According to the World Health Organization, achieving targets for control of leprosy by 2030 will require disease elimination and interruption of transmission at the national or regional level. India and Brazil have reported the highest leprosy burden in the last few decades, revealing the need for strategies and tools to help health professionals correctly manage and control the disease.The main objective of this study was to develop a cross-platform app for leprosy screening based on artificial intelligence (AI) with the goal of increasing accessibility of an accurate method of classifying leprosy treatment for health professionals, especially for communities further away from major diagnostic centers. Toward this end, we analyzed the quality of leprosy data in Brazil on the National Notifiable Diseases Information System (SINAN).Leprosy data were extracted from the SINAN database, carefully cleaned, and used to build AI decision models based on the random forest algorithm to predict operational classification in paucibacillary or multibacillary leprosy. We used Python programming language to extract and clean the data, and R programming language to train and test the AI model via cross-validation. To allow broad access, we deployed the final random forest classification model in a web app via shinyApp using data available from the Brazilian Institute of Geography and Statistics and the Department of Informatics of the Unified Health System.We mapped the dispersion of leprosy incidence in Brazil from 2014 to 2018, and found a particularly high number of cases in central Brazil in 2014 that further increased in 2018 in the state of Mato Grosso. For some municipalities, up to 80% of cases showed some data discrepancy. Of a total of 21,047 discrepancies detected, the most common was “operational classification does not match the clinical form.” After data processing, we identified a total of 77,628 cases with missing data. The sensitivity and specificity of the AI model applied for the operational classification of leprosy was 93.97% and 87.09%, respectively.The proposed app was able to recognize patterns in leprosy cases registered in the SINAN database and to classify new patients with paucibacillary or multibacillary leprosy, thereby reducing the probability of incorrect assignment by health centers. The collection and notification of data on leprosy in Brazil seem to lack specific validation to increase the quality of the data for implementations via AI. The AI models implemented in this work had satisfactory accuracy across Brazilian states and could be a complementary diagnosis tool, especially in remote areas with few specialist physicians. Mycobacterium leprae and Mycobacterium lepromatosis, which affects the skin and peripheral nerves, causing stigma and disabilities that limit community involvement and social engagement [Leprosy is an infectious disease caused by gagement . Accordigagement .Currently, the conventional diagnosis of leprosy is typically based on clinical evaluation alone, especially when histopathological analysis is not available. The clinical diagnosis is based on cardinal signs such as the presence of skin lesions (often with loss of sensitivity), thickening of the nerves, and presence of the pathogen in a skin smear or histological tissue samples. Based on this information, classifications are applied to aid in the understanding and treatment of the disease ,3.The Madrid classification divides leprosy patients into the following four categories: indeterminate, tuberculoid, borderline, and lepromatous . HoweverCurrently, multidrug therapy is the main treatment for leprosy, which is based on schemes supported by the operational classification. The Guidelines Development Group, established by the WHO in 2018, recommends the same regimen of three drugs  for all leprosy patients, with a 6-month duration for paucibacillary cases and a 12-month duration for multibacillary cases. Some evidence suggests a potential increase in the risk of relapse for patients with paucibacillary leprosy using the previous two-drug regimen . TherefoLaboratory diagnosis can help differentiate leprosy from other dermatological/neurological diseases, especially in cases of suspected recurrence, and determine an appropriate treatment duration. In these cases, microscopic examination of the dermal smear is the method most commonly used because it is easy to perform and is of low cost. The bacilloscopy index (BI) is negative (0) in the tuberculoid and indeterminate forms, is strongly positive in the lepromatous type, and reveals a variable result in borderline cases .In 2020, the WHO outlined the goal to interrupt leprosy transmission at the national or regional level by 2030. However, to achieve this goal, it is necessary to routinely implement active case detection and contact tracing. Therefore, it is urgent to improve the tools used for an early and precise diagnosis of new cases [Brazil uses the Sistema de Informação Nacional de Agravos de Notificação/National Notifiable Diseases Information System (SINAN) to deal with epidemiological aspects of diseases with compulsory notification. A leprosy-specific form has to be filled out for each confirmed case, which involves information about the patient, including the number of lesions and affected nerves, grade of physical disability, and demographic variables, among others. All of these data are stored in SINAN’s online database and are available for epidemiological studies -10.The app proposed in this study was based on an in-depth analysis of the SINAN database using machine learning, a research area that focuses on how computers acquire knowledge from data. Machine learning can be subclassified into two general types: unsupervised learning and supervised learning. Unsupervised learning does not have a focus on a predictable output, as its main objective is to identify data patterns. By contrast, supervised learning focuses on an outcome such as determining if an animal in a picture is a cat or a dog . For appThere are some existing apps that were also designed to help diagnose neglected tropical diseases (NTDs). According to the WHO in 2018, an app was developed to facilitate the diagnosis of NTDs of the skin, including leprosy. This app allows health care workers and the public to obtain information about a specific disease, such as its clinical features, management, and geographical distribution, and provides a list of potential diagnoses. The training guide is now updated with recent information and has been translated into an easy-to-use interactive mobile app available free of charge on both Android and iOS platforms . RecentlGiven the above background, the main objective of our study was to develop a cross-platform app for leprosy screening based on AI. This app was designed to recognize patterns in leprosy cases registered in the SINAN database and to classify new cases as paucibacillary or multibacillary, thereby reducing the probability of misclassification by the health center.We divided the stages of app construction into two steps: (1) processing raw data and obtaining a decision matrix, and (2) using the decision matrix to build the app for classifying a case given an input. An overview of the entire process is shown in Initially, we downloaded all SINAN records related to leprosy cases from 2014 to 2019, which were converted to a single Comma Separated Values file. This procedure resulted in a 54-column file containing data on 174,871 cases, with each column corresponding to a specific variable reported by Brazilian health professionals about the leprosy cases notified.Many of these columns (variables) were not relevant to our study. Therefore, we removed those that did not fulfill the criteria as shown in The remaining dataset was composed of the variables age, gender, race, education, grade of disability, operational classification, BI, number of affected nerves, clinical form, municipality ID, number of household contacts, and the number of skin lesions. After this processing, we removed all lines with any entry of “NA” (not applicable), leaving a total of 123,054 cases.The Brazilian Practical Guide on Leprosy was reviewed to define the following criteria to remove cases with any inconsistency: (i) samples with a positive BI are always cases of multibacillary leprosy; (ii) patients with paucibacillary leprosy should have five or fewer skin lesions; (iii) indeterminate and tuberculoid are always paucibacillary forms; (iv) borderline and lepromatous cases are always multibacillary forms; (v) indeterminate cases have no disability; and (vi) a maximum of approximately 18 nerve trunks are evaluated in clinical examinations . After rThe Instituto Brasileiro de Geografia e Estatística (Brazilian Institute of Geography and Statistics), responsible for conducting the census, provides tables containing the estimated population by year and by municipality . These tConfidence intervals of these municipality inconsistencies were calculated for each state of Brazil. We calculated the median of household contacts by city and year. All data processing up to this point was performed using Python 3.8 and WPS spreadsheets.After initial processing with Python, the RF algorithm was applied to the resulting data using the R software package Random Forest. In addition to RF, there are several other machine-learning classification algorithms that could be appropriate for this task, such as naive Bayes , logistiAfter several tests to improve model accuracy, the following subset of variables was used to predict the operational classification of each case: region, state, city, age, number of skin lesions, affected nerves, household contacts, and bacilloscopy. Prediction of operational classification was chosen as the metric for evaluation instead of prediction of the clinical form for two main reasons: (1) Brazilian treatment is based on the operational classification , and (2)This multiplatform app was designed to meet the scientific demand for technological innovation concurrently with the lack of safe and accurate diagnoses in remote regions of Brazil, where training in clinical practice does not always match the international standards recommended by the WHO. In this sense, we incorporated only clinical variables reported by SINAN so that the app would be useful in the Sistema Único de Saúde  throughout Brazil.The decision forest obtained by the RF algorithm from the R package was deployed in a ShinyApp environment, which is a web service for constructing a friendly user interface. A good model must enhance the TPR and decrease the FPR. Thus, the quality of the model may be represented by the area under the ROC curve (AUC) value . The besThe value of each variable in the database has a different weight for the model. Some values approximate a paucibacillary classification, whereas other values approximate toward a multibacillary classification. Representing the distance between paucibacillary and multibacillary as a scale from 0 to 1, we can choose different values on this scale as the limit between the two classifications. These possible values are represented by the colored scale to the right of the ROC curve in Before data processing, the SINAN database had 35,616 lines with at least one NA, 26,539 lines with at least one unknown item , and 15,473 lines with both NA and an unknown item. There were a total of 77,628 cases with missing data, accounting for 44.39% of the total 174,871 cases. Based on available data in SUS, after cleaning the dataset, it was possible to geographically visualize the dispersion of leprosy incidence in Brazil over the period from 2014 to 2018 . A high In addition to showing the geographical extent of the disease, the cleaned database included individuals from 4 to 106 years old (mean of 44 years), with an average of seven lesions, two affected nerves, and three household contacts per case. The BI was not calculated in 37.00%  of cases, and for the remaining cases, 41.18%  of the BI results were positive. In total, the database reported multibacillary leprosy in 76.66%  of patients, who were scattered throughout the Brazilian territory .Starting from the assumption that the error of clinical diagnosis is properly characterized, it was possible to develop a support model based on AI. The RF algorithm presented the smallest mean of misclassification error compared with the other algorithms using 10-fold cross-validation with default hyperparameters considered in the mlr R package  Figure .We next sought to determine if AI can assist in choosing the correct treatment for leprosy. Since the Brazilian Ministry of Health and the WHO suggest patterns  to classify the disease, our group was able to develop this new strategy to help control leprosy. A different model for each Brazilian state was used to improve the prediction in the remaining states; that is, a cross-validation strategy was applied to avoid overfitting by training in one state but testing in others. The number of lesions, incidence, and affected nerves were among the most important variables in the three best models .This study analyzed the SINAN database from 2014 to 2018 considering the epidemiological, clinical, and sociodemographic context of patients diagnosed with leprosy in Brazil. In analyzing the frequency of inconsistencies in the SINAN database , we obseAccording to Grossi et al , there iAccording to WHO goals for 2030, it is necessary to employ strategic methodologies to assist leprosy control. The use of AI is a novel method with potential to expand the capacities to diagnose diseases, especially those that are neglected. The use of AI therefore allows for obtaining higher coverage in the initial diagnosis process and facilitates the sharing of secure information, with the aim to expand and reach a larger number of health professionals .We recognize the importance of a tool to improve the accuracy of insufficiently trained health professionals, especially in the most remote areas of Brazil. The app presented in this work proved to be a promising option to improve the coverage and scalability to the Brazilian health service regarding the choice of an appropriate treatment for leprosy . The traAnother relevant issue to mention involves problems in incorrectly filling out the reporting form. To fill out a SINAN form correctly, it is necessary to list the Madrid Classification and the treatment according to the operational classification. Therefore, a patient given a classification of indeterminate or tuberculoid has to receive treatment for paucibacillary leprosy, whereas a classification of borderline or lepromatous requires treatment for multibacillary leprosy.According to the Brazilian Ministry of Health in 2017, a case with a positive BI result should be considered as multibacillary leprosy. However, doubts arise for cases that are considered to be borderline and close to the tuberculoid pole. Despite the difficulty of correct classification, these cases are generally considered to be multibacillary leprosy [In addition to the implementation of an algorithm that helps choose the correct therapy, the use of intelligent data collection devices would allow for higher quality and validation . Such deNotably, the high accuracy (92.38%), sensitivity (93.97%), and specificity (87.09%) of this app provide a multiplatform method to support scalable characterization/classification for numerous other neglected diseases in remote communities in Brazil and worldwide.As previously mentioned, SINAN is a platform launched to manage notifications from each Brazilian state. The records of this platform are obtained from assessments made by many health professionals with different levels of qualification. Thus, the quality of data depends on many factors, including (i) quality of the items requested by the forms and their correct interpretation, (ii) correct clinical assessment of the patient, and (iii) proper filling out of the forms. In addition, it is important to note that the possibility to add more items of information about serological and molecular integrated tests for leprosy diagnoses could undoubtedly improve the accuracy of the method, as we have done in our research group . Lastly,The proposed app showed good accuracy to classify a case as paucibacillary or multibacillary leprosy by recognizing patterns in leprosy cases registered in the SINAN database. After validation, this app could be an essential tool to help health professionals make an accurate leprosy operational classification and decide which treatment to use for patients with paucibacillary or multibacillary leprosy considering reducing the likelihood of mistreatment. This study also highlights the importance of improving data collection methods given that prediction accuracy markedly increases with improved data quality.


The Urban Living Lab (ULL) approach has the potential to create enabling environments for social learning and to be a successful arena for innovative local collaboration in knowledge co-creation and experimentation in the context of research and practice in sustainability transitions. Nevertheless, complex issues such as the urban Food-Water-Energy (FWE) Nexus present a challenge to the realization of such ULL, especially regarding their inclusiveness.We present ULL as a frame for a local knowledge co-creation and participation approach based on the project "Creating Interfaces - Building capacity for integrated governance at the Food-Water-Energy-nexus in cities on the water". This project aims at making FWE Nexus linkages better understandable to the stakeholders , and to facilitate cooperation and knowledge exchange among them. This paper focuses on and discusses inclusiveness as a key aspect and challenge of ULLs and on what literature and our experiences in this regard suggest for the advancement of the concept of ULL towards ULL 2.0. These findings often also relate to framing transdisciplinary research in a wider sense. Inclusive and meaningful ULLs need time. Efforts of network building, reaching out to different groups, learning about different perspectives, needs, and interests require substantial efforts that tend to be easily underestimated.2. ULL activities should build on and respond to local needs; therefore, local stakeholders should be involved in the whole process including project definition.3. Research programmes and projects should be constructed in a co-creative way and enable or even enforce the active commitment of local stakeholders.4. For the research process to engage and influence local policy, it is necessary to build a sense of ownership among local decision-makers and to shape a vision for change concerning the local system from the beginning of the process.Sustainability transitions of urban systems need enabling space for learning and experimentation. Such spaces can be created in the form of ULL.Questions of inclusion and exclusion are closely tied to power relations. Linked to these, people are differently enabled to act and take part and social differences in power may be reproduced in ULL.There is a need for further reflection on and definition of the different roles, sensibilities, and qualifications of the involved researchers and stakeholders in ULL regarding skills, co-ownership, power relations, and legitimacy as well as process-related aspects.The complexity of urban systems demands sophisticated approaches that integrate knowledge and methods from different disciplines and academic, and non-academic experts as well as citizens. Sustainability transitions of urban systems need space for learning and experimentation. Such spaces can be created in the form of Urban Living Labs (ULL) as an experimental governance approach . Following McCormick Hartmann, There is a need for clarification and refining within the ULL concept and enabling frameworks. ULLs are widely referred to in literature but with different definitions and ways of realization. The essence remains often unclear  metabolism and infrastructures present a complex socio-technical process of coevolution. Growing in importance in recent years, the FWE Nexus was first discussed at the World Economic Forum in 2008  Nexus of JPI UE and the Belmont Forum and includes 10 partners from Europe and the United States . "Creating Interfaces" facilitates cooperation and knowledge exchange among involved stakeholders by developing and testing innovative approaches for local knowledge co-creation and participation through ULLs in three mid-size cities in Tulcea (Romania), Wilmington (USA), and Słupsk (Poland). The cities were chosen based on similar size, geographic position close to major water bodies, and similarities regarding social aspects, e.g., vulnerable populations. Additionally, existing relationships with project partners—providing access to local stakeholders and knowledge regarding local structures and institutions, topics, and needs—played a role.The ULLs aim to initiate local knowledge co-creation and participation as well as integrative urban planning and urban sustainability. The activities strive at making visible the interlinkages of the urban FWE Nexus and to foster system integration in vision building, decision making, and planning. The approach is to create different kinds of interfaces between knowledge systems, stakeholders of the different systems, and citizen-science-policy/administration. These interfaces are achieved through digital tools (for data collection and communication), workshops, network building, and platforms including visualizations.The project employs a transdisciplinary research design, including co-creation of digital tools, testing of communication methods, and addressing the inclusiveness of transdisciplinary research. Realizing inclusiveness is a major challenge for Urban Living Labs and the experiences in the project reveal key factors that can be the basis for further discussions on enabling and realizing sustainable transdisciplinary research.As Díaz-Reviriego et al.  point ouQuestions of inclusion and exclusion are closely tied to power relations. Power has material and symbolic dimensions and is based on three sorts of capital: social, cultural, and economical , social , scientific, business, and citizens. Stakeholders connected to some institutions, organisations, or entities were invited directly, citizens through project partners and an open invitation. The widest active stakeholder representation was achieved in the case of Tulcea. In all three cases, we involved stakeholders and representatives of authorities of each nexus component at the local level. The ones involved in the food and water component were more receptive than the ones responsible for the energy component. The food and water components are, to some extent, better represented at the local level and that respective local stakeholders have more local capacity and independence than the ones responsible for the energy component.It proved most challenging to involve citizens in all three "Creating Interfaces" project cities, especially at the beginning of the ULL process. We tried to enable broad participation through public invitations and snowballed contacts, but we have not gotten the desired level or breadth of participation . Involving citizens was mostly achieved through going to where the target groups were: in Slupsk (as the target groups are parents), to kindergartens and a community centre; in Tulcea, contacting residents during visits to the study sites and inviting them to workshops; in Wilmington, cooperating with neighbourhood organizations and approaching citizens in community centres. This outreach process was interrupted by the pandemic.We claim that ULLs can be an effective approach to integrate local communities into research and experimentation in a meaningful and inclusive way, especially if diverse community groups are represented in the research process. However, there is a gap in research and literature on who is involved or excluded  with local stakeholders and a focus on the municipalities. This included an initial definition of themes and starting points.While the overall thematic focus is generally defined in the design phase , during the implementation phase, all involved stakeholders should agree on needs, objectives, and methods  showed that the topic of food in educational institutions was an important issue. The institution's previous experience, specifically public kindergartens, in improving the quality of nutrition helped engage the discussion. The research challenge, however, was to integrate the food discussion into the broader context of the FWE Nexus. Another issue was the choice of date and time for the public ULL workshop, which was held on a Saturday (a free day for many professions in Poland). This choice was meant as a way to meet the needs of the citizens, who were not obliged to leave their work to take part in the workshop. However, with a relatively low level of civic activity in Słupsk, citizens could be reluctant to dedicate half of a free day, especially regarding the specific target groups of parents. Similar challenges emerged in Wilmington as to the starting point topic and timing of the workshop.An important challenge for all three ULL was the limited availability of the project team as well as of local stakeholders including citizens. Interviews with investigators in the project revealed an underestimation of the time required for the ULL implementation and capacity limitations due to the framework conditions of the project .Even though trust and trust-building in ULLs are often mentioned as important aspects or even prerequisites of living labs, these aspects still lack thorough investigation  was a key factor for success in this endeavour. In Słupsk, direct relations between kindergarten managers and parents helped to engage them in the activities.It should be emphasized that the experience in Słupsk showed that the process of building trust may concern representatives of public institutions even more than the citizens themselves. In participatory processes, such as the ULL process, expectations and needs articulated by citizens are often treated as criticism of public institutions. The institutions are not always able to respond directly due to the procedures in force, staff resources, or other issues—such as resistance to change of thinking and behaviour resulting from long-lasting habits (such problems emerged in cooperation with kindergarten managers).Targeted communication addressing different publics throughout the process and good communication skills present a key factor for inclusiveness and the success of the ULL. This is especially important for a complex topic such as the urban FWE Nexus, which most people do not immediately or easily understand and often needs explanation. Developing FWE Nexus literacies is a prerequisite for engaging stakeholders on meaningful solutions that suit the needs of the urban communities.This factor touches on a fundamental challenge of transdisciplinary sustainability research: the need for translation. If the TDR approach is taken seriously, cooperation should go beyond noticing and considering separate disciplinary contributions towards some common understanding and also aim at producing mutual and transformational learning . The respective element identified with stakeholders as the most relevant one during the project definition phase, allowed to base the local activities on expressed needs. The interlinkages were then explored, aiming to make the nexus more tangible. In Wilmington, a participatory modelling (PM) exercise on the local nexus interlinkages was realized with citizens and local stakeholders during the public ULL workshop. PM is defined “as a purposeful learning process for action that engages the implicit and explicit knowledge of stakeholders to create formalized and shared representations of reality” . Researchers can play a relevant role here in enhancing the visibility of non-obvious connections and interfaces between elements of the urban FWE Nexus. In Wilmington, the initial choice of linking the ULL to local community energy was changed to food waste reduction after the first ULL workshop and subsequent interviews. This topic proved to better meet the knowledge needs of the community as well as being more tangible.Maintaining contact and providing ongoing feedback even while not engaging with stakeholders enables them to feel involved and valued throughout the project’s timescale, especially if it is long  There is a need for negotiation, co-ownership, co-created problem definitions, and a shared understanding of possible pathways. Thereby, the aspect of power needs to be reflected both as an enabling and disabling factor for meaningfully taking part and regarding degrees of power in the sense of influencing the outcomes of experimentation, knowledge co-creation, and finally planning and policymaking. This strongly includes the dimension of differing knowledge and (attributed) expertise which is especially relevant concerning a highly complex topic like the urban FWE Nexus. In all three ULL, the complexity of the FWE nexus presented a (perceived) barrier for local stakeholders with limited knowledge on the linkages of FWE to participate in debates on the future development of this nexus in their communities.Furthermore, flexibility regarding the process and the resources should be provided as well as ways of enabling additional stakeholders to take part and for defining specific tasks, roles and responsibilities during the process. This is particularly important in the context of knowledge-authority (power) relations, which can affect the shape of the process and the position of stakeholders, e.g., reducing the participation of non-expert citizens. Also, the position of stakeholders due to their expert knowledge  or position  can have a symbolic influence potentially disrupting the process of co-creating knowledge. It also requires an awareness of these risks, especially on the part of the stakeholders responsible for facilitating the process.Active engagement needs time, skills, and resources. Being inclusive and open means to invite actively, to go to where the people are, and to create enabling environments considering different expectations and abilities. Inclusiveness also means that avenues used to contact and retain stakeholder involvement are as comprehensive as possible, making participation as accessible as possible. A closer look at different roles and different levels of inclusion (and exclusion), also regarding different moments in the ULL process, would further sharpen the concept and practice of ULLs  Following Jaeger-Erben et al. , bringinCurrently, research funding is strongly based on the approach of science as taking up societal problems in the form of research questions and remaining in charge of the process and outcomes. These can then be used by society. In process-oriented research, the “messiness of the actual collaborative research process … can only be planned to a certain extent” . This is a good start. We claim that the possibilities for engaging local stakeholders including citizens throughout the whole process in an active and meaningful way could be strengthened through financial setting points and formal prerequisites.basing living labs on local needs, getting access to local communities through local stakeholders as well as the aspect of trust and trust-building. Based on this, we argue that ULL should be strongly embedded or even rooted in their local context and provide openness to integrate responding to the different needs and interests.3) The ULL examples of the project "Creating Interfaces" illustrate the importance of As a basis for this, there is a strong need for exploring the context and actor constellations, including power relations, and for developing relationships and different ways of enabling people to take part. Therefore, ideally, there would be time and resources for exploring the field and for collectively negotiating the project, e.g., in the form of exploratory funding. The next generation of ULLs 2.0 should include deliberate efforts on behalf of the research team to do thorough research into the communities' culture and history in which they are going. This also helps bring the project to where stakeholders are. In our experience, one of the most important factors to create opportunities for participation is to identify the places where stakeholders mingle and meet for various community activities. It is also important to identify a time that is comfortable for stakeholders for additional (non-work) activities. Activities should take place where people are comfortable being, and at times of the day and year that work for them. This is crucial for drawing in all potential stakeholders  ULL 2.0 should be strengthened regarding their sustainability and transformative capacity in a long-term perspective. The project-based nature of classical research-based ULL can set impulses, experiment with and demonstrate new ways of organizing societal problem-solving, and facilitate learning. The question is how these impulses and their outcomes can be sustained after the project ends and the researchers/initiators leave? How can the outcomes be systematically linked to and transform policy and planning? Here again, a key aspect would be funding enabling or even enforcing the commitment of the respective stakeholders through planning or implementation grants, or technical assistance and kinds of “seed” or “take it further” funding for setting up long-term initiatives and structures. This funding would also enhance the legitimacy of strategic ULLs and help for gaining transparency for citizens regarding the impacts their engagement can have. Another path could be long-term labs providing space and basic resources for experimentation.5) Finally, Our ULL experiences and literature offer insights for further elaboration of the approach towards ULL 2.0. To strengthen their transformative capacity, inclusive ULLs require:In conclusion, inclusiveness and meaningfulness to local society are key points regarding the legitimacy and impact of ULLs as well as for ensuring the value of the scientific outcomes. When rethinking the concept of ULLs towards ULL 2.0, these should be strengthened in a co-creative process.


Escherichia coli, Campylobacter spp., and Salmonella spp.) recovered from pooled fecal samples collected from calves, heifers, cows, and the manure pit. A total of 144 dairy farms were recruited in five Canadian provinces , with the help of local herd veterinarians and regional field workers, and in September 2019, the surveillance system was launched. 97.1 and 94.4% of samples were positive for E. coli, 63.8, and 49.1% of samples were positive for Campylobacter spp., and 5.0 and 7.7% of samples were positive for Salmonella spp., in 2019 and 2020, respectively. E. coli was equally distributed among all sample types. However, it was more likely that Campylobacter spp. were recovered from heifer and cow samples. On the other hand, it was more common to isolate Salmonella spp. from the manure pit compared to samples from calves, heifers, or cows. CaDNetASR will continue sampling until 2022 after which time this system will be integrated into CIPARS. CaDNetASR will provide online access to farmers and veterinarians interested in visualizing benchmarking metrics regarding AMU practices and their relationship to AMR and animal health in dairy herds. This will provide an opportunity to enhance antimicrobial stewardship practices on dairy farms in Canada.Canada has implemented on-farm antimicrobial resistance (AMR) surveillance systems for food-producing animals under the Canadian Integrated Program for Antimicrobial Resistance (CIPARS); however, dairy cattle have not been included in that program yet. The objective of this manuscript was to describe the development and implementation of the Canadian Dairy Network for Antimicrobial Stewardship and Resistance (CaDNetASR). An Expert Panel (EP) of researchers was created to lead the development of the dairy surveillance system. The EP initiated a draft document outlining the essential elements of the surveillance framework. This document was then circulated to a Steering Committee (SC), which provided recommendations used by the EP to finalize the framework. CaDNetASR has the following components: (1) a herd-level antimicrobial use quantification system; (2) annually administered risk factor questionnaires; and (3) methods for herd-level detection of AMR in three sentinel enteric pathogens (generic  Salmonella Newport isolates recovered from dairy cattle fecal samples  were multidrug-resistant  is a natural phenomenon that occurs when bacteria evolve and no longer respond to antimicrobial drugs that previously were efficacious. Major economic losses and animal health and welfare problems have been described as the consequences of AMR , 2. Manyesistant . Infecti animals . Many ban people . It is en people . For then people .To address the global problem of AMR, many countries have developed and implemented AMR surveillance systems for humans and animals. A surveillance system can be defined as “a system based on continuous information recording, making it possible to monitor the health status of a given population and the risk factors to which it is exposed, to detect pathological processes as they appear and study their development in time and space, and then to take appropriate measures to control them” . The maiIn addition, this surveillance system should be able to provide estimates of the types and amount of antimicrobials used on farms. Evidence  suggestsRecognizing the interrelationship between AMU/AMR in humans and animals and the need for the standardization of methods between countries , in 2018, the Food and Agriculture Organization of the United Nations (FAO), the World Organization for Animal Health (OIE), and the World Health Organization (WHO) formed a tripartite alliance (FAO-OIE-WHO) focusing on a “One Health” approach to AMR . The “OnSalmonella spp., Campylobacter spp., and Escherichia coli  . In CanaTackling Antimicrobial Resistance and Antimicrobial Use: A Pan-Canadian Framework for Action.” The framework's goal was to strengthen the ability to fight AMR in a coordinated, multisectoral and effective manner  and PHAC recognized the lack of information regarding AMU, AMR, and the importance of improving AMS in the Canadian dairy sector. Together they decided to develop a surveillance system to fill the knowledge gap. This diverse group of researchers had expertise in epidemiology, antimicrobial resistance, dairy production medicine, surveillance system development, and public policy.In order to initiate the development of the surveillance system a 5-year proposal was developed and funded by Dairy Farmers of Canada and Agriculture and Agri-food Canada, under the Dairy Research cluster 3 program, and by PHAC and the University of Prince Edward Island (UPEI). After the initial funding (2018–2022) the intention is to incorporate this system into CIPARS.An Expert Panel (EP) was created to develop a farm-based surveillance framework for AMU, AMS, and AMR on dairy farms across Canada. The EP was composed of researchers from six Canadian universities  and veterinary epidemiologists from the PHAC.In the summer of 2018, members of the EP developed a draft of the surveillance framework. As part of the framework development, it was decided that the surveillance system should be deployed in five regions across Canada. These regions were the communities of Truro/Halifax in Nova Scotia, Montérégie region in Québec, London Middlesex in Ontario, Calgary-East in Alberta, and Fraser Valley in British Columbia, which are part of the sentinel sites from FoodNet Canada, a surveillance system focused on foodborne and waterborne diseases .During the initial development phase of the surveillance framework, a Steering Committee (SC) was created, and the framework was sent to them for comments in January 2019. The SC was composed of relevant stakeholders from provincial and national milk boards , veterinary organizations , PHAC, dairy herd improvement organizations and others. The role of the SC was to provide input on developing the surveillance framework for implementation in 2019 and ensure that the methods to collect farm samples and data were practical and sustainable. In addition, SC members were tasked with disseminating findings from the surveillance system to their respective organizations.After the initial development of the framework, the EP and the SC, came together for a 2-day meeting whereby the framework was introduced and discussed. Suggestions were offered to improve the quality of data generated and introduce the surveillance system to the Canadian dairy industry. The information generated from this meeting was used to refine and finalize the surveillance framework. A final framework was ready for implementation in the spring of 2019.For the implementation of the surveillance system, an operation committee was created. The operations committee was composed of all EP members, regional project managers, regional field workers, technicians and graduate students involved in the system. The role of the operations committee was to provide feedback on the operational issues through monthly meetings after the surveillance implementation and contribute to potential refinements of the surveillance system.Each of the five regions had one regional project manager responsible for overseeing herd selection, the data collection and supervising the regional field workers. The regional field workers scheduled the farm visits and conducted the sampling based on the protocols provided. The surveillance system (CaDNetASR) was implemented in September 2019 and continued for 4 years in the first round of funding. The development and implementation of CaDNetASR is illustrated in The CaDNetASR surveillance includes all the critical components for AMR and AMU surveillance, collecting, analyzing, and reporting AMR and AMU in dairy herds at the farm level. The components of CaDNetASR are described below and are illustrated in As the AMU stewardship was a key component in the surveillance system, the sample size was calculated to estimate an AMU rate with a precision of +/- 0.3 for various antimicrobials based on the assumption that 95% of the farms have AMU rates between 0.001 and 4 ADD/1,000 cows . TherefoOn-farm data collection included annual collection of fecal samples, a bulk tank milk sample (BTM), administration of questionnaires to collect herd management practices, AMU, and risk factor information for AMR related projects/questions. The main sections of the questionnaires are presented in E. coli, Campylobacter spp., and Salmonella spp., in addition to preserving the raw sample following the protocol used by CIPARS (E. coli- 97.1% (544/560); Campylobacter spp.−63.8% (357/560); and Salmonella spp.−5.0% (28/560). In 2020, a total of 574 samples were collected and cultured. 94.4% (542/574), 49.1% (282/574), and 7.7% (44/574) of samples were positive for E. coli, Campylobacter spp. and Salmonella spp., respectively. The information is presented in E. coli and Salmonella spp. were tested against 14 antimicrobials using the CMV2AGNF plate  was implemented for a period of 6 months to quantify AMU. The farmers were advised to deposit all the empty antimicrobials vials  in the receptacles, which were placed strategically where antibiotics might be administered around the farm. The contents of the receptacles were collected and recorded by the regional field workers. In addition, the regional field workers collected information on the antimicrobial inventory at the beginning and the end of the GCA period. The quantities of each antimicrobial were later converted to dose-based metric developed for Canadian dairy cattle as published by Lardé et al. . For theData are managed through a collaborative and integrated computer system developed to store the data generated by the surveillance system efficiently. All data are standardized, validated, and uploaded to the central digital platform. All information stored in the digital platform is protected by restricted access. The data flow is illustrated in An important component for surveillance systems is knowledge dissemination. There is a diverse group of stakeholders interested in data regarding AMU and AMR in dairy cattle. These include veterinarians, academia, industry, policymakers, producers, government, public, among others. After each year, summary findings on AMU and AMR are being sent to participating producers and their veterinarians . ReportsThere is increasing pressure on animal agriculture to justify the use of antimicrobials to treat and prevent infections in animals. Antimicrobial use is the main driver of resistance in target and non-target bacteria in food animals, which can potentially pass to humans via the food chain . In the Antimicrobial stewardship is a key factor for mitigating the effects of AMR  but chanAMS initiatives can have significant impacts on AMU and AMR on farms. For example, in the Netherlands there are compulsory and voluntary programs that affect AMS in farm animals, including dairy cattle. The RESET Mindset Model  was a stMost dairy farms in Canada are in the provinces of Quebec and Ontario, and the production of fluid milk is regulated in Canada using a quota system. Federal and provincial organizations adjust quota to meet expected consumer demand. Milk produced in a province is frequently consumed within the province. Therefore, to ascertain AMR and AMU practices for Canadian dairy herds, it is necessary to conduct surveillance in as many provinces as possible. Each farm is visited annually for sample collection from three different age groups, which can aid in investigating AMR patterns in all stages of dairy production and may help target interventions where they are needed most. Additional data (herd demographic and farm management information) were collected on-farm using two questionnaires. All the information collected is standardized and stored in a central database. In the first 2 years, the questionnaires were administered using standardized spreadsheets that required manual data entry. In the process of validating these data, input errors were found, which had to be corrected. Automated processes for data entry are preferable to manual entry, and in future years, data will be uploaded from a hand-held device directly to a central database without the need for manual data entry.The primary outcome of CaDNetASR is to inform the Canadian dairy industry, the general public, and policy decision makers on the level of AMU and AMR, and the impact that AMS practices have on AMU and AMR on Canadian dairy farms. Recently, 15 countries collecting AMU data at the farm level were identified . Among tHigh quality estimates of AMU from surveillance programs are essential to provide reliable results. AMU estimates can be made from a variety of sources. In Denmark, for instance, there is a national, centralized database (VetStat) that collects AMU data at the herd level. The VetStat was implemented in 2000, and the program estimates AMU by collecting antimicrobial dispensing records from pharmacies, veterinarians, and feed mills for individual farms . In the Since 2018, the Veterinary antimicrobial sales reporting system (VASR) system in Canada has provided an annual report regarding the sales of veterinary antimicrobials considered important for human medicine . The infEfforts in Canada to improve farm-level estimates of AMU are ongoing. One method that has been used is the GCA, which is considered the reference test for farm-level AMU estimates. GCAs are very labor intensive and time consuming, so other approaches for estimating AMU must be found. In Québec, a recent study investigated different methods of collecting AMU data at the farm level . GCA wasAMU data collected by CaDNetASR, was transformed into a dose-based metric, to account for the different dosages among the different active ingredients. The dose-based metric divides the total amount of antimicrobial used (mg) by total animal weight and estimate daily dose for the antimicrobial . There iIn addition to the amount of AMU on farms it is important to determine which antimicrobial is used as well. Some antimicrobials are more important than others in treating infections in humans and their use in animal agriculture should be minimized and used only when other antimicrobials are known to be ineffective. The WHO publishes a regularly updated document, classifying the antimicrobials according to their human importance . In CanaSalmonella spp., Campylobacter spp., and E. coli. These bacteria were selected because they are important zoonotic pathogens, where AMR is a concern or in the case of generic E. coli, it is thought to reflect the reservoir of resistance genes. These bacteria are monitored in other CIPARS' surveillance programs , which has been associated with pig production   . For thin health . To the Salmonella spp. isolates, the idea is to expand to other isolates of interest, as it is anticipated that WGS will be routinely done in the future. The isolate bank will allow for the comparison of data from historical isolates to those collected in the future. In some European countries, WGS is being implemented gradually, and it will be mandatory after 2026  Yearly sampling. This sampling scheme will limit the possibility of tracking seasonal variability; however, each farm is sampled during the same season, allowing comparisons over time; (2) Sample type. CaDNetASR is based on pooled samples from three different ages of cattle and samples from two areas of the farm  under the Canadian Agricultural Partnership AgriScience Program and the Public Health Agency of Canada.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.


Pandemic the COVID-19 is a global threat to rural entrepreneurial businesses with an uncertain ending. Therefore, it is necessary to provide a paradigm model to reduce the negative effects of this crisis, increase the resilience of rural entrepreneurial businesses or even turn this threat into an opportunity for the development of rural entrepreneurial businesses in the long run. This study, using a qualitative approach, investigated the resilience of rural entrepreneurial businesses in dealing with the COVID-19 crisis in Kermanshah province using a paradigm model. Using purposeful and theoretical sampling, 26 cases were selected. The tools used for data collection were open questionnaires (unstructured), individual depth interviews, and taking notes. The results provide a relatively comprehensive model that consists of six basic parts: causal conditions , the phenomenon , contextual conditions , interventing conditions , action strategies (included Planned resilient actions and Unplanned resilient actions), finally, the consequences . In general, rural entrepreneurial businesses in the face of crisis must, through planned resilience measures, both increase their business resilience in the short term, as well as develop the business and gain a competitive advantage in the long run. Finally, based on the findings and in order to developing resilience in rural entrepreneurial businesses during the COVID-19 crisis, some recommendations were presented. Rural areas are considered as the center of production in developing countries, including Iran, and play a key role in ensuring the independence of each country, especially in the field of food security . Rurals Rural entrepreneurial businesses are one of the most important elements of rural economy that through exploitation of entrepreneurial opportunities in rural areas cause job creation and reduce unemployment, increase income and increase productivity and ultimately achieve sustainable rural development . In defiThroughout history, natural and man-made disasters and crises on various scales have had adverse effects on businesses . In thisAlthough COVID-19 directly threatened people's health ; But theResilience is the tendency of a system to maintain organizational structure and productivity, following the disruption of that system [: 8]. In In this regard, the effects of the COVID-19 crisis are very noticeable for rural entrepreneurial businesses in Kermanshah province (western Iran). First, because Kermanshah province has been suffering from unemployment for many years, and second, rural businesses have been largely neglected; While paying attention to this type of business and their prosperity can have a significant impact on solving the problem of unemployment in Kermanshah province. In fact, it can be said that in the context of the COVID-19 crisis, most of the policies have focused on large-scale companies and the industrial sector in urban areas while what is important is the future of microeconomic activities, especially in rural areas . Even inBased on the researches in the field of this study, few and relatively related researches have been done as follows. Beninger and Francis  stated iBased on the reviewed studies, it can be said that so far few empirical studies have been conducted on the resilience of rural entrepreneurial businesses during the crisis. Also, in the studies, the resilience of businesses in the face of crises such as climate change and environmental crises has been considered more, and the resilience of rural entrepreneurial businesses in the face of health crises has been neglected. Therefore, this study seeks to develop a paradigm model for resilience of rural entrepreneurial businesses in dealing with the COVID-19 crisis with a qualitative approach.The present study is limited to Kermanshah province in terms of location. The capital of Kermanshah province is the city of Kermanshah. This province has an area of 24,549 square kilometers. Kermanshah province is one of the provinces located in the west of Iran . KermansThe present study seeks to provide a developing a paradigm model for resilience of rural entrepreneurial businesses in dealing with the COVID-19 crisis using the grounded theory (GT) method. GT was developed by sociologists Barney Glaser and Anselm Strauss in the mid-1960s and published in their 1967 seminal book, Discovery of Grounded Theory . GT is aParticipants in this study included all experts and key informants in the field of research, such as experienced managers of rural entrepreneurial businesses in Kermanshah province who were selected through purposeful sampling and theoretical sampling. Criteria for selecting samples in this study included the following; Managers with at least 15 years of experience in rural entrepreneurial businesses, as well as managers with at least a university degree in fields related to business management, managers with a history of other business crises . To identify the samples, purposeful sampling method was used first. In this sampling method, because the samples may not be easily identifiable at first, the researcher first identifies the key informants. In the following, the researcher reached another informed person by interviewing the informed sample and receiving the necessary data . In otheThe process of working in grounded theory consists of several stages. The first is to identify the research plan. The purpose of this stage is to identify the questions and constraints of the research , 42, 43.The main focus of the research question is “What is this phenomenon?” . In thisThis study also sought to develop a paradigm model for the resilience of rural entrepreneurial businesses during the COVID-19 crisis. Therefore, the following questions were asked to the participants:From the participants' point of view, what factors cause the development of resilience of rural entrepreneurial businesses in the face of the COVID-19 crisis? What factors affect the resilience of rural entrepreneurial businesses? What actions have been taken to develop the resilience of rural entrepreneurial businesses against COVID-19? What are the consequences of these actions?Simultaneously with data collection, the data analysis process began. In this research, we followed Straussian grounded theory (SGT) and used a coding processor from Strauss and Corbin  that incOpen coding is the first data analysis process that focuses on conceptual analysis and classification of phenomena through extensive data analysis . In thisThe open codes identified in the previous step are compared and clustered by axial coding, and finally they are categorized in Subcategories . AccordiWhile according to Strauss and Corbin , axial cCredibility is achieved through long-term communication and interaction with experts and data, which can be achieved through triangulation . For man73.07% (19 people) of the participants were male and the rest were female. All participants had a university degree in the field related to business management so that 65.38% (17 people) had a bachelor's degree, 26.92% (7 people) had a master's degree and 7.7% (2 people) had a PhD degree. The minimum age of participants was 34 years and the maximum age was 57 years and the average age was 46.19 years. These people also had an average experience of 25.30 years, the minimum experience was 15 years and the maximum experience was 35 years.In this research, in open coding, the data obtained from the interviews were examined line by line and the concepts were extracted. Based on the findings, 112 codes were initially identified, which in some cases were duplicates, so refinement was done and duplicate concepts were removed or expressed in the form of a concept. After the final refinement, there are 57 concepts left that were classified into different subcategories based on the semantic load. In the present study, in axial coding, causal conditions included economic management, health factors, human resources management, and adaptation factors. The phenomenon included low resilience of rural entrepreneurial businesses in the face of the COVID-19 crisis. Contextual conditions including social factors; cultural factors and psychological factors. Interventing conditions included business management and legal supports. Finally, action strategies included Planned resilient actions and Unplanned resilient actions, the consequences of which included adapting to crisis conditions and increasing resilience in the long run, and Lack of adaptation to crisis conditions and lack of continuity of business survival in the long run (More details will be provided in the lower sections).According to the perspectives of rural entrepreneurs in Kermanshah province, four factors directly cause the resilience of rural entrepreneurial businesses; these factors include economic management, health factors, human resources management, and adaptation factors.From the participants' point of view, economic management causes the resilience of rural entrepreneurial businesses during the COVID-19 crisis. Participants stated that although COVID-19 directly affects the health of human resources, it has economic consequences for rural entrepreneurial businesses due to the implementation of adaptive and preventive strategies to prevent the spread of COVID-19. Therefore, the participants believed that under these conditions, which face economic problems, the best factor that increases the resilience of rural entrepreneurial business is economic management. Therefore, rural entrepreneurs should seek to increase liquidity through various means including receiving disaster loans (crisis), income diversity, previous financial resources, liquidity management, control and reduce costs, manage and increase sales to improve the resilience of their business.This part of the results is parallel to findings Beninger and Francis ; Le et aFrom the participants' point of view, another factor that increases the resilience of rural entrepreneurial businesses is to prevent the spread of the COVID-19 virus, so to increase the resilience of rural entrepreneurial businesses, it is necessary to follow health principles and protocols. In this regard, participants believed that rural entrepreneurial businesses should be equipped to deal with the COVID-19 virus. Participants stated that addressing the following health factors could cause them to deal with the COVID-19 virus in rural entrepreneurial businesses; equipping the business environment with various sanitary devices , providing disposable health tools to personnel in order to comply with protocols , equipping businesses with early diagnostic tools , adherence to health protocols; daily staff checkup.This part of the results is parallel to findings Beninger and Francis  and Aldivia information technology and virtually) as much as possible, and staff attendance should be shifted in time.Participants stated that the nature of the COVID-19 crisis is such that it directly targets the human capital health of rural entrepreneurial businesses. Therefore, to increase the resilience of rural entrepreneurial businesses, factors that protect human capital should be given priority. Participants stated that personnel information on how to deal with COVID-19 should be updated first, and then human capital skills should be improved through training. Personnel should also perform their duties remotely  Proper management and policy making; (2) Providing infrastructure adapted to crisis situations (increasing antenna coverage in villages in remote areas); (3) Support policies for low-interest (or even non-interest-bearing) lending; (4) Increase partnership and cooperation between enterprises, government and other private organizations; (5) Develop and provide crisis preparedness and management instructions; (6) Government support in providing health services to businesses; (7) Monitoring the proper implementation of health protocols.“Proper management and policy making” means that the government has adopted appropriate policies in response to environmental changes to increase the resilience of rural entrepreneurial businesses, and policies have been based on environmental monitoring. Also, due to the fact that most rural areas in Kermanshah province have weak antennas, the government strengthened the antenna infrastructure in these areas. The government also provided disastrous loans to compensate companies and increase the liquidity of rural entrepreneurial businesses in order to offset some of the losses. To increase the resilience of rural entrepreneurial businesses, the government also provided contexts for increased collaboration and partnership between companies, government, and other private organizations. The government also developed guidelines for how to manage crises and adhere to health protocols, and monitored how to handle them properly.This part of the results is parallel to findings Beninger and Francis , Saad etContextual conditions refer to where a phenomenon occurs and the conditions that allow the development of a strategy . In otheParticipants stated that contextual social participation has increased the resilience of rural entrepreneurial businesses. Participants stated that by joining indigenous and non-indigenous social networks and sharing their experiences of dealing with the crisis, they have provided the context for increasing the resilience of rural entrepreneurial businesses. Participants stated that increased participation and cooperation in adhering to health protocols has led to virus control and thus increased business resilience. Increased cooperation throughout the supply chain in rural entrepreneurial businesses has also reduced costs and increased revenue, and this cooperation across the supply chain has provided increased resilience.This part of the results is parallel to findings Beninger and Francis ; Saad etIn this study, cultural factors include entrepreneurial culture in business and elimination of incorrect and opposing cultures by controlling and preventing the spread of coronavirus.The emergence of crises causes a change in the balance and status of the business environment. On the other hand, environmental changes are the source of the emergence of entrepreneurial opportunities. Participants stated that if rural entrepreneurial businesses have a strong entrepreneurial culture, they can offer creative and relevant products or services for the environment by identifying emerging opportunities and exploiting them in a timely manner. In this way, not only can they improve their resilience, but they can also gain a competitive advantage and turn the crisis into an opportunity for their business to grow and develop. This part of the results is parallel to findings Hanson et al. . Hanson Regarding the elimination of incorrect culture in the region, the participants stated that the culture of the rural community is contrary to preventive measures and health protocols. Rural community culture needs to be reformed and revised based on health protocols to control the COVID-19 crisis to provide a context for increasing the resilience of rural entrepreneurial businesses. This part of the results is parallel to findings Beninger and Francis  and SaadIn this study, psychological factors including increase staff motivation in relation to business continuity, increase staff resilience in relation to business continuity, strengthen the motivation of personnel with coronavirus.Staff motivation should be stimulated in various ways. For example, some participants pointed out that providing incentive leave can increase people's motivation and thus increase business resilience. Some participants said that the minds of personnel should be more resilient and prepared to deal with the COVID-19 crisis. In other words, personnel must be mentally prepared in advance to deal with this crisis in order to provide a more appropriate response when faced with it. Personnel infected with COVID-19 virus should be motivated. Participants stated that the most important capital of rural entrepreneurial businesses is human capital, which should be motivated and mentally supported under any circumstances.Action strategies are programs that can help adapt to a phenomenon, in our context , the resPlanned resilient actions refer to those short-term resilient actions that are taken during the COVID-19 crisis but are aimed at developing and growing the business in a long-term perspective. In this research planned resilient actions include development and modification of marketing strategies based on crisis conditions, human resource training, develop and provide health instructions, monitoring the proper implementation of health protocols, reform of financial management based on crisis conditions, development of crisis-adapted infrastructure and exploiting emerging environmental opportunities. This part of the results is parallel to findings Ngin et al. . Ngin etUnplanned resilient actions refer to those measures that, although in the short run increase the resilience of rural entrepreneurial business, but in the long run lead to business bankruptcy. In this study, unplanned resilient actions include sales of some business equipment and machinery, sale of part of the company shares, temporary deactivation of the business, reducing the quantity of production and decreased production quality.In this regard, the participants stated that resilient measures should be taken in a long-term perspective that will pave the way for business growth and development. In this regard, the participants stated that resilient measures should be taken in a long-term perspective that will pave the way for business growth and development. For example, redesigning the business model and increasing the factors that adapt to the current crisis, such as taking advantage of information technology opportunities, will increase both resilience during COVID-19 and, in the long run, the growth and development of the business.The consequences of implementing resilient behaviors, in our situation, although they increase resilience in the short run, in the long run fall into two categories: adapting to crisis conditions and increasing resilience in the long run, and Lack of adaptation to crisis conditions and lack of continuity of business survival in the long run.What is important is that adaptive measures should be taken in a way that, while being adaptable in the short run, also provides the context for the growth and development of rural entrepreneurial business in the long run.The purpose of selective coding is to identify the main phenomenon and relate it logically to the different subcategories through the paradigm model. To do this, the researcher uses a storyline to describe and justify the relationships between the categories and presents a visual model of the main research topic .There are different criteria for judging which category should be considered the main category.  providesThis category should be the main  category. That is, it can be related to many other categories and their characteristics, but is more suitable for the main category than other candidates. This criterion of centrality is a necessary condition for placing a category at the heart (center) of the analysis: it indicates that this category describes a major part of the changes in the pattern of behavior.The main category must be observed repeatedly in the data. With high repetition, this category is considered as a stable pattern and is consequently related to other categories by the analyst.The main category is easily related to other categories. These communications are not mandatory; rather, they come into being quickly and abundantly. Because the main category is related to many other categories and is repeated frequently, it becomes more saturated in more time than the other categories.The main category in a substantive study has clear implications for a more general theory.Because the details of a main category are generated analytically, the theory moves forward appreciably.As mentioned earlier, the research phenomena included two subcategories (Da1 and Da2). According to Strauss (1987) criteria, the most important phenomenon in this research involved the Da1 subcategory. This subcategory is referenced 26 times.As shown in According to the participants, in addition to causal conditions, the contextual and intervening conditions also affect the phenomenon .Contextual conditions include three subcategories: social factors, cultural factors and psychological factors. These three subcategories include a total of eight concepts. Social factors were referenced a total of 15 times by the interviewees, which included three concepts (References mean: 5). Among these concepts, the most important concept was “Increasing trust, participation and cooperation in observing preventive measures among personnel and customers” with six references (most references). In other words, in the social factors sub-category, the “Increasing trust, participation and cooperation in observing preventive measures among personnel and customers” factor has a greater impact on increasing the resilience of rural entrepreneurial businesses during the crisis. cultural factors were referenced a total of 14 times by the interviewees, which included two concepts (References mean: 7). Among these concepts, the most important concept was “Strengthening the entrepreneurial culture in business with the aim of providing products or services that are creative and adapt to new conditions and gain a competitive advantage” with eight references (most references). In other words, in the cultural factors sub-category, the “Strengthening the entrepreneurial culture in business with the aim of providing products or services that are creative and adapt to new conditions and gain a competitive advantage” factor has a greater impact on increasing the resilience of rural entrepreneurial businesses during the crisis. Psychological factors were referenced a total of 21 times by the interviewees, which included three concepts (References mean: 7). Among these concepts, the most important concept was “Increase staff resilience in relation to business continuity” with eight references (most references). In other words, in the psychological factors sub-category, the “Increase staff resilience in relation to business continuity” factor has a greater impact on increasing the resilience of rural entrepreneurial businesses during the crisis. In general, contextual conditions provided the context for the phenomenon to occur in the study population. Social factors, cultural factors and psychological factors were subcategories that formed contextual conditions. According to the participants, these three sub-categories  directly affected the occurrence of the phenomenon and indirectly (through the phenomenon) affected the action / interaction strategies .Intervening conditions include two subcategories: Business management and Legal supports. These two subcategories include a total of 10 concepts. Business management was referenced a total of 24 times by the interviewees, which included three concepts (References mean: 8). These three concepts include crisis management and proper accountability, condition-based planning for the business, develop and present appropriate strategies for business continuity. Among these concepts, the most important concept was “develop and present appropriate strategies for business continuity” with nine references (most references). In other words, in the Business management sub-category, the “develop and present appropriate strategies for business continuity” factor has a greater impact on increasing the resilience of rural entrepreneurial businesses during the crisis. Legal supports were referenced a total of 59 times by the interviewees, which included seven concepts (References mean: 8.42). Among these concepts, the most important concept was “Proper management and policy making” with 12 references (most references). In other words, in the Legal supports sub-category, the “Proper management and policy making” factor has a greater impact on increasing the resilience of rural entrepreneurial businesses during the crisis. As mentioned earlier, the two subcategories of Business management and Legal support were intervening conditions that also facilitated the occurrence of the phenomenon. In general, according to the participants, these two sub-categories (intervening conditions) directly affected the occurrence of the phenomenon and indirectly (through the phenomenon) affected the action / interaction strategies .When the phenomenon occurred, the study population took action to cope with the phenomenon. In this study, according to the participants, the measures taken were classified into two subcategories, planned resilient actions and unplanned resilient actions. These two subcategories include a total of 12 concepts. Planned resilient actions were referenced a total of 54 times by the interviewees, which included seven concepts (References mean: 7.71). Among these concepts, the most important concept was “Development and modification of marketing strategies based on crisis conditions” with 10 references (most references). Unplanned resilient actions were referenced a total of 25 times by the interviewees, which included five concepts (References mean: 5). Among these concepts, the most important concept was “Temporary deactivation of the business” with six references (most references). According to the participants, these two sub-measures had two sub-categories in consequences, which are discussed below.Finally, according to the participants, implementing action/interaction strategies can have both positive (Fa) and negative consequences (Fb). The consequences of planned resilient actions (positive consequences), while adapting to crisis conditions, provide business growth and development in the long run. The sub-category adapting to crisis conditions and increasing resilience in the long run had five concepts that were referenced 38 times (References mean: 7.6). In the meantime, the concept of “Improvement of business position than before crisis” with nine references had the most references, in other words, this was the most important positive consequence. Negative consequences included unplanned actions that in the short term may have led to adaptation to the crisis, but in the long term would have led to the bankruptcy and destruction of the business. This subcategory had two concepts that had 13 references in total (References mean: 6.5). Meanwhile, the concept of “More vulnerability in the long run” with seven references had the most references, in other words, this was the most important negative consequence. In general, according to the participants, some action strategies such as planned resilient actions can help the resilience of rural entrepreneurial businesses both in the short term and in the long term. If resilient actions are planned, it will lead to business growth and development in both the long and short term. Otherwise, the actions may be resilient in the short term, but in the long run, they will cause business bankruptcy will be. Based on this discussion, the final conceptual model of the research is presented in The purpose of this study is to develop a paradigm model for resilience of rural entrepreneurial businesses in dealing with the COVID-19 crisis with application of grounded theory. The outbreak of COVID-19 led to disruption to businesses, especially rural entrepreneurial businesses. Therefore, rural entrepreneurial businesses need to adapt to change in order to create the desired changes to build a better future in order to survive. Therefore, it is necessary to make systematic plans to increase resilience and use planned resilience strategies. Resilience creates capabilities for businesses that can adapt to adverse conditions and continue to survive and return to development. Resilience helps the long-term survival of rural entrepreneurial businesses. As a result, these businesses can continue to operate by using the dimensions of resilience strategies in the context of the COVID-19 crisis, increasing their resistance to the Corona crisis and overcoming the crisis more developed than before. What should especially be addressed to rural entrepreneurial business managers is that adaptive measures should be taken in the long run in the direction of business development and growth, and any tolerant retaliatory action should be avoided.Grounded theory is a quite powerful tool based on which the factors affecting the phenomenon (the main problem) can be investigated. Therefore, based on this, appropriate recommendations can be provided to solve the problem. Although the infrastructure is currently weak in most villages, the next step is to strengthen the infrastructure, especially in the field of information and communication technology in rural areas. The next step is to upgrade the IT skills of managers and business personnel. Strengthening these infrastructures and upgrade the IT skills of managers and business personnel in rural areas gives rural entrepreneurial businesses the opportunity to redesign their business model based on information technology. The most important consequence is the adaptation of rural entrepreneurial businesses to the COVID-19 crisis and also, the development of information technology infrastructure has led to the development of marketing for the sale of products worldwide. Market development helps both economic management and reducing customer interactions . In other words, by strengthening the infrastructure and developing skills, the context for the use of information technology in rural entrepreneurial businesses is provided, and this means the realization of all four subcategories of causal conditions. Social factors, cultural factors and psychological factors should also be strengthened through cyberspace in order to provide a suitable platform for dealing with the COVID-19 crisis.Grounded theory is a quite powerful tool also because it examines the actions taken as well as their positive and negative consequences one by one. Therefore, with proper planning, negative actions and consequences can be eliminated or reviewed, and positive actions and consequences can be strengthened and expanded. Investigation of the measures taken and their consequences showed that rural entrepreneurial business managers should have a long-term vision for the continuation of their business. In this regard, strategies should be adopted that, while increasing adaptation in the short term, also lead to the growth and development of the business in the long term.Based on the findings, the following suggestions are made;It is recommended that the Continuous data collection, analysis and presentation of information and market trends consumed in the current situation and the coming years with the aim of strengthening futurology and identifying and exploiting future opportunities to gain a competitive advantage;Recommends that the level of creative thinking of managers be strengthened with the aim of increasing the ability to adapt to critical situations;Recommends that managers' strategic planning skills be strengthened, especially in the field of vision drawing and mission determination;It is recommended that the government provide loans and disaster subsidies, as well as business managers to manage cash flow and reduce unnecessary costs;It is recommended that the relevant organizations try to increase and update the skills and knowledge of business personnel in how to deal with and adapt to health by holding training classes ;It is recommended that business owners provide a safe environment for staff and provide free sanitary equipment to staff in order to protect human capital;It is recommended that the IT infrastructure in the villages be strengthened so that businesses can use it to redesign their business model;It is recommended that the field of increasing virtual communication between business owners and relevant organizations in the region and the province be maintained and strengthened to share crisis adaptation experiences;It is recommended that resilient measures be taken systematically and in a long-term perspective in order to increase resilience during the crisis and lead to long-term business growth and development;It is also recommended that the findings of this study be made available to rural business managers through training programs (mainly in cyberspace).For future research, it is proposed to provide a model of adaptation behavior of rural entrepreneurial businesses in the face of the COVID-19 crisis. The most important limitation of the present study can be expressed as the lack of cooperation of some of the study population due to fear of COVID-19.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.EK and FK wrote the first draft of the manuscript. NN contributed in data collection. All authors contributed to conception and design of the study and performed the statistical analysis, wrote sections of the manuscript, contributed to manuscript revision, read, and approved the submitted version.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.


Asthma is one of the most common chronic diseases characterized by sex disparities. Gender bias is a well-documented issue detected in the design of published clinical trials (CTs). International guidelines encourage researchers to analyze clinical data by sex, gender, or both where appropriate. The objective of this work was to evaluate gender bias in the published CTs of biological agents for the treatment of severe asthma. A systematic review of randomized controlled CTs of the biological agents  for the treatment of severe asthma was conducted. The literature search was performed using PubMed and EMBASE without language restrictions. This study followed the corresponding international recommendations. We identified a total of 426 articles, of which 37 were finally included. Women represented 60.4% of patients included. The mean percentage of women in these trials was 59.9%, ranged from 40.8% to 76.7%. The separate analysis by sex of the main variable was only performed in 5 of the 37 publications included, and none of the trials analyzed secondary variables by sex. Only 1 of the articles discussed the results separately by sex. No study included the concept of gender in the text or analyzed the results separately by gender. The proportion of women included in CTs was higher compared to publications of other disciplines, where women were under-represented. The analysis of the main and secondary variables by sex or gender, even the discussion separately by sex, was insufficient. This gives rise to potential gender bias in these CTs. The term “gender” in research could be defined as a systematic mistake associated with social construct, which incorrectly regards women and men as similar/different , whereasGender bias is a well-established term used in biomedical research to show the low sensitivity to gender among low women representation and absence of analysis separately by sex in CTs –9. In PsAsthma is one of the most common chronic and non-communicable diseases that affects around 334 million people worldwide, and its prevalence has been increasing by 50% every decade . Many epApproximately 5–10% of asthmatic patients experience “severe asthma” because they require treatment with high-dose inhaled corticosteroids plus a long-acting beta-adrenoceptor agonist (LABA), leukotriene modifier or theophylline and/or systemic corticosteroids as background therapy to prevent a poor asthma control . Over thCurrently, the biological treatment with monoclonal antibodies has been shown to reduce asthma exacerbations and oral corticosteroid use, and improve lung function and quality of life in appropriately selected patients . Because10.37766/inplasy2021.1.0020) and is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Equity 2012 Extension declaration [This review protocol was registered on the International Platform of Registered Systematic Review and Meta-analysis Protocols , short reports and letters to the editor, due to the absence of complete data from larger CTs.CTs that involved the evaluation of the treatment regimens based on mAb plus other therapies. Those studies that allowed concomitant medications, that is, drugs that are not being studied but which a patient is taking through all or part of a study, were included.An electronic literature search was performed using PubMed and EMBASE on May 1 2020, with no publication date or language restrictions. Search terms included a mixture of MeSH terms and free text (keywords and synonyms) combined with Boolean operators. The search strategy is detailed in Two independent reviewers (BFR and PCG) screened the titles and abstracts of all eligible publications for possible inclusion. To ensure inter-rater reliability, 100% of the articles were assessed independently by both authors. The articles included were full-length read before a final decision on inclusion. Any disagreement was settled by consensus with a third reviewer (ABGG).Reviewers independently extracted data and ABGG examined all extraction sheets to ensure their accuracy. We explicitly stated if there were any missing data from CTs. For each publication, the following variables were registered:Drug in research: omalizumab, benralizumab, reslizumab, mepolizumab or dupilumab.Year of publication.Age: 6 to 11 years (pediatrics patients) and/or ≥12 years old (adult patients).Financing of the trial: pharmaceutical industry or independent .Location: United States, Europe, Japan, Asia, Australia or the rest of the world (ROW).Trial phase: I, IIa, IIb, IIIa, IIIb or IV.Comparator: placebo or active drug (best standard of care or optimized asthma therapy).Objectives of the trial: efficacy and safety, and if a pharmacodynamic/pharmacokinetic evaluation was performed.Diagnosis: severe allergic, referring to the one that requires treatment with high dose inhaled corticosteroids plus a long-acting beta-adrenoceptor agonist (LABA), leukotriene modifier or theophylline and/or systemic corticosteroids, or uncontrolled eosinophilic asthma, caused by high levels of eosinophils.Asthma controllers at entry: medication that patients were taking for asthma control before starting the clinical trial For the analysis of gender and sex differences and in order to characterize the gender sensitivity of the trials, we followed the Spanish recommendations for the study and evaluation of gender differences in CTs of drugs , the FDAPercentage of female authors among all authors.The number of patients recruited.The number of women included and the percentage of women among patients recruited.If there were (or not) sex or gender-stratified results of the main and secondary outcomes.If the discussion of the results was analyzed by sex and gender.If pregnancy was cited as an exclusion criteria, the studies analyzed the interaction between hormone replacement therapy and study drug, included women using hormonal contraceptives, analyzed the interaction between hormonal contraceptives and the study drug, analyzed the influence of the drug on the pharmacokinetics of hormonal contraceptives, investigated the effects of the phase of the menstrual cycle on the response to the drug, and studied the influence of the phase of the menstrual cycle on the pharmacokinetics of the drug.We also applied a subgroup analysis for the variables: date of publication, location, comparator, drug, age of patients, objectives and sample size.426 records were identified through database searching. After the elimination of duplicates, 353 records were screened by title and abstract. We assessed 91 articles for eligibility; 55 were excluded because they did not meet the eligibility criteria. One clinical trial  was idenThe results of the current study show that, in general, the proportion of women included in the CTs of omalizumab, benralizumab, reslizumab, mepolizumab and dupilumab in severe asthma was higher (60.4%) than the percentage of men. This percentage of females included in the studies is similar to the percentage of women with severe asthma reflecting a low gender bias regarding the inclusion of women in these CTs . HoweverPrevious systematic reviews of gender bias that characterized women’s participation in HIV (human immunodeficiency virus)  or depreSeveral studies have proven that asthma affects men and women differently –19. AccoFurthermore, we found that more than half of the trials did not state whether pregnancy was a reason for exclusion. Even so, it is proved that there is a connection between pregnancy and asthma severity, but with a variable effect .The CTs of the five mAb approved for the treatment of severe asthma were included in this study. Nevertheless, the percentage of women included in the CTs of the different drugs varied between them. Omalizumab’s trials were the ones that included a smaller proportion of women, probably related to the fact that it was the first drug launched and therefore its trials started earlier. However, in the two latest CTs of omalizumab, conducted both in 2016, an analysis by sex of the main outcome was performed. In contrast, the most recent CTs of benralizumab included the highest percentage of women, two of them analyzed the main outcome by sex and one discussed the results based on sex. On the other hand, the design of dupilumab’s or reslizumab’s CTs, was similar so the percentage of women included was almost identical. It could be explained by the presence of common research authors in these studies.We should also mention that we included CTs carried out just in children, adults, or both. It is remarkable that a clinical study that enrolled more than 400 inner-city children, adolescents and young adults (6–20 years old)  was the The main strength of this work is that it is the first systematic review performed on the recently commercialized mAb used in severe asthma which tries to assess gender of bias in CTs. Besides, two of the largest health databases that incorporate articles from the highest-impact medical journals, PubMed and EMBASE, were employed without date and language restrictions, and both CTs conducted in adults and children were included.The main limitation was that the exclusion of post-hoc trials could prevent the inclusion of studies that subsequently evaluated variables based on sex. Moreover, pilot studies were excluded because our study assesses variables that are generally evaluated at the end of the clinical trial and preliminary results from pilot studies were commonly included in larger CTs. Similarly, short reports and letters to the editor were excluded due to the absence of complete data from CTs. The design of the study was limited to variables that were included in the CTs such as location or the phase of the study, but we did not analyze other relevant variables such as race or socioeconomic status. Therefore, we are awarded that evaluating the adequacy of women’s representation in CTs involves a more complex effort, so further studies should corroborate these results. Additionally, the cutoff for adult and pediatric age has been established at the age of 12, since most CTs distinguish between patients older or younger than 12 years. However, some adolescents may not reach puberty until they are not over the age of 12.In conclusion, women represented more than half of the patients recruited in CTs of mAb for the treatment of severe asthma. The proportion of women in these CTs was higher than that reported by previous studies about other chronic diseases. However, the analysis of the main and secondary variables by sex or gender, as well as the discussion of the results separately by sex, are limited. Therefore, a potential gender bias in these CTs is found.S1 Checklist(DOC)Click here for additional data file.