Ensuring safe meals with suitable hygienic-sanitary and nutritional features is an essential requirement to guarantee health in different settings. This study aims to evaluate the compliance of collective catering menus adopted in both school canteens and healthcare facilities in a regional area where specific guidelines have been issued, assessing many matters from food weight to single courses and from the use of wholegrain pasta and bread to the rotation of seasonal fruit and vegetables. Overall, 85 menus, edited by freelance professionals and endorsed by the Food Hygiene and Nutrition Service staff of the Local Health Authority, were assessed from 2018 to 2022, highlighting critical issues potentially attributable at a local level to the lack of complete knowledge of the existence of guidelines and official reference documents among nutrition professionals. Since the preliminary outcomes show non-compliance in both sectors investigated, it is essential to continue to strengthen the role of prevention departments entrusted with services dedicated to food and nutritional safety and promote joint official controls performed by healthcare workers and other professionals with different backgrounds in order to ensure safe food for the target population that use collective catering services. In school canteens and healthcare facilities, providing and administering food is an opportunity to promote health through a balanced diet and safe food and offers opportunities for the development of community well-being and the local economy in a sustainable manner, understood in economic, environmental and social terms. In recent years, owing to an increase in the prevalence of obesity in the developmental age population, with a consequential growing risk of long-term complications, the adoption of timely preventive actions is required to support the availability of healthy foods and balanced nutrition throughout the life cycle ,2. The “Since many behaviors, which will become permanent in adults, begin to take shape at the developmental age, it is necessary to define effective interventions, programs and policies for health education and promotion, especially in this population group. As widely reported in the literature, a combination of approaches implemented by a multiplicity of actors is essential in order to successfully fight the high burden of non-communicable diseases (NCDs). Their effectiveness will be strengthened by actions on equity and health determinants and the empowerment of the target population .Recent evidence indicates that the best results of health promotion actions on the target developmental age population are obtained at school. These contexts certainly have a priority role in educational terms, not only for aspects related to culture and education, but for the promotion of healthy and correct lifestyles too ,9. IndeeLikewise, collective catering carried out in healthcare facilities, including hospitals and care homes, must address the needs of specific population targets, which are often heterogeneous, by considering comorbidities and the need to provide special diets. Therefore, health authorities must ensure a suitable control system for both nutritional and hygienic sanitary features of the whole food chain, from production to transport and consumption.In addition, the potential adherence to voluntary certification schemes, such as the UNI EN ISO IEC 9001:2015, UNI EN ISO IEC 22000:2018 and UNI EN ISO IEC 22005:2008 standards, could be useful for raising the safety and quality requirements of food safety management systems ,13,14. TIn this context, new regional guidelines for schools, companies and hospital caterers have been issued in the Puglia region in Southern Italy ,17. The According to the guidelines, in the Italian tradition, lunch is generally made up of a first course, a second course, a side dish and fruit. This distribution can be maintained in collective catering, or, alternatively, a “single course” can be proposed, including both foods rich in carbohydrates  and foods with a good protein composition (legumes). First courses intended for collective catering  must be made up of cereals  and prepared using a variety of different recipes respecting local traditions and replacing dry first courses and soups. As an alternative to pasta and rice, first courses based on barley, spelt, oats, cornmeal and quinoa are suggested, often associated with greens, vegetables and legumes, useful to allow a wide variety of flavors and a reduction in the glycemic index. A valid replacement for dry first courses is vegetable soup, to be served at least once a week, especially in winter. Furthermore, it is useful to frequently promote the use of wholegrains rich in fiber and micronutrients.The second course should consist of white meat , red meat , fish, meat-based products , eggs and cheeses, with suitable preparations for all age groups, promoting an adequate rotation. Due to the fatty acid content, following the indications provided by the Italian guidelines for a healthy diet, cured meats should be limited and possibly proposed as a replacement for red meat.In general, each meal should include a side dish of vegetables of at least three different types during the week, alternating between cooked and raw; bread with no added fat and with a reduced salt content; and seasonal fruit of at least three different types during the week, if ready to eat. Potatoes are not considered vegetables and should be offered as a first course once every two weeks. For the dressing, for both raw and cooked food, only extra virgin olive oil should be added, due to its recognized nutraceutical value. Aromatic herbs should also be used, while limiting butter and salt intake. Moreover, iodized salt is preferred to other salts. The use of bouillon cubes containing monosodium glutamate or any other food matrix containing it is prohibited.The general aim of this study is to evaluate the conformity of school and healthcare facility menus to the new regional guidelines for schools, companies and hospital caterers. The study was carried out in a five year period between 2018 and 2022 by the Food Hygiene and Nutrition Service (SIAN) of the Local Health Authority ASL BT (LHA), as the competent body for official controls. The specific aims of the investigation are targeted to: (i) assess the compliance of the menus adopted in both school catering services and healthcare facilities, subject to endorsement by the SIAN staff of LHA; (ii) analyze the types of non-compliance detected, hypothesizing the origin and suggesting corrective actions; and (iii) evaluate the need for subsequent on-site official controls in order to evaluate the conformity between the endorsed menu and the type of meals actually administered.Overall, in the BT province, 72 comprehensive institutes (CIs) and didactic circles (DCs) benefit from a school canteen service. The 72 CIs and DCs are school aggregation units, including 218 schools of any type or level. In the same territorial context, 18 accredited healthcare facilities are present, which are hospitals or private structures that provide services on behalf of the National Health Service.In the years 2018–2022, the SIAN of ASL Barletta–Andria–Trani (BT) LHA received 85 requests for menu endorsements, of which 67 were from CIs/DCs that contained a total of 199 school units and 18 were from accredited healthcare facilities. Hence, as represented in All menus, edited by the professionals of each structure , were submitted to the LHA for assessment by SIAN staff. Checklists with the requirements to be met were used in order to precisely evaluate the menus proposed.In compliance with the regional guidelines for school catering, menus must be specifically edited to meet the needs of pre-school and school-age subjects ,18. WithAll menus must be divided into two seasonal versions, one in autumn–winter, for the months from October to March, and one in spring–summer, for the period from April to September, structured taking into account a differentiation over four weeks (one month).p < 0.05.The proposed menus were evaluated and the results were reported in a database using Microsoft Excel©. All statistical data analyses were carried out using the software R version 4.0.3 (10 October 2020) . The normality of all the variables was evaluated with a D’Agostino–Pearson normality test. Categorical data were represented as numbers (n) and percentages (%). The χ2 test was applied to evaluate the difference in proportions. The level of significance, indicating evidence against the null hypothesis for all statistical tests performed, was set at The processing of results relating to the menus specifically for use in school catering shows numerous critical issues in relation to the compliance observed, as shown in All schools included legumes on the menu, and no school decided to benefit from the choice of using cereal grains or wholegrain pasta and bread. Only 8.9% of schools did not use prepacked foods such as fish fingers, just 11.9% of schools respected the correct food weight and only 17.9% rotated seasonal fruit and vegetables.Overall, 34.3% have cooked ham on the menu, in more than half of the schools a single course is provided and in 88% of the schools potatoes are correctly considered a substitute for pasta and not a side dish. Almost 90% of schools have menus divided into autumn–winter and spring–summer seasons.The results of the evaluation of the menus applicable to healthcare facilities are listed in All the institutions investigated offered legumes on their menus. Only two food establishments out of 18 provided both grain cereals and a single course on the menu, just three establishments provided wholegrain pasta and bread and only one-third of establishments did not use prepacked foods.Almost half of the structures had cooked ham and potatoes on the menu as a first course, only partially respecting the seasonality of fruit and vegetables. Overall, 77.7% of healthcare facilities respected the seasonal subdivision of the menus into autumn–winter and spring–summer and more than 80% of the establishments served the correct food weight.Analyzing the data derived from school catering and healthcare facilities, wide divergences emerge between the expected data and the observed data. The statistical tests also show significant differences between the expected data in accordance with the guidelines and the data observed and assessed by the SIAN staff.A correct and balanced diet is an essential requirement for people’s well-being. From the data collected and examined in our study for school catering, the intake of legumes is fully compliant with the consumption recommended by the regional guidelines. The additional foods investigated and evaluated show statistically significant non-compliances. Potatoes, a source of complex carbohydrates, continue to be included in menus as a side dish, even though they are not vegetable and, consequently, they should be offered as a replacement for pasta and other cereals, both as a first course or in association with a meal lacking in additional carbohydrates. Cereal grains such as barley, spelt, quinoa or wholemeal bread and pasta, usually belonging to the Mediterranean food model and essential for their fiber and micronutrient  contents, were not included in any presented menu. A single course, sufficient to cover the energy and nutritional needs of a complete meal , is only partially available in the examined menus, despite the guidelines recommending its constant presence at least once per week. The presence of prepacked products further indicates the failure to adhere to the guidelines, which recommend the exclusion of processed and packaged products. Among these, fish fingers and fish sticks are commonly used above all in school canteens. These foods consist of fish-based products with a high percentage of carbohydrates, saturated fats and trans fatty acids compared to the contents of fresh fish, as they are ultra-processed products, breaded with breadcrumbs, wheat flour or potato starch and herbs, then fried with vegetable oils, which are often not even specifically indicated among the ingredients. The high palatability of these foods is not only as a result of the oil used for frying, but also a result of the high salt content. Therefore, it is a pre-fried food with a higher content of carbohydrates than proteins, it is rich in fat even when cooked in the oven and it is highly caloric compared to a fresh or frozen fish fillet; moreover, it is high in salt and low in omega-3 polyunsaturated fatty acids. In addition, the weekly amount of cooked ham served on menus is not compliant, resulting as too high. Considering the high amount of sodium, saturated fats, cholesterol and additives, such as nitrites and nitrates, monosodium glutamate and polyphosphates, this food matrix should be offered no more than twice a month.Furthermore, the incorrect subdivision between autumn–winter and spring–summer menus consequentially means that the seasonality of fruit and vegetables is not fully respected too.Criteri Ambientali Minimi (CAM)—Minimum Environmental Criteria for the collective catering service and the supply of foodstuffs [The seasonality of the menus is not adequately respected, although particular attention is recommended to ensure the seasonal rotation of vegetables when choosing vegetable side courses. This topic is currently regulated in our country by the official document odstuffs .Recent studies have investigated the nutritional quality of menus adopted in schools located in other countries, highlighting non-compliances attributable to a lack of healthier options and highlighting a lack of macro- and micro-nutrients and a high salt content. By promoting specific projects and carrying out official follow-up controls, in some virtuous contexts it has been proven that compliance with respect to the guidelines appears to be very high ,22,23. INotably, one further non-compliant criterion observed concerns the food weight, which did not always comply with the guidelines. Respecting weight is of fundamental importance to guarantee that children have the right caloric intake, which is connected to height and weight growth according to different age groups. Providing an adequate food quantity is essential for receiving the correct nutrition and achieving the right energy requirements if placed in a context based on prevention and health promotion. This approach is undoubtedly useful for school-age children benefiting from a canteen service in order to promote a sense of awareness with respect to the appropriate quantities of food to be eaten daily. However, administering food in adequate quantities can be difficult, so it is essential that the canteen personnel are fully aware of the reference portions. In order to make this activity easy and truly implementable, the portion, as well as the weight, must be calculated by nutrition professionals and adapted to the needs of each individual, taking into account gender, age, physical activity and health status. Resorting to the aid of a scale is not always possible in operational terms; consequently, the need to train food business operators (FBOs) arises. It would also be advisable to create operating instructions with photo guides, useful to quickly highlight the compliance between the action performed by FBOs during the plating phase and the document stating the reference quantities. The regional guidelines indicate the ideal weights of each food, enclosed in a summary table that makes it possible to identify in an intelligible way the correct amount of food expected for subjects at each development stage.Similar to school catering, the same non-conformities emerged in healthcare facilities, with the exception of legumes and weights. Sure enough, these last items assessed met the specifically recommended energy and nutrient needs ,25.It should be noted that school catering cannot be considered as the mere satisfaction of nutritional needs, but as a moment of education and health promotion. Eating at school represents a convivial moment, useful for enriching the home food model through new flavors, tastes and food experiences and managing the difficulties some children have with food they have never eaten—which are often protective in terms of health—or food with a taste not appreciated for the first time. Meals served in the school canteen offer greater guarantees both in terms of hygiene and nutrition and are preferred over the consumption of food brought from home as they are more susceptible to targeted official controls .If for the school-age population the acquired healthy food style could be maintained for life, the correct nutrition in healthcare facilities is even more essential, since it correlates with a favorable prognosis for the patient. Malnutrition is common in hospitalized/institutionalized patients, especially in frail and elderly people with cognitive impairment, and negatively affects prognosis. In this population, it has been demonstrated that malnutrition worsens the quality of life and increases morbidity and mortality . It has -Visual checks of the hygienic sanitary state of the raw material;-Visual checks of label information ;-An assessment of compliance with the specifications indicated on the transport document or invoice ;-The control of transport temperatures for perishable products;-Congruity with respect to the type of product ordered ;-Internal laboratory checks ,31,32,33From our investigation, it is evident that in order to adequately respond to the provisions of the regional guidelines, FBOs should implement multiple activities aimed at continuous improvement, taking into account various aspects in order to ensure compliance with the sector legislation. In detail, FBOs assigned to food delivery must carry out direct actions on supplies through:Menu verification should also take into consideration some matters, in particular the perceived quality through the periodic collection of information relating to consumer satisfaction, which can be used as a basis for inducing improvements; the evaluation of surpluses and residues through a quantitative and qualitative assessment of food not distributed, both single-portion and multi-portion; and the courses rejected by consumers, for the redefinition of weights, portions, recipes and sensory characteristics.For catering businesses, it would also be advisable to adopt an information technology (IT) management tool, useful to guide and monitor all production stages, starting from goods delivery to creating a virtual warehouse suitable for providing information on the lot, expiry dates and products in stock, facilitating the rotation of raw materials at the same time. Depending on the daily menu, the application could have multiple purposes, e.g., scheduling the supply; indicating the weight of each course; suggesting previously endorsed menus according to the seasonality; implementing blockchain mechanisms for goods management and control; and daily tracing of raw materials and the destination of the final product up to it being served.A list of qualified suppliers, including data useful for assessing their reliability and qualification criteria, must be created, taking into account the history of the collaboration; test orders; certifications related to the quality and safety of the food product; and the results of audits directly conducted at the supplier’s establishments. For the purpose of a correct supply in compliance with the rotation and seasonality of the products, it is essential to monitor order fulfillment times, which is useful for guaranteeing the on-time arrival of goods.Sustainable diets have a low environmental impact and contribute to food and nutritional safety, as well as to a healthy life for present and future generations. Moreover, this approach contributes to both the respect of biodiversity and ecosystems, optimizing natural and human resources . In addiFor the prevention and management of food surpluses, it is useful to carry out calculations and continuous monitoring. Subsequently, the reasons underlying why any excess is generated should be analyzed by means of questionnaires, for example . The reduction in food waste is possible through the implementation of various strategies, such as the correct structuring of menus, the improvement of organoleptic qualities and the preparation of targeted foods ,37,38.In order to increasingly reduce food waste, the European Commission has recently proposed to integrate and amend the Directive 2008/98/EC. In particular, it has been suggested to add the wording “often good after” next to “best before”. This will allow eventual benefits from this feature during the supply phase. In any case, this would not exempt the FBO from evaluating any risks to which the product may be exposed, from the packaging integrity to any other aspect that may affect the condition of food, which must be suitable for human consumption . Taking Although our investigation is representative of the collective catering activities at the local level, it deals with a provincial area of reference. Therefore, the results cannot be extended either to the regional or national level, where, in addition, the norms can be different. Furthermore, at present, our study is based on the evaluation of menus for LHA documental endorsement in a preventive phase. Follow-up studies are necessary to assess the effective implementation of the suggested correction measures over time and to evaluate on site the correspondence between the foods on the daily menus and the foods actually served.Nevertheless, to the best of our knowledge, this is the first study that evaluates the compliance of the proposed menus with specific regional guidelines. It is essential to highlight that, at this preliminary level of checks, only a partial compliance with the provisions of the law has emerged. It is therefore essential to plan and continue promoting actions in this field, aimed at verifying the activities undertaken by these types of food businesses. It should be noted that professionals in this field always drew up the analyzed menus; nevertheless, without official controls performed by the LHA, they would have reached the tables of collective catering users with significant critical outcomes. This underlines the importance of both controls and the monitoring performed by SIAN on one hand, and, on the other, the need for dedicated training events to make freelance professionals aware of the correct way to draft menus. From these findings, it follows that there is a need to continue to strengthen the role of the Services of Prevention Departments dedicated to food and nutrition safety, to continue to invest in terms of employing professionals with a multidisciplinary background and to continue targeted training to guarantee joint official controls performed by physicians, biologists, dieticians, food technologists, health visitors and environmental health officers ,43.In school canteens and in healthcare facilities, providing and administering food is an opportunity to promote health through a balanced diet and safe food, offering the prospect of the development of the community’s well-being and local economy in a sustainable way. The collective catering sector is of particular importance, which is directing increasing attention to the issues of the quality and sustainability of products offered to consumers according to the principles of “catering promoting health”. Our study reveals critical issues regarding the drafting of menus that are not always in compliance with the guidelines. Therefore, it is essential for the LHA to evaluate the proposed menus, followed by official controls on both the compliance of the menus during the daily food delivery and on the hygienic conditions of schools and healthcare facilities ,44. At tFinally, both nutrition professionals responsible for drafting menus and FBOs must be adequately trained, to meet the minimum requirements for collective food services and projects to manage food surpluses.


Little is known of the scale of avoidable injuries presenting to medical services on a national level in the UK. This study aimed to assess the type and incidence of preventable wrist and hand injuries (as defined by the core research team) at a national level in the UK. 28 UK hospitals undertook a service evaluation of all hand trauma cases presenting to their units over a 2 week period in early 2021 identifying demographical and aetiological information about injuries sustained. 1909 patients were included (184 children) with a median age of 40 (IQR 25-59) years. The commonest five types of injury were fractures of the wrist; single phalangeal or metacarpal fractures; fingertip injuries; and infection, with the most common mechanisms being mechanical falls and manual labour. This is the first extensive survey of preventable hand injuries in the UK, identifying a need for further work into prevention to reduce healthcare burden and cost. 50% of injuries presenting to hand surgeons are preventable, with the most common injuries being single fractures of the wrist, phalanx and metacarpal. Few preventable injuries were related to alcohol or narcotic intoxication. Further research is needed to identify how to initiate injury prevention measures for hand injuries, particularly focussed towards hand fracture prevention. Recent work in the US identified a significant burden of disease associated with hand and finger lacerations, predominantly in men presenting with knife injuries.Some hand injuries are avoidable, yet they constitute an acceptable risk of day-to-day living, such as playing sport. To enable further research in this area, a recent definition of preventable or avoidable injuries has been established.The aim of the study was to firstly determine the feasibility of data collection pertaining to preventable wrist and hand injuries at the national level in the UK and secondly to describe the type and incidence of these injuries. The study aimed to highlight the common causes of preventable injuries, to identify key areas potentially amenable to intervention, and to understand the cost to the NHS and burden of injury upon society.Volunteer consultant orthopaedic, plastic or hand surgeons who were willing to undertake an evaluation of preventable hand injuries over a two-week period from 00.01 hrs on Monday 22 February 2021 to 24:00 hrs on Sunday 7 March 2021(Supplementary Table 1) were sought throughout the UK. The participating hospitals (n=28) represent a mix of district general hospitals, major trauma centres and specialist academic and teaching institutions . Each hoa priori . Specifically, it was considered that injuries associated with sport were not preventable, as there are inherent risks to playing sport but the benefits of playing sport outweigh the risks involved. Moreover, boxer's fractures were considered not preventable without change in human behaviour. These data were entered into a spreadsheet with drop down menus to optimise accuracy and a descriptor column in case of doubt. The descriptors of the injury mechanisms were assessed  to evaluate whether they were preventable or not; when in doubt, they were considered to be not preventable. The cost of each individual treatment could not be assessed in detail; however, data on the treatments provided an indication of the costs involved.Data including patient demographics, types and mechanisms of injury as well details of whether the patient admitted to being intoxicated or under the influence of illegal drugs at the time of presentation to the ED were collected. Preventable injury criteria were decided Data was descriptively analysed only due to the nature of study design.Data were available from 28 hospitals representing a reasonable geographical spread throughout the UK. In total, 1909 patients were eligible for assessment, including 184 children under 16 years of age. There were 1118 men, and 789 women; and in two patients, the sex was not recorded. There were slightly more injuries on the right side (right 955 vs left 919) with bilateral injuries in 35 patients. The median age of all patients was 40 years ; the median age of the adults (≥ 16 years) was 44 years ; the median age of the children was 10 years . The median time from injury to attendance in the ED or at their general practice surgery (GP) practice was 0 days . The median time from attendance in the ED or at their GP practice for review by a specialist was 1 day .The five most commonly recorded injuries were fractures of the wrist, single phalangeal or metacarpal fractures, fingertip injuries and infections . HoweverThe mechanisms of injury are shown in This study demonstrates that it is possible to describe preventable injuries in patients presenting to hospitals in the UK. Furthermore, it was found that a large number of preventable and non-preventable hand injuries are presented to hand specialists in the UK. However, the data were collected during a period of national lockdown secondary to the COVID-19 pandemic. Therefore, the results are likely to be an underestimate of the true burden of injuries during “normal, non-pandemic” socialising situations. This study was planned as a pilot prior to a definitive study to compare injuries during a national lockdown to a period of relatively normal activity.Data were collected from 28 hospitals covering an estimated catchment totalling over 14 million people. Considering this sample to be representative and extrapolating this to the rest of the UK population, we estimated that approximately 4500 potentially preventable injuries occurred each week, totalling over 230,000 per year.et al. estimated that the medical and societal cost of hand injuries each year was $740 million in the Netherlands.Furthermore, a high proportion of fractures compared to soft tissue injuries were observed. In general, these injuries often require multiple hospital visits and specialist input from both surgeons and therapists.,,Men were considerably more likely than women to suffer injuries in general and preventable injuries in particular. The most common location for preventable injuries was at home, but injuries also occurred at work, despite the national lockdown. We considered that almost all injuries at work are preventable. At home, the preventable injuries were primarily associated with mechanical falls and do it yourself, in addition to injuries around doors and those associated with kitchen activities. Extensive work has been undertaken historically to address safety issues at the workplace, but high level reviews note a lack of evidence for several recommendations provided in the health and safety measures.There are limitations to this study. This study was undertaken during the COVID lockdown, and in a less unusual time the data generated may have been different. Inevitably, not every patient would have been accounted for; some may have been referred out of the catchment area ; and some patients may have been missed. Additionally, not all the data were complete. Another particular limitation is that the assessment of preventable and non-preventable injuries is biased by subjectivity. Efforts were made to limit subjectivity via consensus agreement between three individuals. The costs were not formally analysed, meaning that only estimates were made based on previous studies.Furthermore, defining preventable and non-preventable injuries within a category based on mechanism rather than a free text analysis on a case-by-case basis can be considered as another limitation. This definition method was designed to be pragmatic, encouraging clinical collaborators at multiple sites to engage in data collection. We felt that through an iterative process we could establish a ‘best case’ definition of what was or was not preventable, which could be suitably used with this study design. As a multicentre study that required data sharing, data had to be anonymised and classified into injury groups prior to being sent to a central study team for analysis. This prevented secondary disclosure of data, but this also meant that some granular information was lost. This granular data would enable more specific definition on a case-by-case basis. We did consider further case definition at each site, but the potential for case definition variation between sites and low interobserver reliability was considered significant enough to introduce bias. When formulating study design, we felt that the external validation throughout a wide geographically and socioeconomically mixed area, along with a greater sample size was worth the loss of granularity at each site. This method enabled us to obtain the most complete data possible at each of the 28 sites, and aided in the design of a replicable method of descriptive analysis of data. A limitation of this technique, however, is the potential loss of the nuance of injury mechanism, which could lead to misclassification.We must also acknowledge that the data was collected during a unique period, where communal activities such as contact sports did not take place due to lockdown restrictions. Whilst this makes the data associated with the pandemic interesting, a lower than anticipated proportion of preventable injuries may have been presented. Future work is needed to compare data collected during this period to a comparable period without restrictions in place. This is a multicentre audit, but it should be complimented by other studies focussing on smaller study areas that offer greater granularity of information.This is the first extensive survey of preventable hand injuries and shows how common they are in a representative sample of 28 NHS trusts  in the UK. Preventable hand injuries are common and potentially expensive. Investing in the prevention of injuries would appear worthwhile.The study was approved at each contributing site with local research governance approval prior to data collection.GG and MH conceived the study and GG, MH and JCEL designed the study method. All collaborators and ALW acquired the data. JCEL performed the data analysis, with GG, MG and JCEL interpreting the data. JCEL, MH and GG drafted the final manuscript. All authors were involved in the acquisition of data and in drafting, reviewing, and editing the final manuscript. JCEL, MH, GG, and ALW had full access to all data in this study. GG and MH are guarantors.National Institute for Health and Care Research Barts Biomedical Research Centre (NIHR203330); a delivery partnership of Barts Health NHS Trust, Queen Mary University of London, St George's University Hospitals NHS Foundation Trust, and St George's University of London.This work acknowledges the support of the The funding source had no role in the study design, collection, analysis, interpretation of data, writing of the manuscript, or decision to submit for publication.Further data may be available upon written request to the authors, noting that aggregated data will only be released to prevent secondary disclosure of data from the pseudonymised dataset.http://www.icmje.org/conflicts-ofinterest/) no support was received from any organization for this study.All authors have completed an ICJME conflict of interest form that is uploaded with the article; (


This paper estimates the effect of antibiotic usage in humans and food-producing animals on the prevalence of resistance in zoonotic bacteria in both humans and animals. Using comprehensive longitudinal data from annual surveillance reports on resistance and usage in Europe, we find that antibiotic usage in food-producing animals and antibiotic usage in humans are independently and causally related to the prevalence of resistance in both humans and animals. The study considers simultaneous and total usage of antibiotics in humans and food-producing animals to identify the marginal effects and joint effects of usage on resistance of both groups. By employing lagged-dependent variable and fixed-effects specifications, we provide a lower and an upper bound on the effects on resistance. The paper also contributes to the scant literature on how antibiotic use in humans is related to resistance in other animals. AntimWhile usage of antimicrobials is a primary contributor to resistance, evidence suggests there are socioeconomic, institutional and environmental factors which also play a role –11. The This paper therefore undertakes an empirical analysis of the relationships between use of antibiotics in human and animal populations and antibiotic resistance in both populations using national surveillance data. We evaluate four possible effects: use in animals causing resistance in animals; use in animals causing resistance in humans; use in humans causing resistance in humans; and use in humans causing resistance in animals, as indicated in 1.1.The extensive use of antibiotics in livestock contributes to the emergence of antibiotic-resistant bacteria in animal populations , 16, 17.1.2.While it is believed that the widespread use of antibiotics in food-producing animals is a significant source of antibiotic resistance in humans, the specific impact on human health is poorly understood , 24, 25.1.3.There have also been numerous studies of the effect of antibiotic use in humans on resistance in humans. Several studies have focused on specific populations, such as a nursing home or hospital, and demonstrated that increased antibiotic use tends to precede increases in resistance locally –37. At a1.4.To our knowledge, there is only one other study that examines the relationship between use of antibiotics by humans and resistance in animals . Howeverdirectly through excretion of antibiotics into the environment; but it may also affect humans indirectly through the increase in antibiotic resistance in animals who then interact with humans, sharing antibiotic resistance genes. And the resistance in humans could easily be transferred back to animals. Given these parallel mechanisms allowing resistance to spread, a true “One Health” approach requires a holistic approach which accounts for use in humans and in other animals.An important omission in these studies is the recognition that antibiotic use in humans and animals is occurring simultaneously. In this situation, it is reasonable to consider usage of antibiotics in both animals and humans can potentially affect resistance levels in all species at the same time. Use in animals, for example, may affect humans This paper thus brings together comprehensive data on usage in humans and food-producing animals of 11 antibiotic classes and occurrence of resistance in three bacterial species common in humans and food-producing animals from European surveillance reports over 11 years in 31 countries. This allows us to make numerous contributions to the growing literature on antibiotic use and resistance.or other animals. Our study introduces an analysis with usage in both humans and food-producing animals, allowing us to identify the marginal effect of usage in humans and animals separately. We are also able to estimate their joint effect. Adda attempted to do a similar analysis using data from US states , on antimicrobial resistance in zoonotic and indicator bacteria from humans, animals, and food, which is published annually. EFSA along with the European Centre for Disease Prevention and Control (ECDC) prepares the report on the occurrence of antimicrobial resistance in isolates from human cases and in isolates from animals and foodstuffs. Participating laboratories of both member and non-member states of the European Union (EU) report their data on antimicrobial resistance. ECDC’s protocols for harmonized monitoring and reporting of resistance in humans and food-producing animals are followed, during the reporting process, to overcome challenges of comparing antimicrobial resistance data from various countries using different laboratory methods and different criteria for interpreting resistance .Salmonella, and Campylobacter. For Salmonella, data on total number of isolates tested and number of resistant isolates are available for several selected serovars of importance. The reports also provide similar data for two most important Campylobacter species. These reports, however, did not include data on resistance to Escherichia coli in humans. For this bacterial species, we therefore used data from the ECDC Surveillance Atlas of Infectious Diseases  data. MIC refers to the lowest concentration of an antimicrobial agent that is required to inhibit the growth of a microorganism under standard laboratory conditions . This me2.2.Carbapenems.Antibiotic usage data for humans were extracted from the IQVIA MIDAS database. IQVIA reports the total volume of sales of antibiotic molecules used in human medicine based on national surveys. We included only the antibiotic molecules that were also present in resistance data. Antibiotic molecules were then aggregated by class  and quantified in metric tonnes. Thus, human antibiotic usage in tonnes varies by country and class and is available annually for the period 2008–2018. We extracted data on antibiotic usage in food-producing animals from the ESVAC database. The ESVAC project collects sales data of veterinary antimicrobials in participating European countries. The data is in tonnes for antibiotic class for 27 member states of the EU and 4 non-member states from 2008 to 2018 . Usage d2.3.per capita drawn from the World Bank Databank  specification:where per capita, and the Corruption Perception Index as additional covariates in the sensitivity analysis section, but we do not anticipate these control variables to have a substantial effect on the coefficients of interest, given the use of country fixed effects or the lagged dependent variable. The error term is given by We include unit fixed effects in FE estimation, denoted by The use of the two specifications enables us to check the robustness of our findings using alternative identifying assumptions. That is, findings from both specifications should be broadly similar. Moreover, according to Angrist and Pischke , fixed eFurthermore, we carry out sensitivity analysis of our findings based on these two specifications. First, to test for robustness of these results, we replicate these regressions after lagging the usage variables by 1 or 2 years. Second, we alter the sample definition, excluding outliers and including only specific bacteria. Third, we include covariates that have been shown to be related to antibiotic usage or resistance , 38, 55.4.Tetracyclines are the most heavily used antibiotics class in food-producing animals while in humans, Penicillins are most used. Our data does not include Carbapenem use in animals. Given the high variation in use across different antibiotics, we tested exclusion of heavily and lightly used antibiotics, as described below.Campylobacter exhibits the highest average resistance in food-producing animals followed by Escherichia coli and Salmonella. In humans, Campylobacter also exhibits the highest resistance followed by Escherichia coli. The distribution plots and central tendency tables in As seen in The correlations between log-transformed antibiotic usage and resistance measures for food-producing animals and humans generally show a positive relationship. Cephalosporins and Tetracyclines). We go a step further and disaggregate these relationships by year and by bacteria for each country. Results are presented in We show similar plots with the data disaggregated by year , bacteriThese plots reveal positive correlations between antibiotic usage and the prevalence of resistance for a given year, country, bacteria and antibiotic class. The positive association exists within the same group and across groups. That is, usage of antibiotics in animals is positively related to occurrence of resistance in animals and in humans. Similarly, human usage of antibiotics is positively related to resistance levels in humans and in animals.After exploring the correlations described above, we estimate the relationship between antibiotic usage and resistance using regression analysis. The results from our models are presented in The cross-species effect of usage on resistance is particularly important in this analysis. It is clear that higher usage can lead to higher resistance, but causality can also flow in the other direction, since with higher resistance, more antibiotics might be used to treat an infection. However, there is no direct mechanism by which higher prevalence of resistance in animals should lead to more intensive use of antibiotics in people. The cross-species effects are therefore naturally interpreted as being causal.To further investigate the causal effects, we go a step further. Instead of using contemporaneous usage we lag the usage variables by 1 and 2 periods. This addresses the problem of reverse causality, since resistance in the current year should not have any effect on usage in preceding years. The results are presented in 4.1.To check for robustness of our results we estimate both models after excluding possible outliers. We exclude penicillin, aminoglycosides and amphenicols separately from our data and run the models. As shown in Sensitivity analysis reveals our results are robust to different sample definitions. When the sample size is restricted by including only one bacterial species at a time, the statistical significance is naturally lower. The effects are always statistically significant for the fixed effect estimates, but not necessarily for the LDV specification. The range of resistance effects when we exclude countries with populations less than 6 million people are also robust and close to estimates in 5.The inherent convolution of growing antimicrobial resistance makes it difficult to understand the exact ways in which it spreads among domesticated animals, humans, and the environment. This paper aims to shed light on the relationships between usage and resistance between and across human and food-producing animal populations in Europe. It highlights relationships that have not been covered extensively in the existing literature, specifically, the effect of usage in animals on human resistance and the effect of usage in humans on animal resistance. Using data from European surveillance reports, the paper shows that simultaneous and combined antibiotic usage in food-producing animals and humans have a positive impact on the incidence of resistance in both the populations.What is novel in our analysis is that we simultaneously include both human and animal use of antibiotics when examining the relationships with resistance. This enables us to observe the marginal relationship between antibiotic use and resistance in humans and animals separately, conditional on use in the other group. Moreover, our econometric approach enables us to infer causality at an ecological level. That greater use of antibiotics would increase the prevalence of resistance is of course not surprising: however, we are able to quantify this effect within a range. In addition, we are able to show for the first time the effect of human use of antibiotics on the prevalence of resistance in food-producing animals.The estimated effects are both substantial and statistically significant. Strikingly, the lower and upper bounds of the effect of antibiotic use in animals on resistance in humans are not smaller than the effect of antibiotic use in humans. The estimated elasticities are, from the perspective of long-term impact on resistance, disturbingly large. Even at the lower bound, an increase in antibiotic use in animals of only 10% is expected to increase the prevalence of resistance in animals by around 2% and in humans by around 0.3%. Since, as we show in a recent paper, resistance tends to persist over a period of years, increases in usage may lead to long-term increases in resistance .Our study has numerous limitations. We are only able to provide the average effects of usage on resistance for Europe as a nation. Our data do not allow us to explicate clear mechanisms of how usage affects resistance within or across human and food-producing animal populations. There are several factors at play that determine the occurrence of resistance against antibiotics among bacteria. This includes the ancient molecular mechanisms behind the emergence of resistant bacteria and the natural concentration of antibiotics and resistant genes in the environment –58. It wvice-versa, resulting in increased morbidity and mortality (Antibiotic usage has been linked to an increase in resistance in both humans and food-producing animals, making it a critical public health issue. Injudicious use and over-use of antibiotics within and across clinical and agricultural settings provides a favorable environment for the emergence of antibiotic resistant bacteria, causing infections that are difficult to treat . The potortality , 63. In ortality . One immortality . Along wortality , 66. Morortality . TherefoIt is notable that this study’s data are drawn from European countries, which tend to have relatively low rates of antibiotic usage and resistance . Since a6.To summarize, this paper provides new insights into the complex relationships between antibiotic usage and resistance in humans and food-producing animal populations in Europe. Our analysis reveals that usage of antibiotics by both humans and food-producing animals has a significant and statistically relevant effect on the rates of resistance in both groups. The estimated own-and cross-elasticities are worrying and highlight the potential long-term impacts of antibiotic usage on resistance. However, the study has limitations, including the lack of clear mechanisms explaining the relationship between usage and resistance and the inability to account for environmental factors. Antibiotic resistance is a critical public health concern, and policymakers need to promptly adapt a multi-disciplinary approach which engages all relevant stakeholders and acknowledges the interdependence of animal, human and environmental health. Simultaneous usage of antibiotics in various sectors and direct and indirect sharing of resistance across humans, animals and environment calls for a need to implement integrated strategies to monitor usage and resistance across heterogenous One Health dominions.10.5683/SP3/RXHWFP.Publicly available datasets were analyzed in this study. This data can be found at: PRISM Data: University of Calgary’s Data Repository—Replication Data for: the effect of antibiotic usage on resistance in humans and food-producing animals: a longitudinal, One Health analysis using European data, doi: SR and AH: conceptualization, data verification, investigation, methodology, writing, and review and edit. SR: literature review, data curation, and formal analysis. AH: funding acquisition and supervision. All authors contributed to the article and approved the submitted version.AH’s work was funded by Canadian Institute for Health Research [Grant #170388], Canadian Institute for Health Research [Grant #387609] through the Global 1 Health Network, and Major Innovation Fund program of the Ministry of Jobs, Economy and Innovation, Government of Alberta through the AMR—One Health Consortium.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The relationship between an anesthetic procedure and cancer is a common theme of various research papers and systematic reviews. Prostate cancer, although it has a high incidence, is one example for which we currently do not know the possible benefits of anesthetic techniques. Our article starts from the current knowledge of the influence of anesthetic drugs and anesthetic techniques, and we propose where we should go in the future to elucidate its role in prostate cancer recurrence.Prostate cancer has become a major health problem in men. Its incidence is increasing as the average age of the affected population tends to be higher. Of all the possible treatments, surgery is the gold standard in its treatment. Surgery produces a deregulation in the immune system that can favour the development of distant metastases. Different anesthetic techniques have raised the hypothesis that different anesthetic drugs influence tumor recurrence and prognosis. Some mechanisms are beginning to be understood by which halogenated agents in cancer patients and the use of opioids may negatively affect patients. In this document, we group together all the available evidence on how the different anesthetic drugs affect tumor recurrence in prostate cancer. Cancer remains one of the diseases with the highest mortality and morbidity in the world. In cancer patients, the main cause of death is not the primary tumor, but tumor recurrence.Prostate cancer has the highest incidence in men with tumor diseases of the urinary tract and is one of the main health problems of any health system.Many patients diagnosed with any type of tumor will require surgical intervention as part of their cancer treatment. However, surgery, with undoubted curative power, has also been related to the progression of tumor disease. Surgical manipulation results in a significant systemic release of tumor cells. Whether these cells cause metastasis depends largely on the balance between the aggressiveness of the tumor and the adaptability of the organism . DiffereThe administration of anesthetic and analgesic drugs can promote or inhibit tumor spread by causing transient immune impairment at the time of greatest risk of oncological cell spread, such as during surgery.Currently, prostate cancer is the most common malignancy among men, surpassed only by skin cancer. Prostate cancer is also the second leading cause of cancer death in men in the United States. In 2023, an estimated 288,300 men in the United States will be diagnosed with prostate cancer, accounting for 27% of all male cancers. It is the fourth most commonly diagnosed cancer in the world. Prostate cancer is also the second leading cause of cancer death in men in the United States .The main treatment for prostate cancer is surgery. One of the main concerns among cancer patients is recurrence after cancer surgery. The results after radical retropubic prostatectomy depend on the local evolution of the tumor that can be defined by the risk in the D’Amico classification, the stage of lymph node involvement and the margins of the resected tumor . In addiThe hypothesis that anesthetic drugs and techniques play a role in the recurrence of prostate cancer is based on other studies that have shown their association with the recurrence of other urological tumors, such as bladder tumors ,21, sincIn the rest of this paper, we describe the following points:2. Anesthesia and Prostate Cancer2.1. Hypnotic Agents: Propofol and Halogenated Agents2.2 Opioids2.3 Regional Anesthesia3. Statins4. Discussion: Towards a New Paradigm5. ConclusionsPropofol seems to have a protective effect against the tumor progression of prostate cancer, while inhaled agents have been described as pro-oncogenic, in line with other tumor lines such as breast  or colorVolatile anesthetics and intravenous propofol have distinct influences on both cancer cell biology and host immunity. Several in vitro studies have shown that the exposure of tumor cells to volatile anesthetics is associated with the increased expression of prometastatic and protumorigenic factors through signaling pathways including hypoxia-inducible factor 1α and transforming growth factor β/Smad , and cytPropofol exerts a protective effect through various mechanisms, including an anti-inflammatory effect, COX-2 inhibition and PGE-2 reduction, increased CTL activity and decreased pro-inflammatory cytokines . PropofoIt has been postulated that volatile anesthetics can suppress both adaptive and maladaptive immunity, especially of NK, while propofol has been reported to preserve host immunity. This notion has been supported by the recent literature reporting the potential benefit of propofol-based TIVA over volatile anesthesia on overall survival, but not on recurrence in operated cancer patients .Propofol acts both on prostate tumor cells, inhibiting proliferation and promoting apoptosis, and at the immunological level, producing an anti-inflammatory effect and stimulating NK cell activity . One of Activation of androgen receptors is related to greater tumor progression and metastasis, with androgen inhibition being the treatment of choice in advanced prostate cancers. Propofol decreases androgen receptor activation  as well There are in vitro studies that attribute to propofol a role as an adjuvant with the different chemotherapeutic agents used in prostate cancer. Qian et al.  demonstrAt the clinical level, there is only one prospective study that compared TIVA with halogenated drugs (sevoflurane and isoflurane) that found no statistically significant differences in biochemical recurrences  .Since opioids are the standard treatment for pain, they are an important mainstay in anesthesia. However, there is a trend to limit the use of opioids in the perioperative period due to their numerous adverse effects, including nausea and vomiting, hyperalgesia, addiction and death, and to consider a multimodal approach to pain.At present, there is concern about the protumor effects that opioids may have . From anLennon et al. observed that synthetic opioids stimulate the endothelium, thus facilitating cell migration and proliferation, in addition to promoting angiogenesis with an increase in the release of VEGF . The intThe mU opioid receptor (MOR) has been associated with the evolution of cancer. In fact, MOR overexpression is related to a higher incidence of cancer metastasis .Multiple studies have linked cancer recurrence with the use of opioids in the perioperative period. However, the current evidence is less conclusive in the case of prostate cancer.There are studies that have found less biochemical recurrence in patients undergoing radical prostatectomy by epidural anesthesia versus opioid-based anesthesia . The stuOn the other hand, a recent clinical trial compared biochemical recurrence in 146 patients with prostate cancer scheduled for prostatectomy in two randomized groups: non-opioid anesthesia and opioid-based anesthesia. It was concluded that opioids do not modify biochemical recurrence rates or disease-free time in patients with an intermediate or high D’Amico risk after prostatectomy . NeitherThe use of locoregional techniques for multimodal anesthesia and analgesia seems to increase the survival rates of cancer patients due to a decrease in the systemic response to surgical stress, since it is known that sympathetic activation has an immunosuppressive role that favors the development of metastases, as well as the sparing role of opioids and other anesthetic drugs such as halogenated ones . FurtherA recent literature review concluded that in prostate cancer surgery, the risk of mortality is reduced with the use of regional anesthesia, but no association between the anesthetic technique and survival free of progression or biochemical recurrence was found . The metA study by Sessler et al. investigated whether the use of general anesthesia versus regional anesthesia and analgesia in cancer surgery can produce a reduced rate of recurrence or metastasis, due to its lower impact on the immune system. They examined opioid-sparing anesthesia  and its impact on recurrence rate compared to general anesthesia alone. They demonstrated that locoregional technique can attenuate the cytokine changes caused by surgical stress by producing an increase in the serum levels of IL-12 and IFN-γ and a decrease in IL-6 and IL-10. Therefore, the highest levels of IFN-γ/IL-12, important cytokines for the CMI response, are maintained during the perioperative period in favour of a Th1 environment  Table 1Table 1.The use of locoregional techniques for anesthesia and multimodal analgesia seems to increase the survival rates of cancer patients due to a decrease in the systemic response to surgical stress, since it is known that sympathetic activation plays an immunosuppressive role that favors the development of metastases from a distance, as well as for the sparing role of opioids and other anesthetic drugs such as halogenated ones .Although statins are not part of the anesthetic arsenal, due to their importance and high prevalence in patients with prostate cancer, we considered its inclusion in this article. Years ago, the relationship between the accumulation of cholesterol in prostate tissues and prostate cancer was demonstrated . SpecifiStatins reduce cholesterol by inhibiting 3-hydroxy-3-methyl-gluratil coenzyme A (HMG-CoA) reductase, a key enzyme in the mevalonate pathway and currently one of the most widely used drugs against this tumor. Deregulation of this pathway may increase the risk of prostatic tumor progression . On the Murtola et al. did not demonstrate an association between prostate cancer risk and statins in their 2007 study  but founRegarding the risk of recurrence after radical prostatectomy, Allot et al. found that statin treatment decreased the risk of biochemical recurrence by 36% . On the Despite advances in hormonal treatments, most prostate cancer patients undergo surgery for radical prostatectomy . During In prostate cancer, mechanisms of tumor immune escape also include the suppression/exhaustion of tumor-infiltrating cytotoxic T lymphocytes, inhibition of suppressor NK cells and upregulation of immunosuppressive immune cells .IFN-γ (the most investigated factor), TGF-β, TNF-α, IL-6, IL-17, IL-15, IL-27, complement factor C5a and other soluble molecules secreted by TME components, as well as hypoxia, also favour metastatic development .Experimental studies have revealed that the intracellular pathways ERK/MEK, Akt-mTOR, NF-kB, WNT and JAK/STAT are involved in the regulation of PD-L1 in prostate cancer. Blocking PD-1/PD-L1 signaling using drugs can prevent immune escape from the tumor .Because the inflammatory and immunological status of the patient is critical for cancer recurrence, it is critical that surgeons and anesthesiologists understand these factors and apply them to perioperative management. For years there has been a growing interest in how drugs used in the perioperative setting may affect the modulation of SMT and impact the survival of the cancer patient undergoing surgery.Current evidence supports the antitumor effect of total intravenous anesthesia (TIVA) with propofol in cancer surgery mainly due to the positive regulation of NK cell and T helper cell activity. In contrast, the use of volatile anesthetics appears to induce cancer cell proliferation and migration in in vitro studies. On the other hand, a recent meta-analysis reviewing the effect of perioperative regional anesthesia on cancer recurrence concluded that regional anesthesia did not reduce the rate of cancer recurrence in cancer surgery over general anesthesia in cancer patients . StudiesThis paper reviews the current evidence on the effect of anesthetic drugs in prostate cancer and although work on the effects of drugs used perioperatively as modulators of SMT appears promising, the current evidence does not support a change in anesthetic practice or the use of specific agents or techniques in order to reduce the risk of cancer recurrence in prostate cancer surgery. Overall, the impact of anesthetic technique on prostate cancer outcomes remains unclear . This coThus, as yet, no anesthetic–analgesic technique has demonstrated a direct correlative causality between its use in the perioperative period and a reduction in prostate cancer recurrence or an increase in disease-free time. However, knowing the different signaling pathways through which these drugs can modulate phenomena such as cell migration, apoptosis and neovascularization, among others, can generate coadjuvancy with the rest of the therapeutic measures provided to the oncology patient.Our research group proposes the need to interpret the use of anesthetics in relation to the prognosis of patients who are going to be operated on due to prostate cancer. It would also likely be beneficial to evaluate the use of anesthetics against other tumors as a non-curative therapeutic tool but coadjutant towards the reduction in tumor recurrence. At present, all works are focused not on knowing if different anesthetic drugs can help reduce cancer recurrence in patients, but if they reduce it per se equating the anesthetic action to surgical therapy or chemotherapeutic drugs. Although this may be the case in some types of tumors, being able to initially demonstrate a modulation that reduces the possibility of tumor recurrence should be enough to decide the ideal technique for each tumor disease, and in this case, for the choice of anesthetic drugs used for patients with prostate tumors. If we look at the example of cardioprotection by halogens, the modulation of different enzymatic pathways is enough to electively use inhaled drugs in this group of patients, although the complication of a coronary anastomosis is unavoidable.Currently, progress in this field is based on new markers and mediators of high sensitivity and specificity, and with a fundamental weight in the process of tumor recurrence, which will allow us to evaluate in future studies if there really is an antitumor modulation that by itself does select a type of anesthetic technique/drugs, similar to cardiac surgery.Further work is needed to identify biomarkers to better understand the influence of anesthetic technique on tumor progression and to select the optimal anesthetic drug for each cancer patient, generating an individualized anesthetic plan according to the characteristics of the patient and the tumor process. In this respect, the coding process may also be of great importance.Our new paradigm on knowledge in this area is based on the proposed idea of anesthetic action as a weapon in helping reduce cancer recurrence, and we believe that through the use of non-coding RNA, we could be able to demonstrate it.Non-coding RNAs, in particular microRNAs, play an increasingly important role in the fields of oncology and anesthesia. Current evidence suggests that the beneficial or detrimental effects of anesthetics during cancer surgery are mediated by genetic and molecular mechanisms . UndoubtReview articles have already investigated the role of lncRNAs in prostate cancer and have proposed the use of lncRNAs as biomarkers . LncRNAsAlong these lines, it has been suggested that anesthetics may influence the surgical outcome of cancer through miRNA changes both positively and negatively ,83. The Evidence is clarifying how deregulation of the tumor microenvironment can favour metastatic development. We know that in the perioperative period, the use of anesthetic/analgesic techniques plays an important role in the survival of cancer patients undergoing surgery by interacting with the immune system. We believe that the type of cancer should be considered as an important factor in the clinical decision to choose a specific anesthetic plan, which is why we need more studies that show pharmacological interaction with the prostate cancer cell, since most of the current works on this type of tumor are contradictory and do not have a high level of evidence. It is also necessary to carry out studies that analyze the influence of drugs such as dexmedetomidine, NSAIDs and beta-blockers on prostate cancer.It would be essential to identify the relationships between the RNAs that favor the progression of prostate cancer and the modulations that the drugs used in the perioperative period produce on these RNAs; in this way, we would understand what effect the use of these anesthetics has on patients with prostate cancer and we could develop an antitumoral anesthetic plan.


Co-creation, characterised by artists and patients creating a joint work of art, may support patients with the integration of life events into their life story, such as living with cancer. In the process of co-creation, resonance relationships between patients, artists and material may evolve that support integration. We aim to investigate if and if so, how resonance relationships occur from the perspective of the artist.Being affected, touched and moved; Self-efficacy and responding; Moments of uncontrollability; and Adaptive transformation. In addition, two case descriptions are presented.We used the first 10 audio recordings of supervision sessions between eight artists and their two supervisors on ongoing co-creation processes with cancer patients. By conducting a qualitative template analysis in AtlasTi, we searched for the presence of resonance, as defined by its four main characteristics, We found resonance relationships to be present in the studied co-creation processes where moments of uncontrollability can lead to a next step in the process of co-creation and as such form an important factor within co-creation.The current study suggests focus on elements of resonance relationships within co-creation, specifically practising with uncontrollability while working with art, could strengthen interventions targeting integration of life events in advanced cancer patients. The experience of living with cancer can reduce quality of life of patients . InterveIn previous studies on co-creation, artists indicated that the relation between patient and both artist and material is of a reciprocal nature and forms an important factor facilitating the co-creation process. Artists suggested that the co-creation process only becomes meaningful when patients become engaged , 11. AnoThe reciprocal nature of relations which actors have with their worlds is acknowledged by theories on resonance , 17, as A resonance process may unfold when one is sufficiently responsive to others, oneself and the world. An open attitude, the ability to be affected and the flexibility to change one’s perspective are prerequisites to experience resonance . ResonanBeing affected, touched or moved by the world is the first experience of a subject, which may stimulate an intrinsic interest in that which affects him or her. This intrinsic interest comes forth when one’s core values are affected in contact with the world, which becomes evident through bodily sensations, emotions and thoughts. (2) Self-efficacy unfolds when the person is able to actively reciprocate the call of that which affected him or her. (3) Uncontrollability is the element that is ingrained in the full experience of resonance. We cannot know when and how the world is going to affect us, nor do we know beforehand how to relate to being affected by the world. If one does not have the ability to be open to new experiences or to the unexpected, there is no possibility for resonance. (4) Adaptive transformation takes place when the person who is affected is able to respond effectively, which in turn changes both the person’s experience in the encounter with the unexpected as well as the person him or her-self.(1) According to Rosa, relations that contain these four main characteristics of resonance affect and change those who have these relations , 22. In In this study, we will first investigate, if and if so, how resonance relationships, as defined by their four main characteristics, occur within co-creation processes, from the perspective of the artist. Secondly, we will investigate how artists use these resonance relationships within co-creation.For the current study, we interviewed professional artists who are participating in the In Search Of Stories project (ISOS) . ISOS, fWe used a qualitative study design in which we audio recorded supervision sessions between professional artists and their supervisors as they reflected on co-creation processes with palliative cancer patients within the ISOS project. Artists and supervisors were not trained in, or familiar with resonance theory, nor were the supervision sessions based on resonance theory.We have first used template analysis to search for the presence and content of characteristics of resonance relationships within our study material. Secondly, we have used directed content analysis of specific sections of our study material to investigate how artists use resonance relationships within co-creation. All presented quotations and constructs were translated from Dutch into English by YW.To investigate our first research question—if and if so, how resonance relationships occur within co-creation processes—we looked for the presence and content of the four main characteristics of resonance by means of template analysis , 26. TemTo investigate our second research question, how artists use resonance relationships within co-creation, and to deepen our insights from investigating our initial research question, completed co-creation processes were selected. Co-creation processes from start to finish illustrate the full temporal developments within resonance relationships. The audio recordings of the supervision sessions of these cases were analysed by means of directed content analysis , 29. DirThe study was performed in line with the principles of the Declaration of Helsinki. This study was exempted from ethical approval by the Medical Ethics Review Committee of the Academic Medical Centre, since the Medical Research Involving Human Subjects Act was not applicable (reference number: W20_436 # 20.483). Written informed consent from every participating patient was obtained at the start of their enrolment. The professional artists interviewed for the current study were employed within the ISOS project and therefore informed consent from them was not applicable.In total, ten supervision sessions focussing on the co-creation process with the patient, involving eight of the eleven artists and two supervisors, were available at the time of the study. The other three artists were not yet involved in a co-creation process within the ISOS project. The eight participating artists were musicians, visual artists, scenographers, a theatre composer and a creative writer (see Table To investigate our first research question—if and if so, how resonance relationships occur within co-creation processes—we first looked for the presence of the characteristics of resonance, which are described in the final template see Fig. , and secMoments of uncontrollability was further subdivided into Expressions in a sequence, Making space to be surprised, Looking for the field of constant tension, Exposing the sting of the experience of uncontrollability and Attunement. Some labels of the characteristics were slightly extended to better encompass their content. The final template is shown in Fig. The final template mainly resembled the preliminary template; however, uncontrollability showed to be multi-layered and included several distinct dynamics and mechanisms. Therefore, the characteristic The characteristics of resonance relationships are described in detail and illustrated with artist’s quotations in Table Two cases are described to illustrate the temporal aspect of our findings on the second part of our first research question, how resonance relationships, as defined by their four main characteristics, occur within co-creation, and, more importantly, to answer our second research question, how artists use these resonance relationships within co-creation. These two cases are examples of different approaches in resonance relations that can be used by artists in co-creation processes. During the co-creation process, resonance relationships can provide a point of focus to alternate with moments of uncontrollability. Artists kept the patient interested and connected to the co-creation process during moments of uncontrollability by focussing on either or both resonance relationships. In case one, the artist puts more emphasis on the resonance relationship between patient and artist, whereas in case two, the artist puts more emphasis the resonance relationship between patient and material Table .Table 5CTo the best of our knowledge, this is the first study describing that within co-creation, from the perspective of the artist, uncontrollability has a central role and showed to be multi-layered and included several distinct dynamics and mechanisms. Also, artists both actively use attunement and keep the patient interested and connected to the co-creation process during moments of uncontrollability by focussing on either or both resonance relationships. Furthermore, resonance relationships, as defined by their four characteristics, are shown to be present in co-creation.One of the main characteristics of resonance theory, uncontrollability, plays a central role in co-creation as it affects the patient and invites responses from within the patient which can be expressed in subsequent stages of the work of art. Also, the encounters with uncontrollability can influence the perspective of the patient which can change over time. Uncontrollability also shows similarities to the element of uncontrollability in life events. These experiences of uncontrollability are sometimes referred to as experiences of contingency, which are described as having a nature to befall us unexpectedly . ContingAttunement is the word artists use to describe the level of resonance within resonance relationships. Artists consciously and actively attune to the patient to establish a high intensity of resonance. Attunement illustrates that resonance not only automatically emerges but that artists consciously support the establishment of a high intensity of resonance. In addition to this, artists also actively modulate the level of attunement and subsequently the intensity of resonance in the resonance relationship between patient and both material and artist. In this way, both the intensity of the patient’s experience of working with the material and the patient’s own emotions can be influenced. In attunement, there is conscious and active participation from the part of the artist in reaching out to the patient and adapting or adjusting to the patient. Our findings on attunement connect to a larger field of research where attunement is described as a factor influencing content and outcomes of various processes, as for instance in looking at art , art theAlso, we found that during the co-creation process resonance relationships can provide a point of focus to alternate with moments of uncontrollability. Artists keep the patient interested and connected to the co-creation process during moments of uncontrollability by focussing on either or both resonance relationships, i.e. between patient and material, between patient and artist, or both.Finally, within co-creation, resonance relationships between patient and both artist and material occur. These resonance relationships are defined by the four main characteristics of resonance theory: being affected, self-efficacy, uncontrollability and adaptive transformation. In our research, we found uncontrollability to be multi-layered encompassing five distinct modes of operation within co-creation. Also, artists consciously stimulate the emergence of resonance relationships. If these modes of operation and conscious creation of resonance relationships are also present in resonance relationships in other settings, this would be a further elaboration of resonance theory. As artists and their supervisors were not trained in, or familiar with resonance theory, the finding of the four main characteristics of resonance within co-creation could be seen as some form of confirmation of resonance theory as described by Rosa .The total of the above-described findings could be used as a template to further unravel and understand the intricate process of co-creation.Strengths of the study include that the artists were very experienced in their field of expertise, had previous experience in working with co-creation and had a high level of reflection on processes within themselves and in relation to the patient. Also, the involvement of artists with different fields of expertise and their ability to work with hybrid art forms contributed to creativity in the art making processes and as such positively affected artist-patient dynamics. A limitation of the study is that only the perspective of the artists is used while the perspective of the patients might be different. Thus, findings of the current study need to be confirmed by studies on the patients’ perspective.This study showed uncontrollability and attunement to be important factors in co-creation. The study confirmed the presence of resonance relationships within co-creation and showed how these resonance relationships can be used within co-creation. Focus on elements of resonance relationships within co-creation, specifically attunement and practising with uncontrollability while working with art, could strengthen interventions targeting integration of life events, i.e. experiences of contingency. Interventions using art, specifically the joint creation of a work of art, may contribute to supportive care for survivors with advanced cancer. Yet, further research to confirm this in patients and to evaluate effects on quality of life is needed.


China experiences a serious shortage of soybean supplies and relies heavily on international trade with high vulnerability and large uncertainty, which maybe sows food security risks. It is of great significance to analyze the structural evolution of the global soybean trade network and its implications to China for ensuring food security. This paper constructed a global soybean trade network (GSTN) and analyzed the structural evolutionary characteristics of GSTN from 2000 to 2020 using the complex network analysis method and simulated the impact of targeted destruction on China through scenario analysis. The results showed that GSTN was gradually complex exhibiting a small word and a scale-free network property. The global soybean exporter was dominated by some major soybean-producing countries in America. The US played an important role in maintaining GSTN’s robustness. China was the world’s largest soybean importer; unfortunately, its soybean imports relied heavily on a few countries, and the anti-interference ability of China’s soybean trade tended to decline. Therefore, China’s soybean trade was increasingly vulnerable to being tightly controlled by other countries when some uncertain factors occurred, such as trade frictions and changes in policy decisions from importing and exporting countries. The US and Brazil were key countries with significant soybean trade ties to China. To assess the impact of the two countries on China’s soybean trade, targeted destruction method was used through destroying them in the network. Targeted destruction scenario analysis indicated the two countries played important roles in the anti-interference ability of China’s soybean trade. Brazil played a positive role in China’s control of soybean trade flows, while the US did not. Some policies for China’s soybean production and international trade were proposed. A balance between the domestic production and import of soybean is needed. Optimizing the soybean trade import system and seeking more trade partners is crucial. Improving soybean self-sufficiency is the fundamental way to reduce the high-import dependence. The study provided some insights for coping with international market fluctuations and improving the sustainability of China’s soybean trade. Soybean is one of the important major food crops in China. It is not only the raw material for soy products but a commodity crop with industrial uses both in the livestock and edible oil sectors. Those sectors have grown rapidly in response to dietary shifts towards more animal protein  . AccordiThe complex network method is an important tool to study the characteristics and dynamics of international trade systems using topological features, which was widely applied in public transportation ,6, air qThe international grain trade flow is affected by policy decisions , diplomaWeighted and directed global soybean trade network G =  is constructed in this paper. V represents a collection of countries or regions; E is the trade direction between countries, and W denotes the weight of edges connecting the exporting country to importing country. The basic topological properties of complex networks include network density, path length, network diameter, weighted degree, betweenness centrality, closeness centrality, clustering coefficient, and modularity. The brief meanings of these indicators are summarized in ρ) refers to the ratio between the actual number of edges M and the maximum possible number of edges in the network. It is used to measure the closeness of trade between countries. The value range of network density is . The closer the value is to 1, the closer the trade ties between countries. For a directed network, N is the number of nodes.Network density (L) of the network is the average of the shortest distance between any two points, presenting the efficiency of trade between countries. i and j, and higher average path length means higher transmissivity efficiency.Average path length (Dia) is defined as the maximum distance between any two nodes (countries). The value of Dia is proportional to the scale of the network and can be used as a measure of the network size.Network diameter  indicates whether a node is in the shortest path (geodesic) of any two other nodes and shows the control of the node over the resource flows. k to pass through the geodesic between node i and j, andi and node j. The points with higher betweenness centrality usually play a more important role in the network.Betweenness centrality  is an indicator that measures the distance between a node and all other nodes in the network. It is used to consider the independence and resistance of nodes when they are under the influence of external factors. It shows the ability of a particular country to protect itself against trade risks from other countries, with the range of . The closer the value is to 1, the stronger the anti-interference ability of the country.i and its neighbor nodes Clustering coefficient (C) represents the ratio of the maximum number of connections between Q) is used to measure the degree of division of the communities in a network and to compare the communities with the whole network.Modularity  is calculated by Hyperlink-Induced Topic Search (HITS) algorithm, which is designed to rank webpages initially [p generated by running the algorithm. A node with a higher hub value than the other nodes plays a hub role in the network. The initial Hubp and Authp of each node are set as 1 and updated in every iteration step until they are stable through the following formulas:Hub value . Network efficiency (E) is often used to evaluate network robustness, especially the connectivity between nodes and the overall efficiency . Targetewww.fao.org/faostat, accessed on 15 May 2021). According to UN FAO Norms and the International Convention on the Harmonized Commodity Description and Coding System (HS) standard, the code for soybean is HS1201. In the FAO Trade Matrix data, each bilateral trade volume is reported by both the exporting and importing countries. Theoretically, the export volume reported by country A to country B should be equal to the import volume reported by country B from country A. However, the data is often not the same in reality. Considering import countries need to impose tariffs on imported goods, it makes the import data more precise. Through reviewing the data, we also found that the data recorded on the importers was significantly more complete than those recorded on the exporter. Therefore, data of soybean import quantity is used with five-year intervals selected  for analysis.Bilateral trade data for soybeans in this paper are from the FAOSTAT Detailed Trade Matrix database  a small-world property. It is reflected by the low path length and the high clustering coefficient of the network, which enable any two countries in the network to connect through other countries with a higher trade efficiency. (2) A scale-free network property. It means severe heterogeneity and inhomogeneous distribution of degree. The node degree distribution of the GSTN have a power law feature, i.e., a few nodes have an extremely large number of connections, while most nodes have a small number of connections . In FiguThe Louvain community division algorithm is often used to detect communities or clusters in large networks. It uses a hierarchical approach to partition nodes into communities by optimizing a modularity score that measures the density of links within communities. We employed the Louvain community division algorithm to distinguish the communities of GSTN in 2000, 2005, 2010, 2015, and 2020 . CompareThe community number of GSTN presented an upward trend, and the network structure became multipolar. The trade network could be roughly divided into two main communities in 2000, namely the Europe–America community and the Asia community. In 2005, the GSTN was composed of three communities: North America and parts of the Asia community, China and the South America community, and the Europe community. In 2010, GSTN can be briefly divided into two major communities: the America–East Asia community and the Europe–Africa–West Asia community. The largest community including 158 countries appeared in 2015: the Europe–Asia–North America–Oceania community, forming the GSTN along with the South America community. However, in 2020 the trade network evolved into four main communities, i.e., the Europe–America community, the Asia–South America community, the Africa–Middle East–South Asia community, and the Southern Europe–East Africa community. The modularity indicator oscillated throughout the study period  indicatiIn order to identify the importance and change of major import and export countries in global soybean trade, we showed the dynamic ranking of the top-ranked countries in terms of weighted degree, weighted indegree, and weighted outdegree during 2000–2020 . The US,According to the ranking of closeness centrality d, the toFrom the analysis of The largest community China participated in occurred in 2000 when 54 countries traded closely with China, such as the US, Argentina, and Japan. In 2005, the community China joined included 18 countries, mostly from Asia and Africa. Around 2010, China entered the community with the US and Brazil, which was attributed to the large trade volume with them. Then, Brazil’s exports to China continued to increase after its share surpassed that of the US in 2013 . China wCloseness centrality can reflect the node’s anti-interference ability to cope with external changes and disruptions. The rank of China’s closeness centrality continued to decline, falling from 16th in 2000 to 71st in 2020 . It indiAs described in Compared with the pre-disruption, the closeness centrality of China showed a decreasing trend in all three scenarios . We noteThe betweenness centrality of China showed a different trend after the destruction . The betThe US was the largest soybean trade partner before 2013, and the share of the US soybean was 52.0% in 2000; however, the share fell to 35.1% in 2013, then Brazil overtook the US as China’s largest source of soybeans. Due to the Sino–US trade friction, the share of the US was at an all-time low in 2018 of only 18.9% of China’s total soybean imports. To bridge the gap, China turned to South American countries, such as Brazil and Argentina. In 2020, China’s soybean importing quantity reached 100.3 Mt, more than that of 2017, and the majority of importing was from Brazil and Argentina. It indicated that on the one hand, Brazil and Argentina played a crucial role in the soybean trade of China; on the other hand, China had the ability to reduce the trade risk and meet importing demand when the US decreased trade volume.Trade network analysis could help explain the trade characteristics and dynamics of a country and further assess the relationship between domestic production and international trade and, therefore, provide suggestions for production and trade. We discussed the implications of the structural evolution of the global soybean trade to China’s soybean production and international trade.Only when food production is sustained can a country maintain its international competitiveness for a long time. Compared with industrial mechanization countries, China’s soybean production is still dominated by household farming making it difficult to achieve large-scale production and economic effects . Althoug2) at the end of 2019 and to increase the sown area to 150 million mu (10 million hm2) by 2020. However, acreage increased only slightly in 2020 and actually decreased by 15% in 2021 [Based on targeted disruptions and scenario analysis, we found China’s soybean import was vulnerable to be controlled by the leading trade countries  in GSTN. The share of China’s soybean imports from the US and Brazil accounted for over 85% in recent years. High dependence on foreign soybeans leads to large uncertainty for China’s soybean market when unexpected events arise. Nowadays, the international trade situation is a real roller coaster. During the trade friction between China and the US, China imposes a 25% tariff on imported US-made soybean , meaning in 2021 . Hence,  in 2021  accountiSigning trade agreements is conducive to promoting the growth and development of trade. Some measures, such as cutting tariffs and granting most-favored-nation treatment, are used to create good trade relations among countries. In 2001, China joined the World Trade Organization and made some commitments in agricultural trade, including not restricting soybean imports and reducing import tariffs. Since the Second Amendment to the Asia-Pacific Trade Agreement came into effect in 2018, China has cut soybean import tariffs to zero for some partners to counter the risk of insufficient soybean imports. Lowering soybean tariffs to reduce the import cost, increasing the quantity of soybean imports, and promoting import source diversification are important advantages for China to sign trade agreements. However, we should also note that uncertainties in the international market will bring volatility and risks to the Chinese market. If a flood of low-priced foreign goods enters the domestic market, domestic industries will be severely affected. Currently, China’s soybean supply is monopolized by several transnational companies, which seriously threatens the safety of China’s soybean industry . TherefoImproving soybean self-sufficiency is the fundamental way to cope with international market fluctuations and reduce high import dependence. To strengthen the planting area and yield is the primary measure. Some studies pointed out that profit was the greatest factor affecting grain production . StatistUsing the complex network analysis method, this paper analyzed the structural evolutionary characteristics of the global soybean trade and simulated the impact of targeted destruction on China through scenario analysis and finally discussed the implications to China’s soybean production and international trade. The results showed that the GSTN was gradually increasing and complex for the last two decades, exhibiting a small-world and a scale-free network property. With time elapsed, the GSTN became multipolar from two to four communities. The global soybean exporter was dominated by some major soybean production countries, such as the US, Brazil, and Paraguay. The US played a pivotal role in maintaining the GSTN’s robustness and had an enormous voice in global soybean trade. China was the world’s largest soybean importer; unfortunately, its soybean trade was increasingly vulnerable to being tightly controlled by other countries, especially the US and Brazil. In terms of controlling soybean trade flow, the existence of Brazil played a positive role to China, while the US did not. Although it seems unrealistic for China to rely solely on domestic production to meet the demand in the short term, a balance between domestic production and the import of soybean should be taken into consideration to reduce the high import dependence. Optimizing the soybean trade import system and seeking more trade partners are necessary and crucial for China. Measures can be taken to increase the acreage and yield to improve soybean production, such as raising the purchase price of soybean, improving subsidy policies and income insurance policies for soybean producers, breeding high-yield varieties, and exploring suitable planting methods and techniques. The study provided some insights for coping with international market fluctuations and improving the sustainable development of China’s soybean trade.This study has its limitations. The period 2000–2020 was determined in this paper considering the frequent emergencies  in recent years. However, it cannot completely reflect the whole picture of the changes in global and China’s soybean trade. A longer time series analysis with more data is necessary for future research. Multiple scenarios need to be included in the scenario analysis of targeted disruptions to simulate the impact on China. Additionally, the integrated telecoupling analysis for the relationship between soybean trade and food security is also a focus in our future research direction.