricultural issues introduced in the past year. The new indicator to capture the effects of nitrogen fertilizer, the sustainable nitrogen management index, replaces nitrogen use efficiency and nitrogen balance, which had been used up to that point. In 2012, the following countries achieved the highest scores on the criteria to be maximized: Singapore on the LPI and CPI; the USA on the Q&S; and Serbia, Argentina, and Singapore on the EPI. The aim of all exporters is for their products to reach destination countries in the best possible condition; as such, notifications are an obstacle that could hinder or even prevent the import of products. Many of the countries analyzed did not receive any notifications in 2012 , while others, such as Pakistan, India, and Thailand, had to deal with situations that seriously damaged their trade relations .Small variations are observed in 2014, with the USA and Switzerland leading the LPI, New Zealand the CPI, Cambodia the EPI, and the USA also heading up the Q&S. Regarding notifications, Serbia and Argentina receive the most. Lastly, in 2016, Singapore once again took the lead in logistics, Switzerland scored the highest in the CPI, the USA achieved the best score for the EPI and Q&S, and Argentina maintained its position as the country with the most notifications. However, in 2014 and 2016, around 60% of countries did not receive any notifications at all, and 36% received only one. In this respect, there is marked improvement in terms of a reduction in notifications for EU cereal imports.The TOPSIS, ELECTRE, and CE models were applied to the countries presented in The selected framework makes it possible to assess the risk associated with the institutional and economic conditions of the different suppliers and rank them accordingly. Overall, the results in However, analyzing the average results, the three models show that, along with Canada and Switzerland, the USA is one of the countries whose exports apparently present the lowest institutional risk; at the same time, it is one of the main suppliers of cereals to the EU. According to the multicriteria framework, trade with Pakistan, Cambodia, and Kazakhstan appears to be least advisable, yet their exports to the EU represent a considerable share of the total. In addition, if European importers gave greater weight to food risk-related issues, in no case would they choose Ukraine as the top supplier ; there wMCDM methods have proven to be effective in prioritizing countries by taking into account structural drivers of food risk. The method could provide a picture that would match the actual trade ranking if only the selected criteria related to political and structural factors underlying food risk were considered in the importers’ decisions. Actually, However, the actual ranking of EU cereal suppliers depends on other considerations, in particular, trade costs. This is illustrated by the different positions that cereal suppliers occupy according to the trade agreements signed with the EU. Thus, the results highlight differing situations, such as those of Switzerland and Norway, which are members of the European Free Trade Association (EFTA), but which occupy very distinct positions as cereal suppliers. Another country that merits attention is Singapore, which is the EU’s most important trading partner among all the ASEAN members. This successful relationship led to the signing of an FTA in late 2019, which represents a step forward in their bilateral trade, opening up the possibility of eliminating customs duties on imports, as well as other measures to boost imports of goods (Council Decision (EU) 2019/1875 of 8 November 2019). This Asian country did not receive any notifications in the three years analyzed. It also ranked first on the LPI, scored highly on the Q&S 2016, and registered the best corruption score in 2012. However, its cereal exports to the EU were around just 0.6% of the total EU’s cereal imports in 2016, and even lower in 2014 and 2012 . Given the less relevant position of Singapore as a cereal producer, it is not expected that the FTA and the country’s favorable position in the risk safety ranking will significantly boost its exports to the EU.Furthermore, bilateral relations between the EU and Canada are currently bolstered by the Comprehensive Economic and Trade Agreement (CETA). Under this agreement, import quotas and tariff rates will be progressively reduced and eventually eliminated entirely . Figure The nearly 20-year period analyzed demonstrates the EU’s trade deficit with respect to the Canadian market, indicating the importance of Canada as an international supplier of cereals. The trend equation confirms the progressive increase over time, a trend which will be substantially bolstered by the aforementioned trade agreements. In this case, the favorable risk assessment supports the hypothesis that Canada will improve its competitive position in the EU market.A country’s income level can be related to some extent to domestic capacity and infrastructure for food and feed quality and control. Therefore, in line with the objectives of this paper, ANOVA was carried out to test the null hypothesis of independence between countries’ positions in the ranking and their income levels. To that end, the mean CE values for three years were used, along with the World Bank’s country classifications by income level for 2016 .Analysis of variance (ANOVA) divides the variation in the ranking into two categories: between-group variation (if it is due to differences between groups) and within-group variation (if it is due to differences within each group). As shown in column 6 of The Tukey–Kramer test was then used to determine which groups differ from each other and their quantification in terms of CE, which would mean that they would occupy different positions in the ranking.The results reveal the existence of two clearly differentiated subsets: one consisting of countries classified as lower-middle income, and the other consisting of upper-middle and high income. In addition, the EC score rises from 0.6661 to 0.8468, corresponding to the income groups at the extremes . In the In summary, countries with better capacity to manage food safety will normally be more qualified to achieve better positions in multicriteria food risk assessment. MCDM can easily be applied by panels of experts from cereal importing firms. The approach offers a structured method with a prevention tool that considers country risks and can modify selections based exclusively on market variables such as price and volume. Validation of the framework for cereals suggests that scaling up the method to other value chains would be straightforward.As suggested, actual purchasing choices consider other variables not related to supplier risk. An implication of the study is that actual trade choices would not exactly match the results of the risk evaluation. However, actual import decisions must be weighed with the results of the risk evaluation assessments, which can become a crucial component of trading decisions. Although up to the present, supplier costs have been a determining factor of import choices, in future, food safety considerations could have increased influence, which means further difficulties for low-income countries.The globalization of markets and advances in logistics have meant that distance is no longer a barrier to international trade; however, this has inherent problems, such as those associated with the entry of products which are in poor condition. As health reaches paramount importance in future trade relations, food risk is a factor that should be prioritized in the process of choosing a supplier country for a particular food, since a population’s health depends on the quality of the food it eats. This paper suggests an MCDM methodology that can be easily extended to risk prevention strategies for food traders. Our methodology supplies a tool that takes into account several markers of food safety risk related to the exporting country’s conditions. This research proposes the use of three MCDM methods to establish a ranking of countries that supply cereals to the EU, applying choice criteria based on food risk assessment. The results reveal clear differences between the classification carried out according to purely micro/macroeconomic patterns compared to the proposed criteria. Thus, for example, Ukraine, the main exporter of cereals, would not be in the top position according to the food risk criteria (occupying position 18 in the ranking according to TOPSIS and 17 according to ELECTRE and TOPSIS), while Norway would move upward in the ranking (position 4 according to ELECTRE), even though it does not currently supply large volumes of cereal to the EU (position 22 in the supplier ranking in 2012 and 2016).Although the rankings obtained using the different methods are not the same, they do show certain similarities, revealing the most suitable countries according to their level of food risk. All the countries in the top positions have been described by the World Bank as high-income. They are developed economies whose distance from the EU does not present an obstacle. However, Asian and South American countries should seek improvements in all food risk criteria in order to strengthen trade relations with Europe. Beyond the usefulness of the proposed methodological framework, a possible policy implication of the analysis is that, in the future, strengthening food safety considerations in importer choices could involve further difficulties for lower-income exporters.This contribution supplies a framework for institutional risk assessments of food safety that can be further developed with more focused indicators from international databases. The approach offers a structured method with a tool for supplier selection that considers country risks, and could be extended to a wide range of food value chains.The research carried out is not without its limitations; the use of synthetic indices to assess certain aspects of the countries, such as logistics, quality, and sustainability, could be criticized, and these could be adapted to the specific conditions of the studied value chains. These indicators are strongly conditioned, not only by possible errors in the sample, but also by the treatment of the variables and their weights, leading to a loss of rigor in clarifying the characteristics of each country. Risk factors can also be influenced by local shocks to the economy or the sanitary conditions of exporting countries, such as crop shortage or plant disease. We believe that the MCDM framework can be adapted to these circumstances and extended to different value chains. Finally, in future research, a more specific analysis should be carried out, focusing on certain geographic areas where the availability of official statistics would give rise to a more in-depth study.


Food loss and waste (FLW) has become a central concern in the social and political debate. Simultaneously, using FLW as a bioenergy source could significantly contribute to closing the carbon cycle by reintroducing energy into the food supply chain. This study aims to identify best strategies for FLW management in each of the 17 regions in Spain, through the application of a Life Cycle Assessment. To this end, an evaluation of the environmental performance over time between 2015 and 2040 of five different FLW management scenarios implemented in a framework of (i) compliance and (ii) non-compliance with the targets of the Paris Agreement was performed. Results revealed savings in the consumption of abiotic resources in those regions in which thermal treatment has a strong presence, although their greenhouse gas (GHG) emissions in a scenario of compliance with climate change targets are higher. In contrast, scenarios that include anaerobic digestion and, to a lesser extent those applying aerobic composting, present lower impacts, including climate change, suggesting improvements of 20–60% in non-compliance and 20–80% in compliance with Paris Agreement targets, compared to the current scenarios. Renewable energy production policies in Spain are determined by the international context and European Union (EU) recommendations, which are looking for a more sustainable and low-carbon economy to achieve the Paris Agreement targets. Among them, the goal of limiting global warming to well below 2 °C above pre-industrial levels and pursuing efforts to limit it to 1.5 °C stands out , which aIn this framework, the energy produced from non-fossil organic material of biological origin, so called bioenergy, is being promoted as a substitute for non-renewable energy to reduce GHG emissions and dependency on energy imports . NowadayFLW has become a central concern in the social and political debate, as at least one-third of all edible food production is wasted worldwide throughout the entire FSC (20% in the European Union) . This esBeyond reductions in FLW, the European Commission is promoting the so-called waste hierarchy, positioning prevention at the top , and reqThis study conducted an LCA following the international standards from the International Organization for Standardization (ISO) 14040  and ISO The main function of the system is the management of FLW under different simulated scenarios. In order to measure this function, a suitable functional unit has to be defined, to which all the inputs and outputs are referred. In this case, the treatment of one metric ton of FLW in each Spanish region in the respective year of analysis was assumed as the functional unit.This LCA has a cradle to grave approach , includiScenario 1 (S1). Represents the baseline scenario taking into account the current FLW management in each region shown in , accordiScenario 2 (S2). Replicates the current situation in Germany regarding FLW management , where AScenario 3 (S3). This scenario prioritizes the use of AD systems, assuming that 75% goes to AD, 20% to AC, and the rest is divided between landfill (2.5%) and thermal treatment (2.5%).Scenario 4 (S4). This scenario is based on current Danish conditions, where over 90% of the share of biowaste is incinerated . Thus, 9Scenario 5 (S5). This scenario is based on the increasingly promoted claim that FLW is a valuable resource that should never end up in landfilling sites . It is a2 will tend to be increasingly higher [Scenario 6 (S6). Landfilling and thermal treatment are not considered in this scenario, so 50% of FLW is treated in AC, and 50% in AD. The argument for avoid including thermal treatment plants in S6 refers to the fact that, similarly to what has recently occurred to coal plants in many nations including Spain, thermal treatment plants will potentially have problems with regard to providing energy to the system by the year 2030. More specifically, they will have serious difficulties in maintaining competitiveness against other technologies in an environment highly conditioned by the European response to climate change, in which the cost of COIn order to determine the most optimal FLW management strategies for the 17 regions, six different scenarios, including the baseline scenario (S1), were analyzed within this study by implementing them in all regions and all the analyzed years  of FLW generation and management in the 17 regions regarding the four stages of the FSC, the 11 FLW categories, and the four management options considered. To calculate the data for the stages of agriculture production, and processing and packaging, data reported by the Spanish Ministry of Agriculture, Fishery and Food ,45 were AC was modelled using the professional database of the GaBi software , which cAD was modelled using the Ecoinvent database , includiThermal treatment was based on the professional database of the GaBi software  for the Landfill with biogas recovery includes biogas and leachate treatment and deposition. Sealing materials  and diesel for the compactor were also included. The modelling was based on the landfill process for municipal household waste from the professional database of GaBi . AccordiThe different FLW treatment techniques have been developed according to the models extracted from Aldaco et al. :AC was mThe avoided burden for electricity from AD, thermal treatment, and landfill, are based on the electricity mix simulations according to the TIAM-UCL model, which are shown in The scenarios under study are multi-output processes in which the management of FLW is the main function of the system and the production of electricity, steam, and compost are additional functions. Therefore, the environmental burdens must be allocated among the different functions. To handle this problem, ISO 14040 establishes a specific allocation procedure in which system expansion should be prioritized . The eneIn order to quantify the potential environmental impacts of the scenarios modelled, six environmental impact categories shown in  were selThe selection of impact categories was carried out considering the most relevant impacts linked to organic waste and its treatment. In this sense, climate change, due to anaerobic organic decomposition, was highlighted as an important indicator to be considered. The presence of different waste treatment technologies, namely thermal treatment, pushed towards the inclusion of human toxicity and air quality categories, such as photochemical oxidation. Acidification and eutrophication were selected due to the presence of acidic gases and high amounts of nutrients in FLW, respectively. Finally, abiotic depletion was modelled considering the displacement of fossil fuels and resources in the systems in which electricity and fertilizers are generated from FLW. It is acknowledged that other assessment methods could have been chosen to conduct certain impact categories, but the use of one single method constructed with the same methodological basis was prioritized.The main limitation of the present study is the uncertainty in the data used, the main sources of uncertainty being the amounts of FLW generated and the type of management for the different FLW categories in the reference year, as well as the trends until and during the modelled time. Moreover, it is difficult to link FLW generation and management, as the whole process takes time and in the meantime a fraction of the mass might be lost . Differences can also occur due to import and export of waste, as well as unaccounted fractions. Moreover, although information is available regarding the different treatment and disposal methods, existing statistics generally refer to the generation of biodegradable municipal waste, not to the generation of biowaste or FLW . BiodegrA debatable assumption made in this study concerns the selection of the LCA approach to solve the multi-functionality issue mentioned in Additionally, the evolution of FLW generation until 2040 was first considered using a logarithmic regression based on the projection of the World Bank Group  regardinFinally, it is important to remark that each simulation will always represent a simplification of reality.Within this section, results from two different analyses are presented and discussed. Due to the heterogeneity of the management strategies implemented in the 17 Spanish regions shown in , which wIn order to see the influence of the different FLW management technologies, one cluster of regions can be made for Cantabria (CT), Balearic Islands (BA), Galicia (GA), and Basque Country (PV), where thermal treatment plays an important role (more than 25%). Thus, results show that the use of thermal treatment is related to a significant decrease in Abiotic Depletion Potential (ADP) (up to 15%), as it presents the highest level of energy generation and, therefore, the greatest savings in terms of resource consumption are achieved. A second cluster of regions can be made for Andalusia (AN), Principality of Asturias (AS), Castile-La Mancha (CM), Canary Islands (CN), Extremadura (EX), and Region of Murcia (MU), where FLW management is carried out almost entirely through landfilling with energy recovery (between 92% and 100%). A third group of regions are those that combine the use of landfilling and AD, i.e., Aragon (AR), Castile and Leon (CL), La Rioja (LR), Community of Madrid (MA), and Valencian Community (VA), with AD percentages ranging from 22% to 67%. All these obtained results are similar, with an increase in the consumption of ADP over time  and Chartered Community of Navarra (NA), in which AC reaches values of 19% and 12%, respectively g for NA.Concerning the impact categories of Global Warming Potential (GWP), Eutrophication Potential (EP), Photochemical Ozone Creation Potential (POCP) and Human Toxicity (HT), there is always a slight increase over time across all clusters. This increase is more pronounced in FLW management configurations that present high rates of incineration.Analyzing the influence of the Paris Agreement framework on the results, the relation is clear for some impact categories and technologies. The energy mix has a great influence on the Acidification Potential (AP) impact category. Results show a big decrease in AP for the 2DS when landfill is the main technology in the FLW configuration (clusters 2 and 3), since the electricity mix, with higher weight of renewable sources, has a lower environmental burden in AP. However, this is not visible in the configuration with a high share of incineration (cluster 1). In this case, Regarding ADP, values are always positive (increase from 2015) and higher for BAU comparing to 2DS, except for the configurations in which thermal treatment plays a key role. In the latter case, 2 associated with the energy mix until the year 2040. In comparative terms, only the regions with the presence of FLW thermal treatment show a reduction in the consumption of abiotic resources (ADP) related to the ones in which such technology is not present. This is due to the higher energy efficiency of thermal treatment and, therefore, the resources avoided in obtaining energy according to the energy mix projections. Furthermore, this is even more evident in the BAU framework, with a higher consumption of non-renewable resources. The remaining impacts are higher when the thermal treatment is included within the FLW management alternatives, showing the lowest environmental burdens in the regions where AD and AC are used. This is especially remarkable when complying with the Paris Agreement targets, in which the impact is only reduced in regions without thermal treatment plants, since FLW combustion emits a higher amount of acid gases and particles than to obtain their equivalent energy considering the mix in the 2DS scenario.Concerning the impact categories of GWP, EP, POCP and HT, as mentioned before, there is always a slight increase over time, and values are higher under compliance of the Paris Agreement targets  comparing to BAU. The main reason is that the avoided burdens of cleaner energy according to the energy mix of the 2DS framework report lower credits comparing to BAU  worsens the GWP by up to 20% in all regions in the BAU framework. If compliance with the Paris Agreement targets is attained , a worsening in GWP is also general for all regions, but in this case the energy recovery from FLW implies an increase in GWP of approximately 60% for AN and CM, in which the management strategy would go from landfilling to thermal treatment, and higher than 80% for CL, in which thermal treatment would replace landfilling and AD. However, the latter case can only be approached as a theoretical reference, as in the other regions in which there are already management options other than landfilling, and in which its replacement in the short or medium term has no practical value.Discarding the substitution of landfill by thermal treatment, all the other scenarios present significant improvements compared to the current scenarios, reaching improvements through AD and AC  above 60% for CL and AN in the BAU framework (above 80% in compliance with the Paris Agreement targets), higher than 40% for CM under the BAU framework (above 60% in compliance with the Paris Agreement targets), and around 20% in practically all the other regions. The analysis of the results for the rest of the impacts studied showed a similar trend, as shown in Consequently, decisions on investment in technologies in the future need to be regional instead of national and always attend to environmental and technical criteria (such as those presented in this work) and oversimplistic and short-term political evaluations. This could be an important path for future research on regional planning, considering other factors as the transport costs, the spatial occurrence of specific FLW generators (such as primary production or food processing and packaging industry), the regional demand , the acceptance of society , the on-site demand for energy not connected to season, as well as the physical and chemical characteristics of FLW.AD coupled to AC, which was revealed in this study as the path with the highest reduction across all analyzed impacts , has also been highlighted as an efficient alternative technology, combining biofuel production  with sustainable waste management ,62, as lAlthough, in general, thermal treatment  has gained a bad reputation due to certain environmental impacts, such as the emissions of acid gases, dioxins and furans (PCDD/F), as well as GHG emissions , there aFinally, the results of the current study reinforce the general consensus in the literature by highlighting that landfilling scenarios, with and without energy recovery, are those that present the highest environmental impacts . Hence, The management of FLW in Spain is highly regionalized, and presents as many scenarios as regions and treatment models associated. In this context, it is not possible to define from a technological and environmental point of view a single common centralized strategy for the entire management of FLW in Spain beyond establishing harmonized guidelines and criteria that facilitate both the transition to a circular economy and the reduction in environmental impacts, especially those associated with global warming.Results highlighted how the alternative for energy recovery worsens the GWP in all regions in the BAU and 2DS frameworks by up to 20% and between 60% and 80%, respectively. All the other scenarios presented significant improvements (20–60% in BAU and 20–80% in 2DS frameworks) compared to the current scenarios. Thus, the regionalization of FLW management strategies is corroborated in this study as a way forward in upcoming decades, which should be transcribed in an increasingly regional decision-making capacity for policy-makers, focusing firstly on regional criteria and characteristics of the FLW management systems, instead of national plans seeking uniformity of strategies.Despite the importance of achieving compliance with the EU landfill reduction targets, in general terms, landfilling with energy recovery is the most used technology in Spain with an average of 71%, with some regions reaching up to 100% of FLW management. Promoting this technology, however, both in a 2DS and BAU framework, would increase the environmental impacts in the short and medium term, including GHG emissions by 15%, while the consumption of resources would increase significantly, not complying with the principles of a circular economy. Only those regions in which thermal treatment has a strong presence showed savings in the consumption of resources, although their contribution to global warming under 2DS is higher, as the energy obtained in thermal treatment is not as clean as the one it replaces based on the consumption of non-fossil resources. The results obtained from the scenarios simulated concluded that, on average, those scenarios that include AD and to a lesser extent AC have the lowest impacts—even regarding GHG emissions. Therefore, they comply with the principles of the circular economy and are, also, the most sustainable option from an environmental point of view. In this general context, it is necessary to promote strategies conducive to the source-separated and selective collection of FLW.Nevertheless, for developing decision-making processes for each region, not only an environmental assessment but also a socioeconomic evaluation is needed. These complementary studies would help guarantee the competitiveness of novel strategies, which could be driven by new financial support derived from sources such as the European Commission’s recently presented Farm to Fork Strategy or the future CAP 2021–2027. For instance, certain variables, such as previous and future investment in waste infrastructure, maintenance of the installations, and transport distances of FLW, may be decisive when thinking of developing or not developing potential new strategies of FLW management.Overall, the results of this study reinforced the increasingly promoted claim that FLW is a valuable resource that should not end up in landfills, although prevention and valorization should be prioritized over any other management option, in order to move towards a circular economy in the food sector and, thus, contribute to the mitigation of climate change and other environmental impacts.


Multiple sclerosis (MS) is a neurodegenerative disease that causes anthropometric changes characterised by functional disability, increase in fat mass, and decrease in lean mass. All these variables are related to a greater cardiac risk. The polyphenol epigallocatechin gallate (EGCG) and an increase in ketone bodies in the blood have been shown to have beneficial effects on anthropometric and biochemical variables related to cardiovascular activity. The aim of this study was to analyse the impact of the intervention with EGCG and ketone bodies on cardiac risk in MS patients. A population of 51 MS patients were randomly assigned to a control group and an intervention group (daily dose of 800 mg of EGCG and 60 mL of coconut oil). Both groups followed an isocaloric diet for 4 months. Levels of beta-hydroxybutyrate (BHB), albumin, paraoxonase 1 (PON1) and C-reactive protein (CRP) were measured in serum before and after the intervention, as well as determining functional ability, waist circumference, waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), fat percentage and muscle percentage. After 4 months, in the intervention group there was a significant increase in BHB, PON1 and albumin, while CRP did not vary; a significant decrease in cardiac risk associated with a significant decline in WHR; as well as a significant increase in muscle percentage. By contrast, these changes were not observed in the control group. Finally, results from analysis of variance (ANOVA) revealed a significant time–condition interaction effect, observing that WHtR and fat mass decreased in the intervention group, while they increased in the control group. Multiple sclerosis (MS) is a chronic and degenerative disease of the central nervous system (CNS) of an inflammatory nature and characterised by neuronal demyelination and reactive astrocyte scar formation . ClinicaThe anthropometric changes that appear throughout the disease are related to cardiovascular risk, the prevalence of which is higher for MS patients than the general population . On the Taking these precedents into account, therapeutic alternatives should be considered in order to improve the progression of the disease, therefore decreasing cardiac risk associated with inflammation and oxidation as a result of an increase in body fat. Kim et al. proved that a ketogenic diet administered in MS mice models slowed down the progression of the disease, improving motor disability and hippocampal atrophy . FurtherEpigallocatechin gallate (EGCG), the main polyphenol found in green tea, reduces the severity of the disease in animal models of autoimmune encephalomyelitis (EAE), as brain inflammation and demyelination damage decrease . This isIn terms of its cardioprotective activity, this polyphenol also has been described to improve many cardiovascular risk markers. In particular, it reduced lipids in the blood on a circulatory level, improved ischemia-reperfusion injury in cardiac myoblast cells, decreased myocardial oxidative stress, improved the endothelial function of blood vessels, attenuated inflammation and protected the function of cardiomyocytes in the myocardial tissue . In addiTherefore, the objective of this study is to analyse the impact of supplementation with EGCG and coconut oil as a source of ketone bodies in the blood, on cardiac risk in a population of patients with MS by examining anthropometric variables and biomarkers of cardiovascular risk.An exploratory/pilot study was conducted by means of a clinical trial. The clinical trial ID for this study is NCT03740295.The population sample was obtained from the main state-wide MS associations who were previously informed about the study. Sixty-seven people volunteered to take part in the study. Eligibility criteria included: patients over 18 years of age diagnosed with MS at least 6 months previously and under treatment with glatiramer acetate and interferon beta. In addition, the possibility of moving without the need for a wheelchair or walker was required to be part of this study. On the other hand, the exclusion criteria applied to the volunteers included: pregnant or breastfeeding women, patients with tracheotomy, stoma or with short bowel syndrome, patients with dementia, those evidencing alcohol or drug abuse, patients with myocardial infarction, heart failure, cardiac dysrhythmia, symptoms of angina or other heart conditions, patients with kidney conditions with creatinine levels two times higher than normal markers, patients with elevated liver markers three times higher than normal or with chronic liver disease, patients with metabolic or endocrine diseases such as hyperthyroidism or diabetes, patients with acromegaly, patients with polycystic ovary syndrome or MS patients who were included in other research with experimental drugs or treatment.Participants received information on the study including the defined objectives and the tests and analyses to be carried out, as well as signing an informed consent. Before the intervention, participants registered their solid and liquid intake from the last 7 days. In order to facilitate this registration, patients were provided with information about the weight of each portion of the different types of food  and the ®” software  where the anthropometric characteristics of each participant and their pathologies were introduced to establish the caloric, macronutrient and micronutrient needs. They were also provided with instructions to not change the prescribed diet for each case (depending on whether they were in the control group or intervention group), including how to cook the food, portion sizes, the products to be bought at the supermarket, as well as to take the capsules on a daily basis at the scheduled times over the 4-month duration of the intervention. Weekly telephone calls were made by team members to each and every patient on Monday mornings in order to verify whether they were complying with the treatment. These calls were made throughout the whole duration of the intervention on a weekly basis. In addition, the subjects had an appointment with the team every 15 days to interview them and verify whether they were following the diet. They were asked questions . No general issues or problems with the diet or capsules were registered.Once the selection criteria had been applied, a final sample of 51 MS patients was obtained and participants were randomly assigned to the intervention and control group. Randomisation without stratification was performed by drawing sealed, opaque envelopes previously arranged in a computer-generated random order. Once the population had been divided into the two groups, the study began on 4 October 2018 and all functional tests were conducted, alongside anthropometric measurements and obtaining blood samples from all participants, which were repeated on 7 February 2019 when the study came to an end. These measurements are indicated in the measurements section. For the 4-month duration of the study, the intervention group followed an isocaloric diet which was individually given and explained. This diet was adapted to the individual characteristics of each patient and divided into 5 meals a day: breakfast, mid-morning snack, lunch, afternoon snack and dinner. It was enriched with 60 mL of extra virgin coconut oil divided into 2 equal intakes , representing: 91.84% saturated fatty acids, 6.23% monounsaturated fatty acids and 1.93% polyunsaturated fatty acids, which were included in the isocaloric diet and adapted to an adult’s nutritional requirements; and supplemented with 800 mg of EGCG  administered in two capsules of 400 mg to be taken twice a day (one capsule in the morning and another in the afternoon), the quantity of which responds to the pharmacokinetic calculations of Feng WY. (2006) .On the other hand, the control group followed the same isocaloric diet as the intervention group for the same 4 months, except for coconut oil. In this group, the diet was also given and explained individually. Furthermore, they were administered placebo tablets . Both groups followed the same instructions. The basal diet for all participants included the following percentage distribution of the 3 main macronutrients with respect to the total caloric value: 20% proteins, 40% carbohydrates and 40% Mediterranean lipids that were not rich in medium-chain fatty acids. This ensured that a state of nutritional ketosis did not occur in the control group, as the percentages and the amounts of macronutrients were not characteristic of a ketogenic diet  and fat mass  of participants in the intervention group decreased from baseline, whereas these variables increased in the control group. In addition, muscle mass , albumin  and PON1  of participants in the intervention group increased while they decreased in the control group  = 12,752; ol group .One of the main problems that MS patients have is a high level of cardiac risk, mainly due to fat accumulation in the abdomen ,51 and mWith the aim of improving this cardiac risk, an isocaloric Mediterranean diet was administered and supplemented with high quantities of EGCG and coconut oil, a source of MCT, which increase the levels of ketone bodies in the blood after hepatic metabolism . Thus, aCardiac risk does not only depend on high fat percentages, but also on related muscle loss ,63. AccoEffectiveness of the intervention on an anthropometric level seems to be specifically confirmed by fat percentage, WHtR and muscle percentage variables, after applying the ANOVA test that associates both the effect of the duration of the intervention with the treatment itself.This cardiac risk decrease associated with anthropometric improvements has also been evidenced at a biochemical level. Abdominal fat accumulation directly contributes to the chronic inflammatory state of the disease , increasWe also obtained an equally significant increase in the activity of PON1, in line with what has been published by other authors who, on the one hand, saw a significant increase in the activity of paraoxonase when administering polyphenol resveratrol in mice with atherosclerosis (ApoE-deficient mice) , and, onFinally, CRP, which is related to the development of MS , did notAll of the positive biochemical changes obtained only in the intervention group are also observed after applying the ANOVA test for albumin and PON1 (whose activity even worsens in the control group), which seems to confirm treatment effectiveness.Despite these promising results, our study does have some limitations. We believe that measuring the variables should be monitored throughout the whole study, and not only before and after the intervention, thereby trying to delve into the activity at a metabolic level of the treatment. It would also be necessary to assess the evolution in the values of other biochemical markers, especially the different types of lipoprotein that are related to the protection or risk of developing cardiovascular diseases. Furthermore, despite there being no differences in the average weight of both groups (intervention and control), the doses could not be adjusted individually according to weight in the study. Finally, due to the exploratory and pilot nature of this study, more stringently designed intervention trials are required in the future.The administration of of the antioxidant EGCG in MS patients produces an increase in ketone bodies in the blood and decreases cardiac risk in MS patients. This decrease in cardiac risk is determined as a result of the improvement of two different variables: anthropometric (such as a reduction in WHR and an increase in muscle percentage) and serum analytes . Therefore, despite the fact that these results should be further studied in depth in future studies, this intervention seems to have potential as a therapeutic alternative to improve cardiac risk in these patients.


BRCA1 mutations. Following chemotherapy, AMH is often much reduced compared to pretreatment levels, with recovery dependent on the chemotherapy regimen administered, the woman’s age, and her pretreatment AMH. Recent data show there may be a long duration of relative stability of AMH levels over 10 to 15 years prior to decline rather than a rapid decline for many young women after cancer. Post-treatment AMH may have utility in determining that ovarian function will not recover, contributing to assessment of the need for ovarian suppression in women with hormone-sensitive breast cancer. AMH measurement provides an index of treatment gonadotoxicity, allowing comparison of different treatment regimens, although extrapolation to effects on fertility requires caution, and there are very limited data regarding the use of AMH to estimate time to menopause in the post-cancer setting.Cancer treatments can be damaging to the ovary, with implications for future fertility and reproductive lifespan. There is therefore a need for a biomarker than can usefully provide an assessment of the ovary and its potential for long-term function after cancer treatment, and ideally also be of value pre-treatment, for the prediction of post-treatment function. In this review we assess the value of anti-Müllerian hormone (AMH) in this context. Measurement of AMH at the time of cancer diagnosis has been shown to be predictive of whether or not there will remain some ovarian function post-treatment in women with breast cancer, in conjunction with age. AMH may however be reduced at the time of diagnosis in some conditions, including lymphoma, but probably not in women with breast cancer unless they are carriers of  Adolescent and young adult cancer survivors can experience many late effects related to their cancer treatment. With substantial improvements in survival following many common cancers, perhaps most importantly in the present context for women with breast cancer , and recOvarian function, specifically the development of ovarian follicles and associated reproductive hormones, contributes directly to reproductive and sexual health in this population. Measures of ovarian function for diagnostic and predictive indications may help clinicians and patients understand their current as well as predicted future ovarian function. While conventional indicators of ovarian function, namely cyclical menstruation, gonadotropins, estradiol, and progesterone remain essential for assessing current ovarian function (growth of larger follicles and ovulation), the last 15 years have seen a substantial interest in the potential value of measuring anti-Müllerian hormone (AMH). The objective of this review is to discuss current understanding of the clinical value of measuring AMH in young cancer survivors at cancer diagnosis and post-treatment. Specific questions we address include whether AMH levels at cancer diagnosis and/or post-treatment predict response to ovarian stimulation in the short-term, and fertility or time to menopause in the long-term. We also discuss how AMH levels reflect current ovarian function and help to estimate the gonadotoxicity of cancer treatments.Other reviews in this collection will address many of the details surrounding the origins of AMH and what is known about its role and value in normal ovarian physiology. For the present context, the key points are that AMH is not produced by primordial follicles, but it is produced by the granulosa cells of growing preantral and small antral follicles. There is a relationship between the number of primordial follicles and the number of growing follicles in the adult human ovary , and theA further important attribute of AMH is that is it detectable in the circulation in childhood as well as in adults, though with complex age-dependent changes , 9. SpecThe measurement of AMH at the time of diagnosis in women with cancer has two important clinical uses. Typically measured in clinics, most immediately, it is of value in assessing the functional ovarian reserve in women considering ovarian stimulation for fertility for egg or embryo vitrification for fertility preservation, and therefore the question is whether it has the same predictive value as in the normal situation in women having assisted reproduction. Second, in conjunction with age and cancer treatment, it may be of value in predicting long-term ovarian function after cancer treatment is completed.Data showing that AMH levels are reduced in women with lymphoma at the time of diagnosis compared to age match controls , 12. ThiBRCA1 and BRCA2 genes on ovarian function. These genes encode proteins involved in the DNA damage repair pathway, which is of key importance in the oocyte  varies by age and by diagnosis/treatment , 34. YouWith AMH levels drawn post-treatment as a reflection of current ovarian function in those patients, age, AMH at the end of treatment, and BMI are factors associated with the rate and extent of recovery in AMH following treatment. In addition to younger age, having a higher AMH at the end of treatment is associated with greater and faster recovery , and higFollowing recovery after cancer treatment, AMH will again decline as it does in all women. Although this is a challenging aspect of the subject to study, whether the rate of decline is affected by prior chemotherapy has been investigated. In an analysis of the rate of decline of AMH in 170 cancer survivors aged 15 to 39 years over a 2-year period, the rate of decline in AMH was similar to that in similarly aged controls, albeit at lower levels overall, and in both younger groups was much slower than in older women, aged 40 to 50 years . A seconIn a recent analysis of recovery of ovarian function following treatment for Hodgkin lymphoma, it was confirmed that women treated with ABVD overall showed a complete recovery of AMH levels, in contrast to those treated with BEACOPP Figure 2Indeed, age modified the relationship between gonadotoxicity and post-treatment AMH trajectories in a large cancer survivor cohort . The traImportantly, in the present context, recovery of AMH after chemotherapy does not reflect an increase in the ovarian reserve, but a recovery in the population of growing (AMH-producing) follicles in the functional ovarian reserve. Similarly AMH levels are reduced in healthy women taking hormonal contraception , and areMany cross-sectional studies clearly show that treatment type is related to AMH levels, both acutely and over the long-term. The first such study to show this was in young women who had been treated for childhood cancer, but who still had regular menstrual cycles thus overtly had normal ovarian function . These wMore limited prospective data are available. In a pediatric cohort of 22 girls with a range of diagnoses and aged 0.3 to 14 years, AMH fell progressively with each course of chemotherapy becoming undetectable in approximately half the group . The keyVariation in AMH levels by treatment also suggest that AMH may serve as a biomarker of gonadotoxicity. Acutely, between cancer diagnosis and end of treatment, AMH levels fell more in those exposed to alkylating chemotherapy exposure, compared to those not exposed to alkylators . LongituThe accurate diagnosis of permanent ovarian insufficiency is of considerable value in patients treated for cancer beyond fertility considerations. Ovarian function is also of importance in hormone dependent breast cancer as it may impact on choice of endocrine therapy. The use of aromatase inhibitors is now established to improve survival in post-menopausal women with breast cancer , but theAMH levels have been shown to be not influenced by tamoxifen co-administration, but they are suppressed by GnRH agonist administration over a period of several months , thus thThe above discussion clearly shows the value of pre- and post-treatment AMH in female cancer survivors for predicting post-treatment ovarian function, serving as a biomarker of treatment gonadotoxicity, and in the diagnosis of ovarian insufficiency, particularly when a sufficient time for early recovery of ovarian function has been allowed to elapse. Pretreatment analysis of AMH level is of value in predicting long term ovarian function in women with breast cancer but its value in other diagnoses and with other types of chemotherapy regimen, particularly when less gonadotoxic are unclear. The interaction with age in this respect is intriguing, and it is likely to require a greater understanding of these adverse effects of chemotherapy on the different compartments and cell types of the ovary. There are promising data that in certain sub-groups AMH may be of value shortly after completion of chemotherapy and ultimately this may be of value in guiding adjuvant endocrine therapy in some women with breast cancer. Current data suggest that AMH is not of value in predicting short term fertility in women following cancer treatment as shown both by specific analysis  and in iAll authors contributed to the article and approved the submitted version.The authors work in this field has been supported by MRC grant MR/N022556/1 (to RA) and NIH HD080952 (to HS).RA has undertaken consultancy work for Roche Diagnostics.The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Evidence indicates that school-based sexuality education empowers children and adolescents with the skills, values, and attitudes that will enable them to appreciate their health and well-being, nourish respectful social and sexual relationships, understand their rights, and to make informed choices. Owing to organized community resistance and prevalent misconceptions, promoting sexual and reproductive health has been challenging, especially in conservative settings like Pakistan. This study aimed at systematically exploring communities’ perceptions regarding implementing school-based comprehensive sexuality education by conducting a cross-sectional community readiness assessment in Islamabad, Pakistan. A total of 35 semi-structured interviews were conducted with community key informants. Following the guidelines of the community readiness handbook, the interviews were transcribed and scored by two independent raters. The results indicate that, overall, the Islamabad community is at stage two of community readiness, the denial/resistance stage. Individual dimension scores indicate that knowledge of efforts, resources for efforts, knowledge about the issue, and leadership dimensions are at the denial/resistance stage. Only community climate was rated at stage three of community readiness, the vague awareness stage. This indicates that, for promoting sexuality education in the Pakistani context, it is essential to tackle resistance by sensitizing the community and the stakeholders through awareness campaigns. In 1994, the International Conference on Population and Development called for the education and promotion of adolescent sexual and reproductive health (SRH) ,3. AccorPakistan is a tough setting for implementing and promoting reproductive health, women empowerment, and sexuality education ,8. It isThe World Economic Forum’s gender parity report 2020 ranked Pakistan 151st out of 153 countries . FemalesAccording to UNESCO, “there is less clarity about how to implement (CSE) and how to scale (it) up in diverse contexts”, especially when confronted with community resistance . ResistaThe literature from Pakistan suggests that a large proportion of the youth supports the introduction of SRH education ,9,10. ThAccording to findings of a literature review conducted by Stith et al. , the folA considerable effort needs to be invested in the development of strategies to increase community support for CSE in Pakistan. There is a lack of research and general discussion of the kind of resistance, possible strategies to respond to resistance, and the role of influencers, leadership, and gatekeepers ,23. HencOur study was based in Islamabad, Pakistan. Islamabad has a population of almost 2 million with 0.3 million households according to the 2017 census . The citAccording to Mouli et al. ,23, therThe key respondents were recruited using purposive sampling. Online searches of institutions involved in sexuality education and/or policy-making were conducted to identify potential respondents. Searches were also conducted to identify community members who might act as gatekeepers for sexuality education. Snowballing was also used to identify and recruit additional respondents. For each tier of the community, five to six key respondents were recruited, as recommended by the CRM handbook . The resThe scoring system used was adapted from the CRM handbook  and is pThe reliability of the independent scores of the two raters was assessed using the intraclass correlation (ICC). ICC measures the reliability of two different raters and, therefore, is used to determine the inter-rater reliability . The intThe two raters discussed and developed a consensual score for each dimension and interview as recommended by the CRM handbook . The gloRegression analysis was conducted to examine the association of the respondent’s characteristics with the consensual scores for each dimension and the global score. Even though the sample size of 35 respondents is a limiting factor for regression analysis, it can still provide some interesting insights about how the respondent’s characteristics affect the scores. Since the scores were given on a nine-point rating scale, the dependent variables range from 1 to 9. Such models cannot be estimated using a linear model because the predicted values from a linear model can go beyond the range of 1–9 . AdditioIn Equation The sociodemographic characteristics of the respondents and a summary of the duration of the interviews are provided in Of the 35 respondents, only 10 responded that currently there were efforts in Islamabad to address sexuality education . On a scAlmost two-thirds of the respondents believed that leadership is not supportive in expanding efforts to address sexuality education in Islamabad . On a scWhen asked to rate how much of a priority sexuality education is for community members in Islamabad, on a scale of one to ten, a mean value of 2.89 was given by the respondents . The resOn a scale of one to ten, the level of community members’ knowledge about sex education in Islamabad was given a mean value of 3.97 . The resRegarding resources for efforts, the respondents thought that there were very few volunteers and little space for conducting activities on sexuality education in Islamabad . They thThe results of the regression analysis are provided in This study aimed to systematically investigate the level of community readiness regarding the implementation of school-based CSE in Islamabad. Overall, the results of this study highlight that community readiness currently corresponds to the denial/resistance stage, which is not conducive to the effective promotion, development, and integration of CSE in the school-based curriculum in Islamabad. The low readiness levels observed were attributed to misconceptions, lack of awareness, community resistance towards efforts, lack or absence of leadership support, and scarcity of resources dedicated to such efforts.The denial/resistance stage of community readiness suggests that some members of the community recognize the issue under discussion but, due to lack of awareness and the prevalence of misconceptions in society, do not recognize its entire relevance . The CRMThe fact that less than a third of the 35 respondents were aware of any community efforts addressing sexuality education in Islamabad and that the lowest readiness score across all the dimensions was observed for community knowledge of efforts, might be due to the associated stigma, that leads to a lack of dissemination of information regarding these efforts to the public . The lowAlthough the global community climate was scored the highest among all dimensions, the score corresponds only to vague awareness among community members. The respondents’ perception that sexuality education is of low priority for community members in Islamabad and that community members might passively support efforts in this regard rather than being actively involved in developing and implementing such efforts resonates with the general stigma and resistance in the Pakistani community towards such efforts . ResistaCommunity members’ reported a lack of knowledge about CSE, the benefits of school-based adolescent health interventions, issues regarding adolescent health in the community, how adolescent health can be improved, and information regarding age appropriateness of sexuality education. These are some of the underlying reasons that nurture community resistance. Although there is evidence highlighting the potential of CSE to improve adolescent health and at the same time empower adolescents to make healthy and right choices as they grow older and develop ,25, therThe low priority given to sexuality education in the community and by the leadership is further reflected in the low score for the resources dimension. Lack of resources is one of the key factors that make the initiation of efforts and programs a major challenge. There is a need for increased awareness and priority building measures to garner community and leadership commitment to work towards developing and integrating sexuality education in the curriculum. Rigorous teacher training to deliver content on sexuality education has also been emphasized as an integral part of successfully integrating CSE into the curriculum ,50,51. IUNESCO’s international technical guidance on CSE stresses that CSE programs should be tailored and optimized in the local context, culturally and religiously, for their uptake and implementation to be successful ,25. In rAlthough the community readiness model offers a systematic methodology to appraise the level of a community’s readiness regarding a specific issue, it also entails some limitations. CRM is a subjective methodology that can be used to conduct a cross-sectional assessment of community readiness . AccordiSchool-level implementation barriers are only a small part of the challenges that hinder the implementation of CSE programs. Other barriers, for instance, policy level planning, leadership engagement, community mobilization, and support, and resource allocation also need to be addressed. For the successful implementation of CSE, there must be an enabling environment, which includes support and investment at the policy and community levels coupled with infrastructural backing. As of today, the community readiness level for the successful implementation of CSE in Islamabad was found to be low. Efforts should be directed at creating awareness, garnering support, and prioritizing CSE within different tiers of the community.


Sleep and circadian rhythm disruption (SCRD) is a common feature of schizophrenia, and is associated with symptom severity and patient quality of life. It is commonly manifested as disturbances to the sleep/wake cycle, with sleep abnormalities occurring in up to 80% of patients, making it one of the most common symptoms of this disorder. Severe circadian misalignment has also been reported, including non-24 h periods and phase advances and delays. In parallel, there are alterations to physiological circadian parameters such as body temperature and rhythmic hormone production. At the molecular level, alterations in the rhythmic expression of core clock genes indicate a dysfunctional circadian clock. Furthermore, genetic association studies have demonstrated that mutations in several clock genes are associated with a higher risk of schizophrenia. Collectively, the evidence strongly suggests that sleep and circadian disruption is not only a symptom of schizophrenia but also plays an important causal role in this disorder. The alterations in dopamine signaling that occur in schizophrenia are likely to be central to this role. Dopamine is well-documented to be involved in the regulation of the sleep/wake cycle, in which it acts to promote wakefulness, such that elevated dopamine levels can disturb sleep. There is also evidence for the influence of dopamine on the circadian clock, such as through entrainment of the master clock in the suprachiasmatic nuclei (SCN), and dopamine signaling itself is under circadian control. Therefore dopamine is closely linked with sleep and the circadian system; it appears that they have a complex, bidirectional relationship in the pathogenesis of schizophrenia, such that disturbances to one exacerbate abnormalities in the other. This review will provide an overview of the evidence for a role of SCRD in schizophrenia, and examine the interplay of this with altered dopamine signaling. We will assess the evidence to suggest common underlying mechanisms in the regulation of sleep/circadian rhythms and the pathophysiology of schizophrenia. Improvements in sleep are associated with improvements in symptoms, along with quality of life measures such as cognitive ability and employability. Therefore the circadian system holds valuable potential as a new therapeutic target for this disorder. Schizophrenia is a severe psychiatric disorder, it is a leading cause of disability affecting nearly 1% of the global population . It is hPer1/2 and Cry1/2, which then feedback to repress CLOCK and BMAL1 transcriptional activity  in which the transcription factors CLOCK and BMAL1 induce expression of the clock genes activity . This coactivity . Peripheactivity . The SCNactivity . Numerouactivity . There iThe mechanisms underlying SCRD in schizophrenia are currently unclear. However the involvement of DA in both schizophrenia pathogenesis and the sleep and circadian systems suggests that it may be involved. Here, we examine the interplay of SCRD with DA in schizophrenia, assessing the role of DA in the regulation of sleep and circadian rhythms, as well as the circadian influence on DA itself.Sleep and circadian rhythm disruption is widespread and well documented in schizophrenia. Indeed sleep disruption has been noted to be associated with mental health problems for over a century and the prevalence of SCRD in schizophrenia was reported to be as high as 80% . These sRecent studies provide evidence that sleep disruption may indeed play a causal role in the development of psychosis. It is clear that SCRD can precede the appearance of psychosis on the one hand, and exacerbate negative outcomes on the other. Fragmented sleep and blunted circadian rhythmicity of behavior have been observed in adolescents and young adults at risk for psychosis  and SCRDDisrupted sleep in schizophrenia is associated with poor quality of life, higher rates of relapse and suicide , and theClinical studies examining melatonin use as an add-on therapy in schizophrenia suggest that it may also be effective at ameliorating sleep disruption in this disorder  in  hundred . Whilst  hundred , these l hundred , and NF-ostimuli .Bdr) is a mouse model of synaptosomal-associated protein (Snap)-25 exocytotic disruption that displays schizophrenic endophenotypes. Their circadian rhythms are fragmented and phase advanced, and there is some evidence that this arises from disruption of synaptic connectivity within the SCN, thus disrupting rhythmic outputs  agonists have been reported to induce sedative effects and increase sleep in humans and rodents  and vasoactive intestinal peptide (VIP) neurons, other key SCN subpopulations involved in entrainment.In the SCN itself, there is a high number of dopaminergic neurons, with  rodents . Early s rodents . More re rodents . Studies in mice . However1R signaling. They showed that DA signaling in the mouse SCN is required for normal re-entrainment following a jet lag-like phase shift in the light/dark cycle  for DA re-uptake, a potential model for schizophrenia. Elevated DA in these mice led to aberrant ultradian activity rhythms with fragmented daily activity, which mirrors the disruptions to the rest/activity cycle observed in patients with schizophrenia . In the absence of an SCN this drives food anticipatory activity (FAA), whereby an increase in locomotor activity precedes mealtimes by 1 to 3 h . DA sign1R and D2R. The D1R heteromerize with the A1R, resulting in an inhibitory action of adenosine to dampen DA receptor response , the rate-limiting enzyme in DA synthesis . NumerouDrd3, and is required for its rhythmic expression in the nucleus accumbens (Per2 is required for its diurnal rhythm in expression, and Per2 mutant mice exhibit reduced MAOA activity and increased DA levels in the striatum (Evidence suggests that these diurnal rhythms are driven by direct regulation of DA signaling components by the circadian clock. The synthetic enzyme TH is under direct transcriptional control by both CLOCK  and REV-ccumbens . In addistriatum . CollectThere are also numerous lines of evidence that the DA system is modulated by melatonin. The MT1 melatonin receptors are expressed in dopaminergic regions of the rodent and human brain, including the VTA and nucleus accumbens where they exhibit diurnal changes in expression . GeneralThere are also changes in extracellular DA levels across the spontaneous sleep/wake cycle. The fluctuations vary between brain regions, but generally levels are higher during wakefulness . In the Overall, it is clear that DA and the sleep and circadian systems interact at multiple levels, and this reciprocal relationship may be a key element of schizophrenia pathophysiology. Numerous studies outlined here have demonstrated the involvement of DA in the regulation of both sleep and circadian rhythms. It is therefore implicated that alterations to DA signaling, such that occur in schizophrenia, would lead to disruptions to sleep and circadian rhythms. Indeed, elevation of DA signaling through genetic and pharmacological approaches leads to disrupted sleep and fragmented rest/activity rhythms . FurtherOn the other hand, DA is also under the control of the circadian clock and exhibits sleep-dependent changes, therefore it is likely that SCRD will lead to dysregulation of the DA system. SCRD is a key feature of schizophrenia pathophysiology, it largely occurs independent of medication status or disease stage  and therTherefore, overall the DA system and the sleep and circadian systems are key modulators of each other. The two have a bidirectional relationship whereby dysregulation of one will lead to disturbances to the other, this will likely lead to a positive feedback loop in which the two exacerbate each other . Given tSleep and circadian rhythm disruption is a key feature of schizophrenia, with deficits present from the level of the molecular clock up to behavioral rhythms. Studies discussed here demonstrate that DA signaling is an important modulator of sleep and circadian rhythms, and therefore constitutes a common mechanism underlying both sleep and circadian rhythm regulation, and schizophrenia pathophysiology. On the other hand, DA is also influenced by the circadian clock and sleep, and the close reciprocal relationship of the two systems appears to be important in the development of schizophrenia. Whilst further understanding of the mechanisms underlying this complex interaction is needed, there are already several potential pathways where dysregulation of DA can lead to disturbances to sleep and circadian rhythms, suggesting that aberrant DA may lead to SCRD in schizophrenia. Nevertheless, targeting sleep and the circadian system holds valuable therapeutic potential to improve symptoms and quality of life for patients.AA and AJ have both contributed to the writing of the manuscript. All authors contributed to the article and approved the submitted version.AJ is in receipt of funding from Circadian Therapeutics Ltd. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The pubCD73 has been detected on human exosomes isolated from plasma and serum  and pleuvia CD39 and CD73, but also carry adenosine and inosine in their inner compartment (via CD39 and CD73, and also by transporting and releasing adenosine and inosine far from the site where they are released, protecting these molecules from metabolism or uptake processes (Exosomes isolated from UMSCC47 cell lines are not only able to produce adenosine, partment . Thus, erocesses . This coThe purinergic signaling plays a critical role in cancer, since adenosine triphosphate is released in the tumor microenvironment upon hypoxia, nutrient starvation, cell death, or treatment with some chemotherapeutic agents. It is well known that adenosine triphosphate acts as pro-inflammatory mediator; nevertheless, the high expression of CD39 and CD73 in tumor microenvironment enhances its conversion into adenosine, which, in turn, is responsible for tumor growth and impaired immune response Many components of the adenosine pathway have been assessed as a therapeutic target or potential biomarker of prognosis. In particular, CD73 has emerged as a promising candidate both as a target and biomarker in different human tumors, as mentioned above, helpful in clinical practice to select patients that would likely respond to CD73-targeted therapy. Many studies focusing on the expression of CD73 in tumor tissue have been published; nevertheless, it has to be noted that results may be different according to the tissue type and its heterogeneity, or to the technics used to measure the expression. Furthermore, the possible effect of pharmacological treatments on CD73 expression needs to be considered. The analysis on tumor tissue is an invasive and painful procedure that could be particularly difficult in patients with metastatic disease. The analysis of the soluble CD73 in biological fluids, which needs further investigations, could represent an additional tool in clinical practice.+ exosomes in cancer, evaluating the possibility to use these vesicles as biomarkers of prognosis. One more point that needs to be explored is the mechanism regulating the cleavage of CD73 from the cell membrane. It could be of great interest to fully understand the stimuli that promote the shedding and/or the production of CD73+ exosomes, evaluating whether the blockade of these processes could impact tumor progression.To date, further investigations are required to better understand the role of CD73RT and SM conceived the manuscript. RT, AP, and SM drafted and reviewed the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.