Second, to investigate possible underlying values of the society and those that influence humans' behavior in the present AMR system, an iceberg model was established. Third, leverage points were assessed to estimate which kinds of interventions would have the greatest effect to mitigate AMR in the system. The present AMR system map implies the potential to identify and visualize important risk factors that are direct or indirect drivers of AMR. Our results show that the tool of system mapping, which interconnects animals, humans, and environment in one model, can approach AMR holistically and be used to assess potential powerful entry points for system wide interventions. This study shows that system maps are beneficial as a model to predict the relative effect of different interventions and adapt to rapidly changing environments in a complex world. Systems thinking is considered as a complementing approach to the statistical thinking, and further research is needed to evaluate the use of such tools for the development and monitoring of interventions.Antimicrobial resistance (AMR) decreases the effectiveness of antimicrobials to treat bacterial infections in humans and animals. The increased occurrence of AMR in bacterial population in humans, animals, and the environment requires the measures to combat a rising global health crisis. The aim of this research was to present current knowledge on AMR in a system map and to identify potential explanations of former identified variables significantly associated with AMR. This study applies a systems thinking approach and uses feedback loops to visualize the interconnections between human, animal, and environmental components in a circular AMR system map model. First, a literature review focusing on AMR and socioeconomic factors, wicked problem, and system change was carried out, which was then processed in a system map to conceptualize the present core challenges of AMR  Over the past decades, the rise of antimicrobial resistance (AMR) in humans, animals, and the environment represents a rising global health crisis . Consequ(…) long-term, multi-dimensional, and fundamental transformation processes through which established socio-technical systems shift to more sustainable modes of production and consumption” Over the last 2 centuries, the dominating scientific approaches relied on splitting complex situations into smaller pieces to understand them , 12. ThiSystems thinking adds to the theories methods and tools we otherwise use in global health, and provides new opportunities to understand and continuously test and revise our understanding of the nature of things, including how to intervene to improve people's health.” . System dynamics , an analysis on relationships among system components, can, on the one hand, demonstrate effective policies that must be maintained and, on the other hand, dismantle those that need to be reinvented , 15. SysAntimicrobial resistance is a sustainability issue that can be described as a wicked problem –19. The The diversity and abundance of AMR vary across the world. A global study that investigates the occurrence of AMR determinants in sewage samples indicates that AMR abundance in most geographical parts is influenced by local or national drivers . FurtherFigure 3).Based on collective knowledge, this study approaches AMR through systems thinking. For our study, this implies that different elements directly or indirectly influencing AMR in the human, animal, and environmental setting are set into the perspective of each other. This qualitative research design leads to a systems' view that can be plotted into a system map . Second, all potential system elements relating to the AMR system were compiled, and boundaries of the AMR system were set based on the literature research and the feasibility to make policy interventions. Next, these system elements were interlinked using positive and negative feedback loops. Third, the AMR system was assessed based on the Iceberg Model. Fourth, to identify potential levers for interventions, a leverage analysis of the present AMR system map was conducted, identifying deep and shallow leverage points.A system is an interconnected set of elements that is coherently organized in a way that achieves something” (“mething”  (p. 11).mething” . In relaThe list of elements in a system can be extended indefinitely; therefore, it is most important to look at the interconnections that are a key part of the system. These interconnections are expressed as feedback loops . Thus, sNext, the system elements were interconnected, and causal loops were assessed with positive and negative feedback loops , 15. TheThe present AMR system map was generated as an iterative process. First, the system mapping was applied manually by the use of post-its to transfer the knowledge of the current state of AMR from the literature review to a system map. Next, the handcrafted system map was transferred to an online tool. For the layout, a simple online program, “Kumu,” was used including an animation function of the feedback loops . DiffereThe “state of the system” is the stock, which for the present AMR system map are the overall bacteria population in the system . This meIn this work, the flows aim to describe potential scenarios as researched by the literature , 29. AddSystem elements and boundaries, together with the system dynamics , facilitated the system mapping.Figure 5 based on the literature research. The questions were developed as a part of the system mapping.The iceberg model is a crucial component of systems thinking because it uncovers mental models, which can be understood as the underlying values of a society and those that influence humans' behavior. The iceberg model is a way to think deeper of a problem, and it allows seeing different layers of a system, such as mapping patterns and trends or underlying belief structures. In systems that are herded by humans, the system structure develops as a consequence of mental models or paradigms . Figure Places to Intervene in a System as a hierarchy of intervention points, which was used to assess the present AMR system . Meadow's hierarchy model  was applied to the findings on AMR-related issues in the literature . When the “food demand” is accomplished, it stabilizes the “social structure” (negative feedback loop). A total of two scenarios were identified that hinder the stabilizing negative feedback loop from “food demand” back to “social structure.” First, if the food supply is defected, for instance, due to unequal distribution of food in the society. Consequently, the “food security” would reinforce malnutrition . Second, if the food supply is based on an unhealthy diet the “food demand” will also reinforce “malnutrition” (positive feedback loop) . Further , 38. ThiAs a result, five interconnected systems of the core AMR system were initially identified , from which three were integrated into the present AMR system map model . For instance, the economic system is linked to AMR due to the losses of productivity if people turn ill or die . In addition, if pathogenic bacteria are resistant toward certain types of antibiotics, it requires more advanced treatment, which is more costly . FurtherGiven the current scientific knowledge, and putting the information into system maps, we have shown that the present AMR system map require deep societal changes to mitigate future consequences of AMR. Therefore, it is important to recognize root causes, such as system structures, values, and goals, and understand the dynamics between system elements. Results from the iceberg model indicated that the mindset out of which the present AMR system arises underestimates the risk and consequences of AMU. This can be ascribed to the fact that outside of the hospital settings, it was estimated that approximately 30% of antibiotics would have been avoidable . JørgensThe present AMR system map showed that system elements “AMU” and “AMR” are mutually reinforcing each other (positive feedback loop), and this vicious circle must be interrupted. The virtuous circle can be explained by the following: if antibiotics become less effective, alternative antibiotics are applied, and therefore, the “AMR” reinforces “AMU” , 23. Altto hinder the exposure to bacteria with resistance genes in order to maintain the effectiveness of antimicrobials. Deep and shallow leverage points were assessed in the present AMR system  , which iAbson et al.  found thOur model takes into consideration that impactful interventions include the provision of tools that grant knowledge and awareness. Improving on these system dynamics would contribute to ensure a long-term handling of AMU and meet the UN Sustainable Development Goals (SDG)  . StartinSupplies of resources , to strengthen the balancing feedback loops on “infection and malnutrition” as one of the main drivers of “AMU.”Empowerment of livestock production without “AMU” as a precaution, to prevent reinforcing feedback loops by antibiotics.Enhancing knowledge exchange  as an integrated part of the system to reinforce the spread of information that enables the handling of antimicrobials as a long-term approach on all system levels.Sustainable transitions of the present AMR system map include different system levels  . For insFourth, instead of linear cause–effect relationships, systems thinking depicts the dynamics as causal loops (circular)  . Accordiircular)  “the staa delay in a feedback process is critical relative to rates of change in the system state that the feedback loop is trying to control” . Third, many of the systems thinking tools could be interpreted differently, because the interpretation can include a personal bias . For inscontrol” . This meTaken all the pros and cons together, the model cannot be used to predict a quantitative effect of interventions. The model did not include the risk factors on an individual level, because the focus of the model was to describe overall drivers at population level/regulatory level. However, the benefit is that the model can be used to predict the relative effect of different interventions. Nevertheless, systems thinking is considered as a complementing approach to the statistical or reductionist  thinking . The gloIn this study, we were able to apply the systems thinking approach to create a conceptual model of how AMR occurrence is influenced by different factors. The model improved our understanding of interconnections and feedbacks between system elements for the establishment of effective interventions. Regardless of some methodological drawbacks, feedback loops depict the potential to act flexible on changes, integrate new knowledge continuously, and adapt the system map to local circumstances. However, our model of the present AMR system map does not show how to solve the AMR challenge, but encourage scientists to deviate only from a linear thinking.Overall, the systems thinking approach include different levels , which gives the study a holistic perspective and can be related to real-life scenarios. Due to the large number of stakeholders involved in the AMR network and bacteria's biological characteristics , determining interventions need to be re-thought and require a circular approach. We suggest that this can contribute to more efficient interdisciplinary cooperation , because the system map depicts different fields in one model.This study shows that scientific approaches construct and bound our understanding of where we can intervene in systems. In the scientific field, we still sit broadly in the paradigm of “problem is on par with solution.” However, the system approach cannot stand alone but must be understood as an extension of the linear cause and effect research methods to improve the validity of results. Therefore, we suggest further research that applies interdisciplinary approaches  and addresses this global health issue with an intent of a system wide transformative change. Eventually, we conclude that the scope of systems thinking can beneficially connect AMR's overlapping scientific fields and aid in pursuing a common goal to fulfill the 2030 Agenda for Sustainable Development.The original contributions presented in the study are included in the article/LM and HV conceived the idea to integrate socioeconomic factors with AMR abundance in a system map, elaborated the idea, and planned the study. LM conducted the literature research and generated the systems maps with assistance of HV. TH supported the work integrating the One Health approach and reviewing the conceptualized feedback loops. LM wrote the first draft. All authors have seen and accepted the final 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.


Antimicrobial resistance (AMR) is a growing global crisis with long-term and unpredictable health, social and economic impacts, with which climate change is likely to interact. Understanding how to govern AMR amidst evolving climatic changes is critical. Scenario planning offers a suitable approach. By envisioning alternative futures, stakeholders more effectively can identify consequences, anticipate problems, and better determine how to intervene. This study explored future worlds and actions that may successfully address AMR in a changing climate in a high-income country, using Sweden as the case.taxation of antimicrobials at point of sale, and infection prevention measures) could each combat AMR in 2050 in Sweden given our changing climate; and (2) actions to take starting in 2030 to ensure success in 2050. Transcripts were thematically analyzed to produce a narrative of participant validated alternative futures.We conducted online scenario-building workshops and interviews with eight experts who explored: (1) how promising interventions  “Addressing the Basics” identified infection prevention measures as highly impactful at containing AMR in 2050 because they would contribute to achieving the Sustainable Development Goals (SDGs), which would be essential to tackling inequities underpinning AMR and climate change, and help to stabilize climate-induced mass migration and conflicts; and (3) ”Siloed Nations” described a movement toward nationalism and protectionism that would derail the “Addressing the Basics” scenario, threatening health and wellbeing of all. Several urgent actions were identified to combat AMR long-term regardless which future un-folds, such as global collaboration, and a holistic approach where AMR and climate change are addressed as interlinked issues.Recognizing AMR to be a global problem requiring global solutions, participants looked beyond Sweden to construct three alternative futures: (1) “Tax Burn Out” revealed Our participatory scenario planning approach enabled participants from different sectors to create shared future visions and identify urgent actions to take that hinge on global collaboration, addressing AMR and climate change together, and achieving the SDGs to combat AMR under a changing climate. Antimicrobial resistance (AMR) is a growing global crisis that claims approximately 700,000 lives per year  and may AMR is a top 10 global public health threat , and whiScenario planning is a type of foresight method that enables exploration of alternative future worlds that might come to pass, and this approach helps to develop understanding about how those worlds can be realized or avoided . Shell OGiven the intersectoral nature of AMR, engaging multisectoral stakeholders in scenario planning exercises is necessary to construct alternative futures that are informed by diverse thinking about the broad forces that may impact the problem, and that allow us to explore each future's consequences to better identify risks and how to mitigate them. To our knowledge, such an exploration has not been undertaken previously for the problem of AMR under changing climatic conditions.The aim of this study was to explore alternative futures and actions needed to successfully address AMR under a changing climate in the year 2050, using Sweden as the case. Sweden has demonstrated success in reducing AMR levels  while coThis qualitative study addressed the Consolidated Criteria for Reporting Qualitative Research (COREQ) checklist for reporting qualitative research . The stuThe study was designed, conducted, and analyzed by a core team  who consulted with an international research team throughout the process. The disciplinary background of the core team comprised public health and epidemiology, with specializations in food safety, AMR, One Health , health We conducted a participatory scenario planning exercise that involved presenting diverse stakeholders with two pre-determined and desirable futures where AMR was successfully addressed under a changing climate circa 2050 in Sweden as a result of two promising interventions, then asking stakeholders to envision what the year 2050 would need to look like to ensure this success, and then “back-cast”  from thetaxation of antimicrobials at point of sale and infection prevention measures—could each effectively address AMR under a changing climate in Sweden in the year 2050. We focused on these two interventions because they would provide a point of discussion for participants to determine how Sweden would need to look in 2050 to ensure each intervention was successful considering climate change impacts. The selected interventions were identified from activities of our broader international research project  which actions will need to be taken starting in the year 2030 to achieve success in 2050.Workshops and interviews were audio-recorded, guided by a pre-tested semi-structured interview guide, and facilitated by our team . Workshop and interview procedures involved a review of the agenda, introductions, and a simple exercise to catapult participants into the year 2050. We then tasked participants to explore (1) how and why To assist discussions, participants were formally introduced to materials that they were sent three days in advance of the workshops or interview. Participants received a causal loop diagram of drivers of AMR in Europe  to use After all workshops were complete, transcribed verbatim transcripts, meeting notes, and field notes were then coded and analyzed thematically. Coding was carried out independently by three researchers  and themes were identified and compared for consistency across two researchers . Any differences in coding or themes were resolved through discussion. Prior to coding and thematic analysis, IAL created a summary of the 2050 alternative futures that participants had described by reviewing the audio-recorded sessions and detailed meeting notes and field notes, sharing these with participants for feedback to ensure they accurately reflected their understanding of discussions. Then, through an iterative process of triangulating emergent themes against transcripts, meeting and field notes, discussions with team members, and participant feedback, a narrative was developed describing participants' constructions of alternative futures where each intervention explored could be successful in addressing AMR in Sweden circa 2050 under a changing climate and the key actions necessary to take starting in the year 2030 to ensure success. Illustrative quotations (identified by workshop or interview day as per approved University of Waterloo research ethics requirements) are provided in the Results section.there is no point of somebody doing something in one part of the world and somebody else not following in a different country or continent” (Day 1 workshop). Second, participants determined to focus discussions on antibiotics and broadly on other non-antibiotic antimicrobials, such as antivirals, antifungals, and disinfectants, which “might themselves be entry points for being selective of antibiotic [resistance] problems” (Day 2 Workshop), noting that looking at antibiotics in isolation would lead to “proposals that actually do not solve the long-term challenge [of AMR]” (Day 2 Workshop). As a result of exploring each of the two promising interventions  through these lenses, participants described three alternative futures: (1) “Tax Burn Out,” (2) “Addressing the Basics,” and (3) “Siloed Nations” . To illustrate, participants noted taxes and tariffs could be increased responsively on different groups of antibiotics that demonstrate increasing resistance based on data, potentially altering the types of antibiotics prescribed and used. Using taxes to incentivize rather than penalize behaviors  was also viewed to potentially motivate people to use and dispose antimicrobials properly.In this scenario, participants explored how and why the ciprofloxacin is the same price as a box of candy” (Day 2 workshop). Second, participants stressed that applying taxes to antimicrobials “can be quite discriminatory on the poor sectors in our community and…the poorer countries in the world to have access to antibiotics that may be lifesaving” (Day 2 workshop). While taxing those who can afford it and providing subsidies to ensure access for those who are less well off could offset inequities, participants strongly felt taxation would not address the issues that underpin AMR and many public health problems, such as access to nutritious and affordable foods and clean water, proper toilets and proper infrastructure such as housing and waste and wastewater treatment facilities. Third, participants described how different taxation schemes across countries could create inconsistencies and lead to “…informal markets that bring additional problems…beyond what we have to deal with initially” (Day 1 workshop). Fourth, building stakeholder buy-in for yet another tax was said to be a hard sell. Finally, participants stressed that if the taxation intervention were to contribute to addressing AMR in 2050, its main contribution would be via the use of tax dollars to fund the types of multipronged interventions that are actually essential to tackling AMR  and that to be successful these interventions would need to be implemented in a context that reflects the “Addressing the Basics” alternative future scenario described below.However, challenges with imposing a tax were viewed to override the potential benefits of this approach. First, participants noted that high taxes would be needed to evoke desired behavior change in wealthier countries like Sweden, where citizens have drug coverage and broad-spectrum antibiotics are inexpensive to buy, e.g., “infection prevention measures were successful in addressing AMR in Sweden circa 2050 under a changing climate. Participants identified infection prevention measures to be a high impact and essential intervention necessary to address AMR. Participants envisioned that AMR will be effectively contained at low levels in 2050 should current trends of increasing global awareness in human and animal sectors about AMR and growing implementation of infection prevention measures  continue, and if there is greater focus on ensuring other measures, such as selective animal breeding, access to nutritious feed and food, and clean water and proper toilets become common place. Participants noted that these measures may create “many positive spillover effects” (Day 2 workshop) that prevent and control diseases and reduce the need for AMU. Prevention measures were also viewed as critical because they contributed to the achievement of the Sustainable Development Goals (SDGs), and the SDGs were identified to be key to addressing the driving factors that underpin AMR, climate change and other complex public health problems, “It doesn't really matter what nice drugs we…come up with or…taxation programs and so on…if there is no access to clean water and healthy nutritious food across the globe and hygiene, sanitation…which also [takes] us back to the Sustainable Development Goals…really the basics…we are lost” (Day 2 workshop).In this future scenario, we asked participants to explore how and why reducing inequalities as far as possible because that reduces other risks that can then have implications for AMR, so fuel, poverty, food poverty.” (Interviewee A), and by achieving the SDGs, participants asserted countries could become economically viable and self-sufficient and better able to address the negative impacts of AMR and climate change. Predicting that human beings will have the same basic needs as today, such as access to clean water, nutritious food, education, employment, and more, participants described six key features of a 2050 future world where the SDGs could be achieved and AMR addressed under a changing climate. Participants were explicit these features were key to achieving this future.Participants stressed that the SDGs enable “finding their voice and insisting on change…in the whole global system of how we work together” (Interview A) leading to an agreed system for accountability where politicians are voted out by their citizens if they do not act appropriately in their running of the country. Policies were also said to align with the redefined values driving society, rooted in sound science, and to transcend the government of the day to ensure previous commitments prevail. These redefined values were also said to drive how services are commissioned, suppliers are selected, how industries are developed and what policies prevail.Because of the COVID-19 pandemic and heightened concern over AMR and climate change, participants said that by 2050, Sweden and many countries beyond had completely redefined their values and how society operates, with less focus on economic profit and a greater economic valuing of health and wellbeing and reducing inequities. Given this orientation, one interviewee imagined that the World Health Organization would serve as an executive agency of the United Nations with greater authority to provide strong leadership and responsibilities to promote health and wellbeing and address AMR and climate change. Citizens were also described as playing an active role in the political arena “…stronger international organizations, [international] cooperation, more international codes and enforcement of common rules” (Day 2 workshop) that uphold the redefined values of health and wellbeing that underpin how society operates. Collaborations between countries that share borders  were also said to thrive in 2050, enabling learning from each other's experiences and sharing the lessons to help the rest of the world. Sweden, still envisioned by participants to be a European Union member in 2050, was said to be a “leader” (Day 2 workshop) in tackling AMR, sustainability, climate change, and helping to realize the SDGs because of their effective application of the European Green Deal and the Farm to Fork Strategy; by applying Sweden's successes and lessons, other countries were seen to be better able to address AMR under a changing climate. High-income countries were also described as sharing human capital, resources and technology with countries that needed it, building their capacity in ways that address the SDGs and, consequently, AMR and climate change.A shift in global power dynamics from the West to the East was envisioned by participants along with the presence of “In line with redefined societal values of health and wellbeing and as a result of education and experiencing the impacts of resistance and climate change in 2050, participants prophesized that the public will eat healthier, be more active, pay more for animal-welfare friendly and sustainable products , and use antimicrobials appropriately. Participants also imagined people using new technologies, such as wearable devices that send early warning alerts to the individual if at risk for a heart attack or other unwanted health events. The above changes were also said to have come about via improved scientific understanding of about how to influence behavior change.who's running the food systems in 2050” (Day 2 workshop). Increased population growth, wealth, and power in the East was described as having a potentially dramatic effect on global food demands that may change dietary patterns in the West. Participants noted these demands could lean toward the East adopting Westernized diets, vegetarian diets, or diets containing far less beef and pork and more poultry and fish. Insect meal was also said to feature to some extent in human diets because of their biomass but may be more likely be used in animal feed. However, given the climate change reality and greater concerns about the environment and animal welfare among the public, participants felt food demands would likely lead to a reliance on de-intensification of food production practices and growth of niche markets that promote animal welfare, use antimicrobials appropriately, and reduce the use of chemicals. Participants also noted that beef prices would “increase beyond inflation” (Day 2 workshop) and be consumed primarily on special occasions. Another view was that both de-intensification and a few large and regulated food production companies would exist to feed the world, and that fewer food animal species would be produced. The potential of producing fewer species was viewed “a double-edged sword,” (Day 2 workshop) as reducing biodiversity could increase the risk of disease emergence that can more easily wipe out the food supply but could also enable greater standardization in farming practices, such as appropriate AMU and more people working on the same species globally so that when problems arise, they can be solved efficiently as a priority.While modeling data was said to likely help determine which types of food animal species to farm based on reduced need for AMU or reduced carbon emissions in 2050, participants also stressed that which foods are available will be strongly based on “Regardless of the food production systems that prevail, participants stressed that innovation and technological advancements would be essential to ensure the negative consequences of AMR and a changing climate are minimized.very important element to reducing… the need for antibiotics…” (Day 2 workshop) under a changing climate. Producing foods using genetically modified organisms (GMOs) or Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) technology was said to “take you to places that are impossible” (Day 2 workshop) at present, as they could help to grow food that could reduce the need for AMU and can thrive in water-scarce conditions. Lab-produced foods  that do not require AMU, are nutritious, and help to reduce health problems such as cholesterol that in turn could contribute to healthier populations, were also envisioned to be more prominent in 2050, with differing opinions on their widespread cultural acceptability. Making food production “too artificial,” (Day 1 workshop) however, was said to potentially limit animal manure use on crops, which may shift the system to rely on artificial manure that could limit soil nutrients or rely on human waste that necessitate waste management systems that are effective in clearing, for instance, antimicrobial residues. Changes in food production were cautioned to potentially lead to job losses for people, such as if food production hinges on a few large-scale corporations.Breeding animals and crops with natural resistance to infections, pests and diseases was identified as a “Smarter use of antimicrobials” (Day 1 workshop) was also described to be a reality in 2050 via the development of early and rapid diagnostic testing and markers of infection and resistant organisms that make dosing “…optimal, precise and responsive to the stage of infection” (Day 1 workshop) in people and animals, ultimately reducing on-farm AMU for metaphylaxis and improving prescribing practices. Antimicrobial alternatives , and greater understanding of the microbiome and microbiota and new ways to addressing AMR transmission that help to reduce contamination in land and water courses in both humans and animals were also described to exist and be widely used in 2050.Participants noted that by 2050, significant discoveries that address bacterial infections will have been made and progress toward tackling viral, fungal, and parasitic infections to prevent and control resistance made. “tougher” (Day 2 workshop) to achieve the basics particularly in low- and middle-income countries. Thus, new developments such as desalinization plants in rural communities and greater access to wells and systems that provide clean water for populations were expected to be well established in 2050 in countries that need them. Also anticipated was widespread smart cities and smart societies that use data to ensure core infrastructure elements are providing adequate clean water and electricity supply; proper sanitation, including waste and wastewater management; and circular economies that repurpose existing waste in ways that support development efforts and minimize inequity gaps globally . One interviewee imagined a traceability system that provides a holistic look over the food supply chain, detecting infectious pathogen emergence at its source and helping to ensure a safe and secure food supply. Artificial intelligence (AI) enabling the processing of information akin to the human brain was said to take rapid diagnostics further by being able to pinpoint infectious disease outbreaks and other safety and prevention issues before they happen at a societal level to facilitate better macro-level decision-making about how best to intervene.While achieving the SDGs was emphasized to enable countries to become self-sufficient and better able to manage the negative impacts of climate change and AMR, climate-induced water scarcity was said to likely make it “Population growth, poor infrastructure and social support systems, and water scarcity in low- and middle-income countries, and large land masses being submerged underwater in historically food-producing countries were said to have potential to drive mass migration, conflicts, and wars. However, international collaboration and the less varied inequities globally due to Sweden and other nations' achievement of the SDGs were envisioned to stabilize migration patterns because countries, particularly in low- and middle-income regions, would be better able to handle AMR and climatic changes in 2050. Sweden was also envisioned to help those who do migrate: participants noted that Sweden's aging population and stagnant population growth, commitment to addressing inequities, and ability to produce sufficient food due to longer harvest periods and sufficient water supply in certain areas as described in the news story of Sweden in 2050 under climate change  used in away from the more efficient global chains to local value chains with a view to ensuring security of [domestic] supply” (Day 2 workshop). One interviewee imagined Sweden and many other countries as becoming independent in, for example, the energy sector to serve the dual purpose of contending with climate change while protecting national interests and avoiding conflicts that could arise when other countries are relied upon for energy needs or other supplies. However, these efforts to “build a wall…” (Day 2 workshop) were said to directly conflict with international cooperation and international trade, which in turn was viewed to threaten the global sharing of resources and technology to build capacity and infrastructure in countries that require the help, particularly developing countries, to deal with AMR and climatic changes. These conditions were said to create instability and catalyze mass migration and increase the potential for conflicts due to water scarcity. Interviewees also described how technological advancements, such as robots and increased automation to carry out jobs that immigrants often fill including working in the farming and service industries and cleaning of infrastructure , were also said to raise question about what social safety net and other mechanisms need to be instituted to minimize labor market disruptions and associated negative socio-economic wellbeing that can limit people's ability to integrate and contribute to society, particularly in mass migration scenarios.The “Siloed Nations” alternative future emerged as a result of participant discussions of the “Tax Burn Out” and the ideal “Addressing the Basics” scenarios. Here, participants described an alternative future where nationalism and protectionism prevail and threaten to derail or destabilize the ideal “Addressing the Basics” future. Participants described the emergence of populistic politicians coupled with the growing trend away from globalization toward nationalism over the past 30–40 years that intensified with the COVID-19 pandemic, to have led some national governments to reassess strategic industries, particularly the pharmaceutical, food and energy sectors, and move them “we need to…move now” (Day 1 workshop) and identified the actions outlined below and illustrated in After exploring the future, we had participants travel to the year 2030, to describe the actions that need to be taken starting at that timeframe to ensure AMR interventions are successful in 2050 under a changing climate, regardless of which future scenario unfolds. Participants clearly stated that AMR is an urgent crisis and if we wait until 2030 to act, we will be too late in being able to tackle it. Participants stressed that “not sexy enough” (Day 1 workshop) because leaders are more interested in exploring new frontiers such as via space exploration. Also, the COVID-19 pandemic, which has eroded international collaborations, created an “economic disaster” (Day 1 workshop), increased mental health issues, and generated a mistrust in science, has led people to switch off hearing about any further crisis. However, participants believed these conditions offer ripe opportunities to “highlight how another bigger pandemic can be coming down the pipeline, which would be AMR” (Day 1 workshop) and to use the lack of preparedness of nations to deal with the COVID-19 pandemic to convince governments and the public to invest in long-term planning, and ultimately move AMR up the policy agenda. Advocacy was identified as the vehicle to mobilize these messages to land and keep AMR high on the policy agenda even when new crises arise and despite the long time it takes for decision-makers to see the positive gains of their investments.Re-establishing AMR as an urgent problem regardless of new crises was identified to be critical. But AMR was described as “Taking a holistic approach characterized by coordinated and multi-pronged actions that directly or indirectly impact AMU or AMR across the One Health system at a global scale were identified as necessary. Expanding the focus to include all agents that contribute to resistance (not solely antibiotic use) and implementing AMR National Action Plans in all countries were deemed to be imperative. Developing smart regulations that involve diverse stakeholders in the design of regulatory standards to address unintended consequences to different actors from the outset was also noted as important by participants. Improving surveillance and monitoring of AMU by gathering unified data globally on actual AMU and antimicrobial disposal was identified to be important given advancements in precision medicine which may erroneously show AMU reducing even though drug potency is increasing. Continued efforts to develop rapid diagnostics, understand animal species-specific dosing of antimicrobials appropriate for the infection and stage of species lifecycle, and research on the microbiome and development of alternatives to antimicrobials were additional measures that participants discussed.A greater focus on promoting healthy lifestyles and preventing illness in humans and animals coupled with de-intensification of food production practices were viewed to be important to tackling AMR. Participants also noted a need to implement effective infection prevention and control measures at airports and to institute a third-party body to assess and improve measures to minimize infectious illness and AMR spread via international travel. One interviewee suggested developing AMR screenings for travelers, immigrants, and as part of health care interventions that require blood pressure and full blood tests as additional measures to avoid reintroducing pathogens eliminated in a given nation or to determine prescribing practices.Because of the importance of innovation to tackle AMR under a changing climate, participants stressed a need to find attractive investment strategies to incentivize industry interest and commitment to develop antibiotics and alternatives such as new feeding strategies, feed additives, bacteriophages, vaccines, probiotics, and provide aid funds to companies for technological and infrastructure development to address AMR and climate change. Many of the technologies described in 2050 were said to already exist now but require further development and participants stressed a need for transparent discussions regarding unintended consequences that may arise should technologies, such as GMOs and AI, become widely adopted. Determining how to deal with potential job losses that may result from technological advancements that enable movement away from use of fossil fuels or changes in agricultural food production systems was also identified as needed.the climate change discussion and AMR, two global issues, closely linked together because there's lots of interactions between both” (Day 2 workshop). Greenhouse gas emissions were described to be already driving de-intensification in some profitable sectors within some countries with intensive high-stocking agriculture. Growing consideration of environmental costs of current actions in turn were said to continue to impact how food is produced, such as a greater orientation to sustainable practices that could have implications for AMU and efforts to prevent AMR development and spread.Participants stressed the importance of keeping “a certain level of welfare for all the population” (Day 1 workshop) were two key elements participants described as necessary to recover from the COVID-19 global economic impact, increase people's ability to make better choices , and get back on track to realize the SDGs. Exploring animal welfare as an under-examined pathway toward achieving the SDGs was also identified.Achieving the SDGs was identified as key to addressing AMR under a changing climate in 2050. Most participants questioned whether this was feasible due to insufficient progress in achieving 2030 milestones and because key goals, such as ending poverty and hunger, have been further compromised due to the COVID-19 pandemic. Creating employment opportunities and achieving “Rebuilding those bridges that were broken in 2020 due to the pandemic” (Day 1 workshop) was identified a priority to realize the SDGs and address AMR and climate change. Fostering international cooperation to reverse “nationalism…and the division between countries” (Day 2 workshop) that have led to budget cuts that compromise human rights and the achievement of the SDGs was noted. Educating countries and farmers about the future economic impacts of AMR and how infection prevention measures can positively impact economic prosperity was said to “take you a long way toward solving AMR without ever needing to talk about it… [make it] easier to get buy-in from key stakeholders,” (Day 2 workshop), and allows learning from experiences around a shared interest across sectors globally which helps foster collaboration. Developed countries taking responsibility to solve problems they cause in other parts of the world was another leverage point identified to rebuild relationships. Eliminating AMU in food production in Sweden, for instance, while sourcing food from developing countries that use antimicrobials to meet market demands was said to shift the problem elsewhere. One suggested action was to test for AMR in imported foods as one opportunity of how to put pressure on exporting countries to improve their production practices; this was also seen as a way for developed importing countries to share resources and help to build infrastructure in exporting countries that need it, to enable them to remain economically viable in the marketplace, which will better prepare them to curb the negative impacts of AMR under a changing climate.“quick fixes” (Day 1 workshop) were also identified.Participants stressed that long-term societal and cross-sector commitment and changes in norms and behaviors are imperative to realize the SDGs, and address AMR under a changing climate. Thus, engaging the public was deemed important. Also important were strategies such as identifying policy levers that tie AMR and climate change to food prices and insurance policies to make the issue relevant to individuals' everyday lives, labeling the antibiotic and carbon footprint of food products using a unified metric to inform purchasing decisions, and using testimonial-based communication campaigns featuring hard-hitting messages about living with the negative impacts of AMR and how to use antimicrobials appropriately to motivate behavior change. Educating students throughout their educational trajectory about AMR, infection prevention, animal welfare, sustainability, healthy eating, physical activity, public health, and how humans connect to ecological systems, was identified as important to improving healthy lifestyles, reducing disease and AMU, and protecting the environment. Cross sector education and training on the benefits and harms of antimicrobials, which antimicrobials to use when and how to use appropriately, the interlinkages between AMR and climate change, and infection prevention measures were deemed to be essential, particularly among farmers who use antimicrobials, and among prescribers, dispensers and retailers who determine which drugs or products are sold and used. Engaging social scientists to help develop interventions that can change behaviors and overcome people's desire for “we can reduce the amount of spreading diseases…by ourselves by washing hands, keeping distance and so on” (Day 2 workshop); illustrating the negative consequences of poor international collaboration; devising strategies to counter politicians from politicizing evidence for their political agendas; creating consistent communications about evidence to not undermine confidence in scientific experts; improving risk mapping to better prepare for future pandemics like AMR; and showing how to influence behavior change via “nudging” (Day 1 workshop).Implementing, surveilling, monitoring and evaluating AMR National Action Plans, climate change policies, and interventions to address the SDGs were identified as necessary to identify best practices, demonstrate progress, advocate for continued investment, and adapt actions in response to changing circumstances to garner policy makers' commitment and keep these issues high on policy agendas. Documenting and sharing best practices and lessons learned from countries that have demonstrated social and economic success in, for instance, reducing antibiotic use in food animals, improving animal welfare standards, or achieving a SDG goal, were deemed to be an important strategy for others to learn how to apply and scale similar practices in their own jurisdictions. The COVID-19 pandemic was also identified to offer a wealth of knowledge that can inform and improve actions to address AMR under a changing climate by demonstrating the importance of infection prevention measures and how “Interviewees identified a need for ongoing vision development where different nations and sectors construct their ideal future scenarios of the world in 2050 and use these visions to find commonalities and ideas about how to address problems like AMR effectively, sustainably, and ethically. Also key was for emerging global powers to learn from the successes and mistakes of their predecessors to create a better vision of the future and how they want their actions to impact themselves and the collective, such as the value they place on producing food that is healthy for consumption and for the environment.taxation of antimicrobials at point of sale and infection prevention measures), participants constructed three alternative futures, contemplated their benefits and consequences, and identified necessary actions for long-term AMR mitigation success.We applied scenario planning methods to explore how a high-income country (Sweden) might address AMR under a changing climate in 2050, a method that has been marked as useful to better tackle complex public health problems (28). Specifically, we used a participatory approach involving experts from multiple sectors that are both traditionally and less traditionally engaged in AMR discussions. By exploring each of two promising interventions  considerations when planning how to address AMR under a changing climate. Our participatory approach was key to generating this knowledge. By bringing together experts that are traditionally and less traditionally engaged in discussions about AMR from human, animal and agricultural sectors, participants were able to share and build on each other's diverse areas of expertise and ideas, and question each other's assumptions, to construct potential pathways to AMR success in 2050.Three criteria to assess the quality of scenarios exist: (1) relevance, in that the scenarios address concerns relevant to users; (2) challenging, in that the scenarios get stakeholders to think about the focal problem differently; and (3) plausible, in that the assumptions and events described are internally consistent , researched, and possible . ThroughAlthough we successfully recruited participants representing diverse perspectives, the perspectives were not exhaustive, and the inclusion of experts from other disciplines may have introduced additional elements to the future scenarios. Future efforts would benefit to institute an iterative process involving other research, practice, and policy actors to further assess if and how these scenarios are relevant, challenging, and plausible to others beyond those engaged in this present study.Our study demonstrates the value of exploring alternative futures because it provides a way to identify potential risk factors and risk mitigation actions to realize a desired goal regardless which future unfolds. By constructing three alternative futures, participants were able to identify several actions that strive to take us to an ideal world where AMR is addressed under a changing climate circa 2050. These actions  aim to address the systemic drivers of AMU and AMR, implicate different government departments and sectors, and thus suggest that an all-of-society and whole-of-government approach is needed to address AMR long-term under climate change conditions.taxation of antimicrobials at point of sale and infection prevention measures were each successful in addressing AMR in 2050 under a changing climate. Here, stakeholders can explore how the “Siloed Nations” alternative future could address AMR, including the six key features highlighted in the “Addressing the Basics” scenario.Given the identified need to continue to protect the efficacy of antimicrobials, for AMR and climate change to be addressed as interlinked issues, for the SDGs to be achieved, and for societal norms to change, future research is needed to elicit different stakeholder perspectives including from pharmaceutical, climate change and environment, energy and information technology, economic and insurance, tourism, immigration, and food and farming sectors, as well as social policy actors, advocacy groups , and the public. Since our study's focus on Sweden reflects a social welfare state with high levels of confidence in core national institutions and political trust  and wher, and SDG 3.d.3   . Given pe basis) , 50 and Identifying interventions that jointly address AMR and climate change, including their benefits and drawbacks in terms of effectively mitigating AMR and keeping AMR high on policy agendas, and interventions that achieve specific SDGs with positive impacts on AMR and vice-versa, will be important to assess. This will require expanding our focus from antibiotics to all substances that drive resistance , and developing integrated surveillance systems that track the use of these substances, AMR, and climate change indicators across the One Health spectrum. It will also require ongoing assessments about how AMR National Action Plans and other relevant interventions such as infection prevention measures, health promotion and chronic disease prevention interventions, and SDG relevant interventions impact AMU behaviors, AMR, climate change, illness, death, and associated social and economic outcomes.Because participants described how a shift in global power to the East could impact the West such as food demands and identified a need for greater international cooperation, future research would benefit to explore how high-income and low- to middle-income countries influence one another now and under alternate future scenarios of climate change and power and governance change.Developing funding mechanisms to incentivize industries to develop technologies and antimicrobial alternatives are needed. Assessing the benefits, long-term consequences, and ethics of technologies  and ensuring transparent discussions involving governments and the public will be important to making decisions about where to direct funding.Greater attention to engaging and building the capacity of advocates  from human and animal sectors and the media to translate evidence to decision-makers and the public is also necessary to raise and maintain AMR as a high-priority issue on national and international policy agendas.Our participatory scenario planning approach enabled participants to create shared visions and identify actions that must be taken now that hinge on fostering cross-sector and global collaboration to address AMR and climate change together, promote health and prevent disease, and achieve the SDGs to effectively address AMR under a changing climate. Taking immediate actions to address AMR will help build resilience toward the changes brought by climate change, and help ensure the provision of food, health, and overall wellbeing over time.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by University of Waterloo Research Ethics Committe (ORE#41781). The patients/participants provided their written informed consent to participate in this study.SEM conceptualized the study design along with EJP, CAC, DW, and PSJ. IAL, SEM, EJP, CAC, and MC were involved in developing the study methods and data collection materials. IAL, SEM, EJP, CAC, MC, TG, AL, PH, MT, DW, and PSJ contributed to methods and the selection of interventions that were explored in our study. IAL, EJP, MC, APD, RG, BSL, and BM were involved with data gathering. IAL and SA led data analysis and all co-authors contributed. IAL wrote the manuscript. All co-authors read, provided revisions in the form of intellectual content, edits and all co-authors approved the manuscript.This study was funded through an operating grant of the 5th Joint Programming Initiative on Antimicrobial Resistance (JPIAMR 2017). Funding was provided by an operating grant from the Canadian Institutes for Health Research  , a Swedish Research Council grant ; and an operating grant from the Swiss National Science Foundation . MT and PH acknowledge support from FORMAS (2016-00227). PH was partially funded by FORMAS Inequality and the Biosphere project (2020-00454) and CGIAR Research Programs on Fish Agri-Food Systems (FISH) led by WorldFish. The funders had no role in the study design, analysis, interpretation of data, or the writing of this article or the decision to submit it for publication.BM is an employee of the Swedish Pharmaceutical Industry Association, and was previously employed by Pfizer AB. He is also a shareholder of several pharmaceutical companies. The remaining 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.


Mohr  Machine learning and simulation synergistically contribute to the discovery of novel cardiolipin-selective molecules. Both molecular simulations and machine learning (ML) can, in principle, be used to perform all these tasks. But the characteristics of each make them uniquely suited to some, as well as highly complementary.3Computation is often used to accelerate the discovery of novel, functional molecules with applications from healthcare to clean energy.ML has demonstrated excellent predictive ability at low cost across a broad range of scientific domains. However, the inductive reasoning used to infer likely relationships between input (molecular structure) and output (molecular property) is fundamentally coupled to the availability of pertinent data. Simulation, on the other hand, generally follows a deductive approach in which computed properties emerge from the application of established physical laws, together with approximations required for computational tractability. Hence, prior data on a specific property is not needed when employing physics-based models for property prediction.4 is an especially suitable approach to drive molecular design given its robust, out-of-the-box performance in low data regimes. This optimization strategy relies on ML to build a cheap, surrogate model of the property being optimized, which is used to define a utility function (or “acquisition function”) that prioritizes candidates for evaluation. In principle, simulation could act as a surrogate for experimental evaluation in a Bayesian optimization framework but, given the considerable cost of molecular dynamics or density functional theory calculations, ML models are the more practical alternative. Reinforcement and active learning algorithms are a more general family of approaches that enable ML-guided decision-making for tasks including and beyond optimization.Molecular design can be framed as an iterative, constrained, and often multi-objective optimization problem. Data for a small number of molecules is acquired, which in turn informs the selection of the most informative subsequent candidates. Bayesian optimizationin silico. Yet, interpretable ML models can also generate insight by revealing subtle patterns hidden across multiple sets of experiments, or in the vast amount of data generated by simulations.Finally, attaining atomic or molecular-level mechanistic insight is of key interest for the understanding of the chemical and physical processes governing catalysis, molecular recognition, and self assembly. Here, simulation has the upper hand thanks to its immediate interpretability and ability to test hypotheses et al.,5 simulation and ML constitute flexible and complementary computational tools to achieve accurate predictions, obtain insight, drive optimization decisions, or all three.As demonstrated by Mohr, Shmilovich In this collaboration, the Bereau (University of Amsterdam), Ferguson (University of Chicago), and Schneider (Johannes Gutenberg University Mainz) groups sought to discover small molecule dyes capable of selectively partitioning into cardiolipin membranes to enable the visualization and quantification of cardiolipin content. Membrane lipid composition has a profound impact on mitochondrial function, and anomalous cardiolipin content has been linked to several pathologies, from Barth syndrome to neurodegeneration. As such, cardiolipin acts as a biomarker for these conditions. Yet, the development of cardiolipin-based diagnostics has been hindered by the challenge of achieving selectivity with respect to other phospholipid membranes.et al. decided to use alchemical free energy calculations to compute the relative thermodynamic stability of a molecule in cardiolipin and phosphatidylglycerol membranes. These calculations rely on molecular dynamics simulations to estimate free energy differences. While their accuracy is limited by finite conformational sampling and the approximations of the molecular model, they are exact from a statistical mechanics perspective.6 The authors created a coarse-grained (CG) model with 6 bead types derived from the MARTINI force field,7 each representing sets of functional groups with different physicochemical properties, to be used in these simulations. Coarse-graining introduces the challenge of back-mapping the CG candidates to molecules, and free energy calculations with CG force fields have not been validated as extensively as atomistic ones. But it reduces the computational burden and enables a hierarchical search of chemical space.As only a handful of cardiolipin probes have been described, and have an unclear selectivity profile, Mohr et al. thus resorted to ML-guided optimization. After running calculations for a diverse set of 100 CG molecules, they performed seven rounds of Bayesian optimization in which 60 CG molecules were evaluated in each round. A Gaussian process model was used to predict simulation output given a continuous representation of the CG candidates as input, which was obtained from a graph encoder that was part of a pretrained autoencoder model . Here, ML is not used to improve the selectivity estimates obtained by simulation, but to focus the free energy calculations only on the most promising and informative candidates, avoiding an exhaustive screen. With this active learning strategy, several candidates with a predicted improvement over the selectivity of the fluorescent dye 10-N-nonyl acridine orange of up to 184% were identified, while having evaluated only 520 (0.42% of the library).The screening library of hypothetical coarse-grained probes comprised over 100K candidates. Given that each calculation requires 24–48 hours on a graphics processing unit, an exhaustive search is infeasible. To efficiently identify molecules with maximal cardiolipin selectivity, Mohr et al. analyzed the results of the simulations with an easily-interpreted linear model with sparsifying L1 regularization . This approach assigned different levels of importance to the chemical patterns present in the CG library considered, highlighting groups that contributed positively or negatively toward selectivity. This analysis revealed that cardiolipin-selective molecules generally have (i) one or two positively-charged groups, (ii) a hydrophobic core, needed for alignment with or insertion into the lipid bilayer, and (iii) weakly polar groups with both hydrogen bond donor and acceptor character.To gain insight into what makes selective cardiolipin probes, Mohr via CG simulations is explored in full atomistic detail. One of these two molecules, quinaldine red, displayed preferential partitioning into cardiolipin-containing model membranes, validating the computational predictions and corroborating the molecular design rules inferred from the model.These design rules were then utilized to manually select two purchasable molecules for experimental validation with differential fluorescence anisotropy. In the future, this selection process may be automated by an inner optimization loop in which the localized area of chemical space identified N-nonyl acridine orange were unsuccessful, definitive evidence that the molecule discovered is more selective than previously known compounds is not available. Yet, the discovery of a cardiolipin-selective compound after the virtual screen of only a few hundred CG molecules, and the experimental testing of only two, is a testament to the power of computation in accelerating the discovery of functional molecules.Because experimental measurements for the known probe 10-et al. shows how simulation and ML can be used synergistically in molecular discovery. The generalizability of physics-based models and the flexibility of free energy calculations were exploited to predict a niche yet important molecular property for which experimental data is scarce. Active learning, in the form of Bayesian optimization, enabled the identification of the most promising candidates at a fraction of the cost of an exhaustive virtual screening campaign. And while more sophisticated interpretable ML approaches are available,8 and further validation of the design rules extracted may be warranted, the linear model used by the authors proved sufficient to drive molecular design successfully.Overall, the work by Mohr 9,10 Similar supervised learning approaches are being explored for the construction of CG models, while unsupervised generative models are providing new avenues to forward- and back-map between CG and atomistic models in an automatic fashion.11 Finally, the development of multi-fidelity, synthetic cost- and prior knowledge-aware active learning algorithms for chemical design may enable optimal decision making tools bridging computation and experiment. With an early example of such an integrated discovery campaign, Mohr et al. have shown how the diversity and complementarity of the instruments present in the computer-aided design toolbox enhances the impactfulness and applicability of computation in molecular discovery.These techniques—alchemical free energy calculations, Bayesian optimization, and interpretable ML—are finding broad applicability in chemical design and design of experiments, even though further advances are needed to increase their accuracy and applicability in diverse chemistry research settings. Among active research areas at the interface of ML and simulations are ML interatomic potentials, which take advantage of in- or equi-variant neural network architectures and may eventually lead to more accurate free energy calculations.M. A. and C. W. C. wrote the manuscript.There are no conflicts to declare.


Hyaluronic acid (HA) is a large non-sulfated glycosaminoglycan that is the main component of the extracellular matrix (ECM). Because of its strong and diversified functions applied in broad fields, HA has been widely studied and reported previously. The molecular properties of HA and its derivatives, including a wide range of molecular weights but distinct effects on cells, moisture retention and anti-aging, and CD44 targeting, promised its role as a popular participant in tissue engineering, wound healing, cancer treatment, ophthalmology, and cosmetics. In recent years, HA and its derivatives have played an increasingly important role in the aforementioned biomedical fields in the formulation of coatings, nanoparticles, and hydrogels. This article highlights recent efforts in converting HA to smart formulation, such as multifunctional coatings, targeted nanoparticles, or injectable hydrogels, which are used in advanced biomedical application. The sub3) bonds . HA is aof water , leadingof water . Becauseof water .In 1942, HA was first used at a commercial level and then widely applied in bioorganic, biochemistry, radiochemistry, molecular biophysics, and compound polymer chemistry . In receThe molecular structure and characteristics of HA and its applications have been widely reported. This article focused on the newly discovered functions of HA and its derivatives, which resulted in formulations such as coatings, nanoparticles, and hydrogels and the novel application in tissue engineering, wound healing, cancer treatment, ophthalmology, and cosmetics of these formulations.3 Da) signaled injury and initiated the inflammatory response , supports their migration, and includes multiple signaling pathways . Their l3 Da) contribute to the suppression of wrinkles in both layers of the skin  for repairing skin injury . This CMin vitro studies had been reported by different groups relevant to drug-loaded nanoparticles with HA polymers to enhance the ability to target the tumor cells.In some types of cancer, HA is used to monitor the progress because of its mucoadhesive property . HA, aloPresently, the potentials of HA in medication transfer have been explored as a carrier of antitumor and anti-inflammatory drugs. HA is reflected as one of the main components of the ECM; similarly, it is the foremost ligand for CD44 and RHAMM , which aHA is a normal element of the vitreous humor of the eye, and it has several effective uses in ophthalmologic surgical procedures. HA is predominantly beneficial as a space-filling matrix in the eye; therefore, intraocular injection of HA in operations is used to preserve the shape of the frontal chamber . HA solu, creams, serum, gels, lotion, intra-dermal filler injections, and facial fillers. The nutricosmetic and cosmetic effects of HA have been connected with its capability to introduce face rejuvenation, collagen stimulation, and tissue augmentation  inhibit macrophage adhesion/activation, whereas the coatings prepared with HA of low molecular weight (< 104 Da) promote macrophage adhesion/activation. In the application of cardiovascular implants, 105 Da was chosen as an optimized molecular weight to fabricate the HA coating, which will endow the surface with better blood compatibility, anti-hyperplasia, anti-inflammation, and pro-endothelialization ability  on EC with pattern scales of 25 μm  to immune phenotype (M2), which contributed to EC growth and functionalization . Inspirein vitro resistance to digestion with hyaluronidase and in vivo long-term retention ability in knee joint, compared with free HA with a high molecular weight. In addition, it has been reported that the HA nanoparticles have potential as nanomedicine in the treatment of inflammatory diseases . Kang et5 Dalton may be the optimal choice for a readily injectable, in situ-forming hydrogel with appropriate biophysical properties to promote vascular cell spreading and sustain vascular network formation in vitro  HA hydrogel was a promising material for cartilage regeneration. Yet, our previous study showed that low molecular weight HA hydrogels had the advantage of promoting mesenchymal stem cell (MSC) growth, which made the hydrogels excellent carriers of MSC delivery, contributing to brain injury treatment (in vitro anti-degradation ability, better mechanical properties, and lower cytotoxicity, suggesting potential applications in regenerative medicine and tissue engineering. The function of the hydrogels was controlled by the ratio of the high molecular weight HA and low molecular weight HA (HA hydrogels with excellent functions have wide biomedical applications, particularly in tissue engineering, wound healing, and drug delivery . The funin vitro . Mondal in vitro also demoreatment . Furtherreatment . Then, breatment reported eight HA .in vivo but also greatly improve a variety of biological functions, such as anti-inflammatory, promoting physiological cell proliferation, and so on (In vivo results showed that the electrical stimulation method by this hydrogel was superior to the present clinical electrical stimulation strategy to promote the healing of infected chronic wounds.Sulfonation is an effective chemical modification method of HA molecules, which can not only improve their stability nd so on . Data shnd so on , which ind so on . Wu et aIn addition, the HA hydrogel itself or coupled with other substrates such as hydrophobic carbon nanodots, chitosan, alginate, and gelatin can be applied for wound dressing because of their excellent anti-inflammation, anti-bacterial property, and biocompatibility .In this article, the relationship between the molecular properties of HA and the advances in biomedical applications was systematically explored. Biocompatibility based on the molecular weight makes HA widely used in all directions of tissue engineering. In particular, low molecular weight HA is favored for wound healing because of its positive effects on cell adhesion, proliferation, and apoptosis inhibition, but it may stimulate an inflammatory response. The targeted interaction with CD44 on the surface of tumor cells makes HA an ideal drug carrier in cancer treatment. Matching lubricity and elastic modulus and excellent biocompatibility ensures that HA becomes the perfect ophthalmic biomaterial. Super moisturizing and anti-aging properties determine that HA is an irreplaceable ingredient in the current cosmetics scenario. Multifunctional coatings, targeted nanoparticles, and injectable hydrogels as novel HA formulations strengthen its effect in the aforementioned applications. Sulfonation, as an available chemical modification technology, not only improves the stability of HA formulation but also greatly improves its biological properties.5–106 Dalton can both inhibit inflammation and promote tissue regeneration; a higher sulfonation degree of HA leads to better stability and biocompatibility, which may form smaller nanoparticles; HA nanoparticles with smaller sizes have higher delivery efficiency because they can cross the cell membrane faster. These findings gradually make it possible to develop the expected composite biomedical platform systems of HA.The future application of HA may focus on composite biomedical platform systems based on sulfonated HA nano-hydrogels, which integrate the time and space of the orderly release of multifunctions including targeted tracking, controlled drug delivery, and precise regulation of different cells as an organic whole. These composite biomedical platform systems will give full play to the respective advantages of new formulations of HA, which require strict standards for the corresponding parameters. The present frontier research shows some preliminary data: HA with molecular weight ranging from 10


It has been shown that PAN-MA and PAN-LA fibers have a tensile strength of 800 MPa that is 1.5–3 times higher than that of other copolymers spun in the same conditions.The influence of alkyl acrylate comonomers in the rank of methyl- (MA), butyl- (BA), ethylhexyl- (EGA), and lauryl- (LA) in ternary copolymers based on acrylonitrile, alkyl acrylate and acrylamide  on their solutions rheological behavior in dimethyl sulfoxide (DMSO), and mechanical properties of the spun fibers have been investigated. To reveal the role of molecular weight, two series of copolymers with molecular weights of ~50 and 150 kg/mol have been studied. It was shown that the nature of the alkyl acrylate does not significantly affect the rheological behavior of their solutions regardless of the length of the alkyl substituent and the content of the alkyl acrylate in copolymers. An exception is the high-molecular PAN-LA, which is characterized by a non-Newtonian behavior at lower concentrations. Two series of fibers were spun from the characterized ranks of low and high-molecular-weight copolymer solutions. For all copolymers, a 2.5–5-fold increase in the strength and elastic modulus of the fiber was found with an increase in  Acrylonitrile actively interacts with acrylates and carboxylates which leads to the probability to obtain a variety of semi-crystalline, flexible-chain copolymers with good spinnability ,2. The fTraditionally, the synthesis of PAN is carried out by anionic ,18,19,20Comonomers are usually introduced in the homopolymer to reduce its degree of crystallinity , improveAlkyl acrylate comonomers are used as internal plasticizers to reduce intermolecular and intramolecular interactions of nitrile groups . Most ofIn , data arIn this work, we tried to answer some questions about the choice and use of various alkyl acrylate comonomers, in particular, the effect of their alkyl chain length and degree of branching in PAN terpolymers with acrylamide of various molecular weights on solubility, viscoelastic characteristics of solutions, the spinnability and fiber properties obtained from them.wM~150 (AlkA1) and ~50 kg/mol (AlkA2), respectively, have been synthesized. The composition and characteristics of the terpolymers are presented in The synthesis of acrylonitrile terpolymers with acrylamide and various alkyl acrylates  was carried out by the RAFT method and described in detail in . Two serBefore dissolution in a solvent, the terpolymer was dried for 4 h at 80 °C using a vacuum evaporator Heidolph Hei-vap produced by Heidolph Instruments . DMSO  was dried using A4 molecular sieves  , and thec[η], which characterizes the volume occupied by the polymer coil in solution and describes the behavior of solutions in dilute and concentrated ranges. The transition concentrations from dilute to a semi-dilute solution (c*) and from a semi-dilute to concentrated entangled (c**) solution were determined by the beginning of the deviation from linear dependences of the specific viscosity of terpolymer solutions in DMSO at 25 °C on the dimensionless parameter c[η], as shown in , which characterizes the excluded volume or the fraction occupied by polymer coils in solution, which made it possible to take into account the differences in the molecular weight of the samples to reveal the effect of the alkyl acrylate nature.For a deeper understanding of the alkyl acrylate comonomers’ role in the behavior of terpolymer solutions, their viscoelastic properties were studied in a wide range of concentrations. The frequency dependences are shown in It can be seen that in the region of concentrated solutions , the behavior of solutions starts to deviate significantly from the model of a standard viscoelastic fluid in the low-frequency region, which obeys the Maxwellian behavior with slope angles in the terminal zone of 1 and 2 for the loss and elasticity moduli, respectively. This is due to the increase in relaxation times in concentrated solutions. It should be noted here that the role of the alkyl acrylate does not significantly affect the behavior of the viscous component of the complex modulus, while the elastic behavior of PAN-LA series solutions does not obey the general dependence, due to the limited solubility of that polymer in DMSO at 25 °C.A sharper decrease in the slope of the elastic modulus with increasing concentration is apparently due to the influence of the long lauryl acrylate fragments, which increases intermacromolecular interactions and leads to some difficulty with its dissolution. The matter is that all copolymers at room temperature, except for PAN-LA1, form homogeneous solutions over the entire range of concentrations under study. However, PAN-LA1 under these conditions is only partly soluble in DMSO up to ~20 wt%. Higher concentrations are stable dispersions containing gel-like swollen polymer fragments b. The coG′ and G″ for solutions of different concentrations. To exclude the influence of the molecular weight of the polymer, the data were normalized through the parameter c/c# characterizing the distance from the critical concentration of the beginning of the entanglement’s formation (c#)  .c/c# ratio, the crossover frequency decreases linearly in semilogarithmic coordinates.At high frequencies (above the crossover frequency), the solution behaves like a cross-linked gel, and its properties are determined solely by the density of the entanglements that have arisen in these conditions. The forerunners of them are fluctuating entanglements, which can be considered as a precursor of rubber-like nodes. As the mesh density increases, which can be characterized by the Thus, among the studied alkyl acrylates, only lauryl acrylate comonomer introduces a certain specificity into the behavior of solutions, which is associated with the difficulty of dissolving PAN-LA, causing the presence of heterogeneity in solutions.Based on the data obtained, concentrations of the copolymer solutions with low and high molecular weights , and typical defects which are often found in fibers spun by wet or dry-wet processes using a coagulant ,59 are aThe diameters and mechanical characteristics of the obtained fibers for a series of PAN terpolymers of various compositions with high (1) and low (2) molecular weights, obtained at maximum draw ratio, are presented in the form of histograms in In both series with similar molecular weights of copolymers, the fibers’ strength with methyl acrylate significantly exceeds the strength of samples with other alkyl acrylates. In the low-molecular series, the strength of PAN-MA2 samples is about 3 times, and the elastic modulus is 1.5–4 times higher than that of fibers obtained from solutions of other copolymers, while the relative elongation at break values is quite high (about 20%), that could indicate the best macromolecular orientation of methyl acrylate containing copolymer during spinning.wM from ~40 to ~175 kg/mol  was observed. It has a decisive influence on the mechanical properties of the obtained fibers.The nature of the alkyl acrylate also has a significant effect on the mechanical properties of the fibers. Among the used alkyl acrylate comonomers, MA and LA have the best properties. Their strength was 1.5–6.0 times higher, and the elastic modulus was 1.1–4.0 times higher than for the other copolymers. The detailed selection of thermal drawing conditions allows obtaining fibers from high-molecular-weight terpolymers, containing MA and LA, with a strength of up to 900 MPa and elastic modulus close to 10 GPa at relative elongation at a break of ~20%.


The results demonstrated that Co3O4 nanoplates obtained at an annealing temperature of 200 °C possessed strong oxidase activity and efficiently catalyzed the oxidation of 3,3′,5,5′-tetramethylbenzidine (TMB) without the addition of hydrogen peroxide to generate the blue color product ox-TMB. Once the annealing temperature was increased to 500 °C and 800 °C, the oxidase activity of Co3O4 decreased rapidly, and was even inactivated. This might be attributed to the relatively large specific surface area of Co3O4 annealed at 200 °C. Besides this, based on the TMB-Co3O4 nanoplate system, a colorimetric analysis method was developed to detect dopamine with a limit of 0.82 μmol/L in a linear range from 1.6 μmol/L to 20 μmol/L.Inorganic nanomaterials with enzyme-like activity have been attracting much attention due to their low cost, favorable stability, convenient storage, and simple preparation. Herein, Co Dopamine is a well-known considerable catecholamine neurotransmitter in the human central nervous, cardiovascular, and hormone systems . A deficIn recent decades, electrochemical sensors to detect dopamine have received wide attention due to their facile operation and response ,13,14. H3O4 is an important p-type semiconductor with wide applications in supercapacitors, batteries, and catalysis, etc.  is the concentration of TMB, υ is the initial velocity, and Vm represents the maximal reaction velocity.Regarding the catalytic activity of the Courk plot :1/υ = Km3O4-200 , CH3COOH–CH3COONa buffer solution , TMB , and dopamine with different concentrations from 1.6 to 20 μmol/L were recorded from 550 to 750 nm. The change of absorbance  at 652 nm versus the concentration of dopamine was applied to obtain the calibration curve. For the determation of the anti-interference performance, dopamine was detected in the presence of KCl, MgCl2, FeCl3, CuSO4, H2O2, glucose, and urea with a concentration of 100 μmol/L.Regarding the colorimetric detection of dopamine, for the dopamine analysis, the absorption spectra of mixtures containing CoRegarding the characterization, the morphology of the samples was characterized using a scanning electron microscope . The crystal structure was analyzed by X-ray diffraction . The absorption spectrum in the range of 550–750 nm was measured using a UV-vis spectrophotometer (TU-1901). The surface area was detected by BET .2 nanoplates were first prepared and employed as the precursor to fabricate the Co3O4 nanoplates by regulating the annealing temperature. The thermal decomposition reaction only took 30 min at the designed temperature. The surface structure and oxidase-mimic activity of the Co3O4 nanoplates were significantly affected by the annealing temperature, as shown in Based on the previous synthetic strategy , the pre2 2, which is 20 times shorter than the calcination time reported in the previous research [Powder XRD was used to characterize the crystal structure of the samples. Compared with the XRD pattern of Co(OH)2 a, the XRresearch .2 presents a hexagonal plate shape with a smooth surface, which is consistent with the previous study [2 nanoplates at 200 °C for 30 min, a black powder was obtained. As shown in the SEM image in 3O4-200 remains in the shape of a hexagonal plate with a size range of 2–15 μm. Compared with Co(OH)2, cracks on the surface of the black samples can be observed due to the evaporation of water produced in the process of the thermal decomposition of Co(OH)2. In addition, the cracks are supposed to increase the surface area, and should eventually enhance the adsorption capacity and catalytic capacity. The surface structure of the samples hardly changed at the temperature of 500 °C , which has an obvious absorption peak at 652 nm (curve 4). On the contrary, the very weak absorption peaks in curve 2 and curve 3 reveal the sharply weakened oxidase enzyme behavior of the Co3O4-500 and Co3O4-800 nanoplates. Therefore, the oxidase activity of the obtained Co3O4 is seriously affected by the annealing temperature. In the process of catalysis, through adsorption for dissolved oxygen on the surface, the Co3O4 nanoplates are capable of catalyzing the dissolved oxygen to release reactive oxygen species accompanied by the oxidation of Co2+ to Co3+ [2−) acted as the main reactive oxygen species for the oxidation of TMB to blue ox-TMB. Due to its loose surface structure and larger surface area, Co3O4-200 nanoplates can adsorb and catalyze more dissolved oxygen to release more superoxide anions, showing stronger catalytic activity for the oxidation of TMB. The curve in 3O4-200 needs to take around 24 min to enter the steady state.The oxidase-like activities of various types of Co to Co3+ . In vari3O4 nanoplates’ performance of an oxidase-like activity, the kinetic parameters of TMB alone were determined by varying the concentration of TMB, keeping the concentration of Co3O4 constant at 3 mg/mL. The absorbance change versus the concentration of TMB at 652 nm for 30 min is shown in m) and maximum initial velocity (Vm) for the Co3O4-200 nanoplate with TMB are 0.058 mmol/L and 1.27 μmol/(L·s), which are greater than the kinetic parameters reported for Co3O4, Co3O4/CuO, and CoOOH [3O4-200 nanoplates possess a high affinity for TMB.In order to better understand the Cond CoOOH ,37,42. I3O4 were explored. Firstly, the TMB-Co3O4-200 suspension was incubated for 30 min at different temperatures while the pH was maintained at 4.0. The absorbance was recorded, and is shown in 3COOH-CH3COONa buffer solution was controlled at 3.6, 4.0, 4.4, 4.8, and 5.2 as the temperature was kept at 40 °C. 3O4 nanoplates possess a good oxidase-like activity at a pH of 3.6–4.4. The absorbance decreases once the pH rises to 4.8 and 5.2. Therefore, the results illustrate that the Co3O4 can maintain a high oxidase-like activity in a wide temperature range from 20 to 60 °C with a pH of around 4.0.Additionally, the effects of temperature and pH on the oxidase-like activity of Co3O4-200 can be used as an oxidase mimic, and can catalyze TMB to produce colored ox-TMB without the presence of hydrogen peroxide. In this research, in order to investigate the applicability of the oxidase-like Co3O4-200, colorimetric detection for dopamine was conducted due to its inhibiting effect on the oxidase-like Co3O4-200 nanoplates. 3O4-TMB mixtures at 652 nm also gradually reduce with the increase of the dopamine concentration from 1.6 μmol/L to 25 μmol/L, and a further increase in the concentration of dopamine only has a minor change in absorbance. The fading of the blue demonstrates that the oxidase-like mimic of Co3O4-200 is inhibited by dopamine. This might be attributed to the fact that dopamine can induce the reduction of ox-TMB, or that dopamine more easily consumes the dissolved oxygen, which eventually leads to the decrease of the amounts of reactive oxygen species [As we found above, Co species . The cor3O4-200 for dopamine detection in the presence of various substances, including K+, Mg2+, Fe3+, Cu2+, Cl−, SO42−, H2O2, glucose, and urea. The absorbance of the TMB-buffer-Co3O4-200 system at 652 nm shows a significant decrease in the presence of 10 μmol/L dopamine, while there are no significant changes in the absorbance for other substances with a concentration of 50 μmol/L. These results indicate that the oxidase Co3O4-200 displays good selectivity for the detection of dopamine.Selectivity is an important property of mimetic enzymes. 3O4 nanoplates synthesized by thermal deposition possessed oxidase activity. The annealing temperature played an important role in tuning the oxidase activity of Co3O4 nanoplates. In these samples, Co3O4 nanoplates obtained at an annealing temperature of 200 °C showed excellent oxidase activity due to their relatively large specific surface area and loose structure. As oxidase mimics, Co3O4 nanoplates were employed to develop a colorimetric sensor of dopamine with a limit of 0.82 μmol/L in a linear range from 1.6 μmol/L to 20 μmol/L.Herein, Co


Currently, molecular hydrogen treatment has the potential to manage the Corona Virus disease (COVID-19) and pandemic based on its anti-inflammatory, apoptosis-resistance, antioxidant, and hormone-regulating properties. Antioxidant properties are beneficial in both animal and human diseases. In agricultural sciences, molecular hydrogen is used to postpone postharvest ripening and senescence in fruits. However, studies on flower senescence are limited to the application of hydrogen molecules during floral preharvest and postharvest. Fortunately, improved tools involving molecular hydrogen can potentially improve postharvest products and storage. We also discuss the benefits and drawbacks of molecular hydrogen in floral preharvest and postharvest. This review provides an overview of molecular hydrogen solutions for floral preservative storage. The floral market is defined by the high quality of the commercial standard pipeline from floral farmers to the final customers. The flowers, which are considered beautiful symbols of love, ceremony, appreciation, and respect, undergo discoloration, bending, or shriveling in commercialized sectors, reducing the quality of the floral products. Preharvest, vase life, and postharvest values are the most important characteristics for evaluating the commercial quality of cut flowers ,2. The p2) has a broad range of biological effects and is a useful tool in medicine and agriculture . Ho. Ho2 candustries , which adustries ,44. H2 test uses ,44. AlthThis paper considered eco-friendly tools to improve cut flower vase life and is intended not only to help scientists, especially florists, to understand hydrogen technologies but also to provide an overview of steps for keeping cut flowers with a long vase life. The use of hydrogen solutions for cut flowers must be investigated and developed , and inn