These sThis overview provides a scientific opinion on this topic and not pretending on a comprehensive review of the research in the field. That is out of the scope of the article, where only representative studies were selected in the discussion.The endless debates between proponents of reductionistic and wholistic concepts in drug discovery research should reach a compromise since both approaches have advantages and disadvantages ,Purified compounds are easier to control to ensure their reproducible quality and efficacy. On the other hand, complex herbal preparation can be more effective due to their multitarget effects on various governing mechanisms of the regulatory systems involved in the pathogenesis of disorders and progression of diseases .The search for a “magic bullet” selectively targeting a single receptor specifically responsive to a pharmacological action is far from reality for at least two reasons.One is related to the pharmacophoric moieties of ligands . They can interact with various degrees of affinity to the same receptor sites allocated at several parts of macromolecules involved in many regulatory processes .For example, salidroside, which dose-dependently stimulates NPY-mediated expression and release of Hsp72 in human neuroglia cells , has theThe pharmacological and toxicological outcomes of these interactions depend on the concentrations. At low concentrations, only a high affinity of the ligand-receptor infection may contribute to the comparatively “selective” effect. In contrast, in high concentrations, the interactions with other proteins may be toxic and less effective .in vitro studies  and IMPS   studies , particuThe second reason is that the pathogenesis and progression of diseases, as well as the recovery of the organisms, are multi-step processes where many players and regulatory systems are involved in the networks of dynamic interactions. These interactions result in various pharmacological effects and outcomes of functional systems.Therefore, it is not surprising that many comprehensive reviews on the pharmacology of herbal medicines include the same type of activities, like immunomodulatory, anti-inflammatory, antioxidant, neuroprotective, hepatoprotective cardiovascular, vasoactive, etc., that are associated with the presence of the same classes of natural compounds, terpenoids, various phenolic compounds, etc. .The use of complex formulations comprising fixed combinations of several plant extracts in TCM, Kampo, and other traditional medical systems suggests that they are more effective and presumably less harmful (in low dose) than their ingredients due to additive (1 + 1 = 2), potentiating (0 + 1 > 1), amplifying (1 + 1 >2) and synergistic (0 + 0>0) interactions of the components of complex herbal preparations. Hypothetically, antagonistic (1 + 1 < 2) and attenuating (1 + 1 < 2) interactions of the components of complex herbal preparations may also have an impact on the overall toxicity .in vitro studies where the effects of several plant extracts and their hybrid combinations on the number and composition of deregulated genes in brain cell cultures were analyzed , and the liana Banisteriopsis caapi (Spruce ex Griseb.) C.V Morton contains the β -carboline alkaloids harmine, harmaline, and tetrahydroharmine (THH)  . DMT hasne (THH) . Oral inne (THH) . The psyne (THH) .Based on the assumption of synergistic interaction of several components, researchers propose that combinations of several active ingredients in one formulation can have superior effectiveness and better efficacy due to multiple effects on various targets .in silico analysis might be wrong due to unknown interactions and crosstalk between molecular targets within molecular networks involved in the cellular and overall response of organisms on the intervention of plants’ secondary metabolites in pathologic conditions. Several studies in humans have not found combined supplementation to be useful for preventing diseases and decreasing mortality (Rhodiola rosea extract in flies is dependent on dietary carbohydrate and caloric contents coupled with interaction with complex dietary components present in bananas, barley, or corn (However, these expectations and predictions based exclusively on ortality . The sysortality . Further or corn .Based on the ligand–receptor interaction, the reductionist concept is not an appropriate model for assessing the efficacy and safety of herbal preparations affecting multiple physiological functions, revealing polyvalent pharmacological activities, and are traditionally used in many conditions .The network pharmacology approach is more suitable for understanding their mechanisms of action and predicting possible toxic effects, new indications for use, and lack of activity .in silico analysis must be based on experimental findings of gene and protein expression of isolated cells (in vivo experiments on rodents followed by clinical studies in humans (However, the results of ed cells  and valin humans .Typically, plant extracts contain at least several active compounds comprising an active pharmaceutical ingredient/substance of herbal medicines, making it challenging to ensure their reproducible quality. Therefore, it is not surprising that systematic assessment and meta-analysis of pharmacological activity and therapeutic efficacy of herbal preparations often conclude that:R. rosea L. roots and rhizome collected at different harvesting seasons from various geographic regions showed significant variability in the chemical composition and the amount of pharmacologically active compounds (R. rosea extracts but insufficient for assessment of their potential efficacy; additional bioassays are needed to ensure the reproducible pharmacological activity of R. rosea extracts (“Research regarding efficacy is contradictory” due to “a lack of independent replications in different studies. More research seems warranted, and rigorously-designed well-reported RCT that minimizes bias is needed” . Inconsiompounds . A high ompounds  and Rhodompounds . The autextracts . The samOverall, “Good quality systems and manufacturing practices enable consumers to have confidence that products are authentic and meet a high specification for quality and safety .The reproducible quality of herbal interventions is the primary issue in ensuring the reproducible efficacy of herbal medicines. Though, along with a lack of independent replications problem there are other concerns related to poor reporting and methodological quality issues, unclear risk of bias, optimized doses, and treatment regimens to rectify and observe the reproducible efficacy in various clinical studies . There iThis expert opinion and conclusions above are based on convincing observations suggesting further extensive research in the field.


Opioid misuse and mental disorders are highly comorbid conditions. The ongoing substance misuse and mental health crises among adolescents in the United States underscores the importance of widely scalable substance misuse preventive interventions that also address mental health risks. Serious video games offer an engaging, widely scalable method for delivering and implementing preventive interventions. However, there are no video game interventions that focus on preventing opioid misuse among older adolescents, and there are limited existing video game interventions that address mental health.PlaySmart). We conducted formative work in preparation for a subsequent randomized controlled trial.This study aims to develop and conduct a formative evaluation of a video game intervention to prevent opioid misuse and promote mental health among adolescents aged 16-19 years  through individual interviews and focus groups with multiple stakeholders . PlaySmart content development was informed by the health belief model, the theory of planned behavior, and social cognitive theory. User-centered design principles informed the approach to development and play testing. The Exploration, Preparation, Implementation, and Sustainability framework informed preimplementation activities. Thematic analysis was used to identify themes from interviews and focus groups that informed PlaySmart game content and approaches to future implementation of PlaySmart.We conducted development and formative evaluation of PlaySmart for older adolescents that addresses the risk and protective factors for opioid misuse and mental health. Nine themes emerged from the focus groups that provided information regarding game content. Playtesting revealed areas of the game that required improvement, which were modified for the final game. Preimplementation focus groups identified potential barriers and facilitators for implementing PlaySmart in school settings.We developed a novel video game PlaySmart offers a promising digital intervention to address the current opioid and mental health crises among adolescents in a scalable manner. The opioid crisis in the United States has affected many individuals and families. Although opioid misuse among adolescents and young adults has been declining in the past few years, death from opioids among this age group has been on the rise . As a reIn 2020 alone, 1.4 million young adults aged 18-25 years and 396,000 adolescents aged 12-17 years misused opioids , and misOpioid misuse typically starts during mid- to late adolescence , suggestDigital interventions, such as serious video games, have shown promise for targeting health outcomes among adolescents and young adults ,18,28-30PlaySmart, to prevent the initiation of opioid misuse among 16- to 19-year-olds at a higher risk for substance misuse. These efforts build on previous work at the play2PREVENT Lab, which developed and evaluated evidence-based video games for prevention among children, adolescents, and young adults [PlaySmart is funded through the National Institute of Health Helping to End Addiction Long-Term Prevention Cooperative (HPC) Initiative. The National Institute on Drug Abuse ’s primary call for HPC was to address the opioid crisis among those who experienced greater risk among youth and young adults aged 16 to 30 years. HPC consists of a coordinating center and 10 research projects funded to test and implement evidence-based interventions designed to prevent the onset or escalation of opioid misuse among at-risk groups of youth and young adults.In this paper, we describe the formative work of developing a serious video game intervention, g adults ,29,53,54PlaySmart, designed to prevent the initiation of opioid misuse among adolescents aged 16-19 years; (2) develop and conduct a preliminary evaluation (playtesting) of a video game, PlaySmart, in partnership with Schell Games and the National School-Based Health Alliance (SBHA) to be evaluated in a subsequent large-scale randomized controlled trial (RCT); and (3) conduct focus groups and interviews among key stakeholders to understand facilitators and barriers to implementing PlaySmart in school settings. An RCT is currently underway to evaluate the efficacy of this video game.The aims of the formative research were to (1) conduct focus groups and interviews to inform the content and storylines of the video game, A total of 3 phases of formative research  were guided by specific evidence-based theoretical frameworks.PlaySmart development was informed by 3 established theories: the health belief model [ef model , the theef model . These tef model ,57. The ef model . The theef model -61. Attief model . As suchef model ,30 to pref model  and thatef model . Social ef model . Improvief model ,64,65 taef model  such as ef model  and founef model .PlaySmart video game development was grounded in these theories with focus group and interview guides informed by them, and theoretical components are reflected in the game content (see focus group guide in PlaySmart aims to increase the perceived risk of harm from opioid misuse (primary outcome), as it has been shown to be inversely related to actual drug use [drug use ,68,69. Pdrug use . The gamTo guide our approach to game development, we used user-centered design principles. User-centered design is an iterative process that prioritizes the end user throughout the design and development phases ,72. It bPlaySmart in school settings, we conducted preimplementation focus groups to assist in understanding potential anticipated facilitators and barriers that could affect future implementation of PlaySmart in school-based settings. Preimplementation activities were informed by the Exploration, Preparation, Implementation, and Sustainment (EPIS) framework [To inform the future implementation of ramework . The EPIramework . The Preramework . During ramework . During ramework . The EPIramework . During PlaySmart video game intervention consisted of 3 phases spanning 2 years, from early 2020 to late 2021 (PlaySmart (preimplementation).Formative work for the ate 2021 . Phase 1PlaySmart through focus groups and individual interviews. Adolescents were recruited from our local partner high schools and targeted e-mails to the SBHA and their youth advisory council (YAC) members. SBHA is a nationwide organization that advocates school-based health care for children and adolescents through the support of school-based health centers across the country. The SBHA oversees over 2500 school-based health centers in 49 states and Washington, DC. The YAC is a youth service group established by the SBHA and is composed of adolescents aged 16 years or older who are passionate about advocacy and share their expertise on health topics that affect students’ age. Adults recruited for the focus groups and individual interviews consisted of adult affiliates of SBHA, OUD treatment providers, an individual in treatment for OUD, and prevention specialists. SBHA adult affiliates were recruited through announcements, and flyers sent through internal listserves. OUD treatment providers and individuals were recruited from the APT foundation, a nonprofit organization and one of the oldest treatment centers in the United States. Finally, prevention specialists were recruited with assistance from officials at Freedom from Chemical Dependency Prevention Works, an international nonprofit organization that aims to provide substance misuse prevention programs in schools. All participants from the development focus groups and interviews received one US $30 gift card for their time.Adolescents and adults from multiple local and national stakeholder organizations engaged in the development of Participants from the playtesting focus groups were recruited using informational flyers and social media advertising on Facebook and Instagram. Owing to COVID-19, the research team had to adapt to web-based recruitment methods and focus group procedures. Web-based recruitment methods involved distributing electronic posters to different social media platforms and via listservs of partner organizations, such as SBHA. Participants either participated in (1) a 2-hour session that consisted of playing a portion of the game, answering follow-up qualitative questions, and receiving US $30 for their participation or (2) six 1-hour sessions that consisted of playing the entire game, completing procedure-based follow-up questions, and receiving a total of US $60 for their participation.SBHA adult affiliates and YAC members were recruited during 2 of the annual national SBHA conventions. Participants in these groups received a US $40 gift card in 1 focus group session.The focus groups and interviews ranged from 60-90 minutes in duration. Questions focused on knowledge of opioids, perception of the risk of opioid misuse, factors contributing to misuse, and narratives from those who were opioid naive or who had personal experience with opioids, such as providers, prevention specialists, or individuals in treatment . In addiPlaySmart, we conducted 60- to 90-minute playtesting sessions with adolescents. Each playtesting session consisted of 2 sessions. During the first part, the participants played the game. During the second part, they completed assessment questions using either surveys (1 group) or debriefing focus groups (7 groups). See To assess and improve the acceptability and usability of PlaySmart was interesting.” Responses ranged from 1  to 5 (a lot).One group played through the entire game and completed 3 surveys on knowledge, perception of risk of harm, and gameplay experience. The knowledge survey was developed by the team consisted of 5 true or false questions related to knowledge about opioids . The perception of risk survey consisted of 5 questions from the Monitoring the Future Study related to participants’ perception of the risk of harming themselves from different forms of opioid misuse , if they try heroin once or twice?”) . OptionsThe remaining 7 groups played different aspects of the video game (storylines and minigames) and responded to open-ended questions. We asked the participants what they thought the purpose of the game was, what they learned from playing the game, what challenges they experienced while paying the game, if gameplay prompts were easy to understand, if the storylines were realistic, and recommendations to improve the game.PlaySmart in school-based settings, a total of 9 focus groups with adults from SBHA personnel and adolescents from the SBHA YAC were conducted. These groups focused on facilitators and barriers, as well as how school-based health officials might be able to implement the game, possible motivations for adolescents to engage with the game, and how the game might be used in their communities. The focus groups were 60-90 minutes in length. Two investigators attended each focus group. One investigator served as the facilitator, whereas the other investigator took notes. Following the completion of each focus group, the team met for a debriefing session and a summary from the debriefing session was compiled.To optimize the implementation of Our analysis was guided via the thematic analysis by Braun and Clarke  to proviLimitations).Data from the participant feedback were qualitatively analyzed to identify common themes. Analyses focused on players’ gameplay experience, and input was used iteratively to improve the game content and design. In this phase, we also assessed knowledge through an analysis of participant feedback on gameplay mechanics and character relations. With the game nearing its’ final form, we verified through participant responses that they understood the themes of the game and acquired the knowledge we were targeting. Because of the limited number of participants (n=3) who completed the quantitative survey on knowledge of opioids, perception of risk of harm from opioids, and gameplay experience, we were unable to analyze these results . Individuals who expressed interest in participating in the development or preimplementation phase provided institutional review board–approved informational sheets for the study. Individuals provided verbal assent if they were younger than 18 years of age and verbal consent if they were older than 18 years before participating. A waiver of parental consent was obtained for adolescents younger than 18 years. For participants who participated in play testing, written consent was obtained if they were 18 years or older. Written parental consent and assent were obtained from adolescents younger than 18 years.Among the high school and YAC adolescents who participated in the developmental phase focus groups (n=52), the average age was 17.1 (SD 0.87) years. The majority were female-identifying  and of non-Hispanic descent . Approximately one-third  of the adolescent participants identified as mixed or other race . The SBHPlaySmart: (1) mode of learning; (2) opioid identification; (3) perceived risk of harm: susceptibility, severity, sequences, or addiction; (4) prescription opioids; (5) opioid accessibility; (6) reasons to use; (7) mental health, (8) support systems, and (9) video game application: mechanics or game and content or storylines. The following section provides a brief description of each theme along with the associated key concepts that were included in the game to ensure that it was relevant, relatable, and accurate.Generally, youth participants cited a lack of drug education, specifically pertaining to opioids. Even when they referenced their drug education, it was often limited to a specific grade level  or to a certain type of drug  who participated in the development work mentioned playing or having played more than one game; 11 (21%) participants did not mention playing any games. More specifically to our intervention, youth participants provided their feedback on video game details, such as mechanics, esthetics, and storyline content. Generally, they recommended that the game be simple but challenging . In termPlaySmart. Game content was directly informed by focus groups and interviews, similar to other digital interventions targeting adolescents [On the basis of the information gleaned from our development focus groups and interviews, our research team collaborated with our game development partners, Schell Games, to launch and finalize the video game intervention, lescents ,75,81-84PlaySmart video game intervention are (1) six storylines that form the narrative foundation: Trading Wisdom, Lean on Me, A Friend in Need, Grandma’s Pills, Tough Love, and A New Direction; (2) six minigames that provide skill-building opportunities: Risk Sense, Stress Sense, Refusal Power, Social Media Game, Choice Power, and Know Power; and (3) a participant tracker: Future Sense. At the beginning of the game, players review their future self in Future Sense to see how poorly their lives turned out because of opioid misuse and are tasked with changing their future by playing PlaySmart. The use of the future self-motivates players to do better in the present by drawing on evidence that shows that imagining the future self and highlighting similarities between the current and future self can influence positive behavior change [The cornerstones of the r change .Trading Wisdom, the player learns to use opioid prescriptions safely, the consequences associated with misuse, and nonpharmacologic and nonopioid alternatives for pain management. In Lean on Me, the player learns about high-risk situations where opioid misuse is likely to occur (party), the role of peer pressure, how to refuse an offer to use opioids, and the dangers of misusing opioids. In a Friend in Need, the player learns about how mental stress increases the risk of opioid misuse, the benefit of seeking support from trusted adults, and how they can be supportive to their friends. In Grandma’s Pills, players learn about the dangers of using prescriptions that do not belong to them, including overdose and strategies from refusing opioids when offered by family members. In Tough Love, the player learns to set boundaries in close relationships where opioid misuse is an issue, and how to support people close to you who are struggling with opioid misuse. In A New Direction, the player learns of mental health resources, existing myths around mental health and stigma and is empowered to seek mental health care when needed. Throughout gameplay, players have options to make a bad or good choice, thus practicing decision-making skills. In addition, we expect to increase the perception of the risk of harm among players through scenarios that highlight the dangers of opioid misuse. Links to other trusted websites such as the National Institute on Drug Abuse are embedded in the game and provide players with an opportunity to continue learning outside the game if they are interested.These 6 storylines encompass major topics that address opioid misuse and mental health. In Risk Sense, the player is tasked with working to prevent risks . By playing Risk Sense, players become aware of the risk factors for opioid misuse. In Stress Sense, players have an opportunity to practice cognitive reframing, a cognitive behavioral strategy [Refusal Power, the player helps the character resist peer pressure to engage in risky behaviors. In a Social Media Game, through posts on social media, players practice advocating for behaviors that deter drug misuse, encourage help seeking from trusted adults and mental health professionals, and support peers who are struggling. In Choice Power, players learn to communicate effectively with others to get the help they need or to avoid getting into trouble. In Know Power, players learn facts about opioids and opioid misuse through conversations with other nonplayer characters. Choice Power and Know Power are embedded within each storyline, whereas the other minigames are shown on the homepage . Youth from the preimplementation focus groups generally agreed that it could be used in their school community as an interactive way to learn, and most of their first impressions highlighted several positives of the PlaySmart game. For example, they spoke about liking the comic-book style of the game, the relatability of each storyline, and the interactive components of the storylines and minigames. They highlighted the importance of training both staff and students to equip them with the necessary troubleshooting skills and to ensure that they understand their rights to confidentiality and data privacy. Much of the discussion regarded optimal strategies for game delivery, and many participants believed that integrating PlaySmart into existing structures such as health classes, clinics, or school clubs would gain the best traction from both students and staff. Focus group participants emphasized the value of incentives for implementing the game in schools, especially because it was a new program and required some human resources to implement effectively. Common suggestions for greater incentives include promoting PlaySmart through social media youth ambassadors, incorporating gamification elements , and framing it as a novel health behavior tool rather than a more traditional form of prevention-based education. This information was used to create PlaySmarts educator’s manual, which was shared with implementation partners as a resource.Participants from our preimplementation focus groups shared the potential barriers and facilitators to implementation as well as information specific to motivation around gameplay and engagement with the intervention. SBHA adult affiliates mentioned the importance of administrative buy-in before implementing The public health impact of concurrent opioid and mental health crises cannot be overstated and underscores the need for innovative approaches for engaging adolescents and young adults in preventive interventions. Given these crises, and with support from the National Institutes of Health HPC Initiative, we developed a novel video game intervention to prevent opioid misuse among older adolescents. This is the first video game intervention to address opioid misuse and mental health issues among older adolescents. Existing game-based interventions for opioid misuse have focused on younger adolescents  and on aPlaySmart, offer an engaging way to prioritize mental health as a central focal point by empowering adolescents to be vocal and intentional about asking for help and by breaking down myths that mental health support is ineffective or worsens symptoms. In PlaySmart, the risk of opioid misuse driven by underlying mental health problems is woven throughout the game, while normalizing help seeking and adaptive coping strategies. To examine the impact of incorporating mental health factors into PlaySmart, our ongoing RCT will also assess the impact of PlaySmart on mental health outcomes.Our formative work revealed that mental health and its connection to opioid use were among the most prevalent themes that arose from the youth focus groups. Preexisting mental health problems such as depression can increase the likelihood of substance misuse, including opioids -9. In adPlaySmart. Involving the end user increases the likelihood of relatable storylines and provides an opportunity to improve the game based on player feedback [In contrast to other game-based interventions to prevent opioid misuse ,52, and feedback ,73. MostOur youth focus groups had good racial representation, including youth identifying as Asian, Black, White, and mixed race, in contrast to a similar study focused on opioid misuse prevention among adolescents . HoweverPlaySmart in school settings, such as incorporating the video game into existing structures, such as a health class, which would allow for greater feasibility. Other suggestions for wide-scale uptake identified from preimplementation focus groups include making PlaySmart available through social media or as an intervention for adolescents waiting at an outpatient clinic, particularly if these measures are incorporated into existing clinic workflows.Creating evidence-based interventions without a plan for real-world implementation can negatively impact effectiveness . Our prePlaySmart video game is a mobile web-based intervention that can be accessed repeatedly by a player through their phones, tablets, or computers, and can be delivered anywhere with internet access. Through this formative work, we demonstrated the feasibility of engaging a comprehensive group of stakeholders  in developing a compelling video game and using user-centered design principles [Video games are very engaging and universally used by adolescents and young adults. Consequently, they offer an innovative way to deliver evidence-based prevention interventions that can potentially be lifesaving. In addition, the inciples ,72 in boquantitative assessments of knowledge of opioids, perception of risk of harm, and gameplay experience. As such, we were unable to provide quantitative summary data on whether there was improvement in knowledge about opioids or perception of risk of harm from opioids in this formative evaluation. In the ongoing RCT, we are evaluating improvements in opioid knowledge and perception of the risk of harm from opioids (primary outcome) and will provide these results following the completion of the RCT. Only 1 participant with OUD participated in this study, which may have impacted the video game content, although this is a preventive intervention primarily targeting adolescents without opioid misuse. Although we assessed factors that would impact usability and engagement during gameplay, the questions did not specifically assess whether adolescents would be motivated to play the game. We are currently assessing factors that would influence motivation in ongoing RCT. Future formative work can assess the factors that can influence motivation, which may influence the final game design. We assessed how familiar adolescents were with video games during the focus groups, but we did not assess perceptions of the game between those who were hard-core gamers and those who were not, which may have informed game design to have the broadest reach across different levels of gamers. Future formative studies on game development should include this information.During this formative work, specifically during playtesting, we had to switch from in-person procedures in schools to web-based procedures because of the COVID-19 pandemic. This occurred during playtesting and affected recruitment and retention during the playtesting sessions. As a result, we had only one group of participants (n=3) who played the entire game and were able to complete The ongoing dual opioid and mental health epidemics underscore the need for effective prevention interventions that can engage adolescents and address accurate information and skill-building in these areas. Video games provide an appealing medium to engage adolescents while translating evidence-based theories into a digestible, easily accessible format that allows for repeated practice of behaviors necessary to prevent opioid misuse and promote mental health in adolescents in real-world settings. Engaging the target audience and other key stakeholders in the development and testing of this digital health intervention ensures that it reflects their voices and perspectives for the greatest impact and reach.


Over the last decade, there has been growing interest and important developments in Autonomic Neuroscience research. In this Research Topic, an international selection of high-quality papers highlighted the latest advancements and the improvements in the research techniques, offering new insights into the role of autonomic nervous system (ANS) activity in regulating metabolic pathways and multiple systems such as cardiovascular, gastrointestinal, renal and immune system.Faber et al. sheds light on the role of the autonomic nervous system in glucose metabolism. Recent independent research has also shown that Pressure Pain Sensitivity (PPS), a parameter that measures the maximum pain and discomfort sensation at the chest bone, in response to a gradually increased pressure during a period of 3–5 s, could serve as an indicator of ANS activity, particularly reflecting the level of ANS disruption  and SGLT-2i administration on modifying IRVF in a 77-year-old patient with HF with preserved ejection fraction (HFpEF), resulting in reduced renal congestion for HFpEF patients.The impact of ANS on metabolism holds great potential in the context of cardiovascular disease, both indirectly, as seen before in the correction of main risk factors such as diabetes, and directly, by influencing heart rate. Johnson et al. aimed to search for reliable markers to distinguish sacral parasympathetic nerves from other extrinsic and intrinsic nerves in the human colon, in order to better comprehend their functional role and the clinical significance of their disruption. Bowel innervation can be divided into two components: a descending innervation, which typically involves the proximal part of the bowel, and an ascending innervation, which typically involves the distal part. In this context, the authors have found that ascending nerves can be distinguished in the colorectum of humans using glucose transporter type 1 (GLUT1) labeling combined with NF200. As regards the control of gastric function, the local GABA(γ-aminobutyric acid)ergic signaling in the dorsal vagal complex plays an essential role , increases gastric tone and motility. Still to be evaluated is the effect of baclofen on gastric motility in the nucleus of the solitary tract (NTS). In their study Bellusci et al. compared the activation of the GABAB receptor on the NTS by microinjecting baclofen into the NTS, and monitoring intragastric pressure. They also compare its action to optogenetic activation of somatostatin (SST). The results of this study show that GABAB receptors in the NTS significantly increase gastric motility and tone. Optogenetic stimulation in vivo and in vitro suggests that these baclofen-activated receptors suppress glutamatergic sensory vagal afferents in the NTS and also inhibit interneurons and inhibitory neurons projecting to the DMV, which, in turn, increase motility through a cholinergic excitatory pathway to the stomach.Another interesting study by Yamakawa et al. established a mouse model of AAG representing an autoimmune dysautonomia, associated with MHC class II, to understand the pathogenic mechanism and pathogenicity of nicotinic acetylcholine receptor (nAChR) antibodies. The amino acid sequence of mouse nAChRα3 protein was analyzed using an epitope prediction tool to predict possible MHC class II binding mouse nAChRα3 peptides. The authors provided evidence that active immunization of mice with nAChRα3 peptides causes autonomic dysfunction as similarly occurs in human AAG, suggesting a mechanism by which different MHC class II molecules could preferentially influence the nAChR-specific immune response, thus controlling the diversification of the autoantibody response.An acquired autoimmune disorder of ANS is represented by autoimmune autonomic gangliopathy (AAG), characterized by autonomic dysfunction, including sympathetic and parasympathetic failure (Vernino et al., In conclusion, this Research Topic has made remarkable contributions, significantly advancing our understanding of various aspects within Autonomic Neuroscience. These studies have shed light on intricate and complex interrelationships between different systems, offering crucial clinical implications for patient management. Moreover, the valuable insights and recommendations provided pave the way for further exploration in this rapidly evolving field.VS: Conceptualization, Writing—original draft, Writing—review and editing. RA: Conceptualization, Writing—original draft, Writing—review and editing. PL: Conceptualization, Writing—original draft, Writing—review and editing. MA: Conceptualization, Writing—original draft, Writing—review and editing.


Moreover, a feature analysis based on the Shapley additive interpretation (SHAP) technique indicates that column diameter is the most critical factor affecting compressive strength. Other important factors include tube thickness, yield strength of steel tube, and concrete compressive strength, all of which have a positive effect on load capacity. Conversely, an increase in column length or eccentricity leads to a decrease in load capacity. These findings can provide useful insights and guidance for the design of CCFST columns.Understanding the load-carrying capacity of circular concrete-filled steel tube (CCFST) columns is crucial for designing CCFST structures. However, traditional empirical formulas often yield inconsistent results for the same scenario, causing confusion for decision makers. Additionally, simple regression analysis is unable to accurately predict the complex mapping relationship between input and output variables. To address these limitations, this paper proposes an ensemble model that incorporates multiple input features, such as component geometry and material properties, to predict CCFST load capacity. The model is trained and tested on two datasets comprising 1305 tests on CCFST columns under concentric loading and 499 tests under eccentric loading. The results demonstrate that the proposed ensemble model outperforms conventional support vector regression and random forest models in terms of the determination coefficient (R The most commonly used CFST columns are circular concrete-filled steel tube (CCFST) and rectangular concrete-filled steel tube (RCFST) columns, a layout that optimizes the use of steel and concrete materials. It makes the complementary action between steel tubes and filled concrete more effective than conventional reinforced concrete and steel structural elements. On the one hand, the CFST system has mechanical advantages over reinforced concrete or pure steel members due to the restraining effect of the steel pipe on the filled concrete, which increases the strength and greatly improves the ductility of ordinary concrete7. On the other hand, the concrete core restrains the inward deformation of the steel tube, retarding the local buckling of the steel tube and enhancing the local stability of the steel tube, thus enhancing the overall stability of the column9. These synergistic effects lead to an increase in strength characteristics over the respective individual parts. Due to the advantages of high strength, resilience, good seismic energy absorption performance, and high fire resistance, CFST columns are widely used in high-rise buildings, bridges, and other structures11.Concrete-filled steel tube (CFST) is an infill element consisting of an outer steel tube and a core of filled concrete13. Although physical experiments provide valuable data and observations, the labor and material consumption of repeated tests are considerable. The finite element method can reduce the number of tests to some extent by computer simulation, but the results of finite element analysis depend largely on the skill level of the modeler due to the complex material properties, contact relations, boundary conditions, etc. Moreover, finite element methods often require high computer configurations14. With increasing interest and laboratory testing, some countries have established equation-based design standards based on extensive experimental results, such as ACI 318 (ACI 2014)15, Eurocode 4 (CEN 2004)16, AISC 360 (AISC 2016)17, and Chinese codes (GB 50936–2014 and GB/T 51446–2021)19. Design codes are currently the preferred method for predicting compressive strength due to their convenience and practicality. However, it's important to note that although many existing design standards can estimate strength, they have specific scopes of application. Additionally, different codes across countries may produce varying outputs under different code models, which can raise questions about the accuracy of the predictions and lead to poor decision-making by designers and engineers. Furthermore, the actual columns' material strength, geometry, cross-sectional length, and slenderness may exceed the applicability of these standards, potentially putting the structure at risk if they are used to calculate strength. Moreover, empirical formulas are typically explicit equations with a limited nonlinear relationship between inputs and outputs. In contrast, machine learning models can capture a more precise and complex mapping relationship between inputs and outputs in an implicit functional form.Compressive strength is the main mechanical property of CFST. Since the accurate design of CFST has an important influence on the stability of the structure, studying different techniques to analyze their compressive strength can provide a better understanding of their behavior. Currently, the experimental method and the finite element method are the two mainstream methods for predicting the performance of CFST components20. It is foreseen that using machine learning to predict component performance will not only provide a reference for actual design but also save significant resources by making full use of completed experimental data and reducing the need for further testing22. Moreover, machine learning is based on patterns between large amounts of experimental data and is much less dependent on the users themselves. In recent years, many scholars have used machine learning algorithms such as artificial neural network (ANN), gene expression programming (GEP), back-propagation neural network (BPNN), fuzzy logic, etc. for the prediction of the ultimate bearing capacity of CFST based on the acquired datasets, and achieved good results32. For instance, researchers have employed a hybrid machine learning approach, combining artificial neural networks (ANN) with particle swarm optimization (PSO) algorithm, to predict the compressive strength of CCFST columns. The accuracy of this method has been demonstrated to surpass that of existing design codes and empirical formulas34. Ahmadi et al.35 used the ANN model to analyze the compression capacity of CCFT short columns under short-term axial loading, and the prediction results showed that the mean relative error of the proposed equation was 13.2%, indicating good accuracy. Hou et al.36 employed BPNN, genetic algorithm (GA)-BPNN, radial basis function neural network (RBFNN), Gaussian process regression (GPR), and multiple linear regression (MLR) models with diameter, length of the column, steel tube thickness, steel yield strength, and concrete compressive strength as input variables to develop prediction models for 2045 sets of CCFST data. The results showed that the developed GPR model reached higher accuracy and wider applicability than the existing design standards, and can reliably predict the strength of CCFST. Muhammad et al.37 achieved good accuracy R2 = 0.949 for ultimate axial capacity using the GEP model on 227 sets of CCFST columns, and the prediction accuracy was better than the design codes and formulas proposed by other scholars. To obtain models with higher prediction accuracy, Quang et al.38 employed a gradient tree boosting algorithm to predict the strength of the CFST column. Compared with random forest, support vector machine (SVM), decision tree, and deep learning, the model proposed achieved higher prediction accuracy.For this reason, some intelligent methods need to be explored to achieve an accurate and fast output of prediction results. The development and application of machine learning techniques provide new insight to solve this problemIn general, machine learning provides an innovative method for predicting the strength of CFST columns. Although some studies have been investigated with good results and progress, more work needs to be done for the two following reasons. (1) The current research is mainly focused on the compressive strength of CCFST under axial loading condition. Studies on the behavior of CCFST columns under different loading conditions are relatively few. A systematic and in-depth study of the mechanical properties of CCFST under different cross-sectional shapes and loading conditions is necessary. (2). The number and type of samples in the database have a significant impact on the applicability and accuracy of the mechanistic model. An extensive literature review can further supplement the number of test samples and the corresponding parameter ranges to build a more comprehensive test database. Additionally, the application of ensemble model in capacity prediction of the CCFST columns is relatively few.D), the thickness of tube (T), length of the column (L), yield strength of steel tube (fy), concrete compressive strength (fc), top eccentricity (et), bottom eccentricity (eb). In light of the successful application of the Extreme Gradient Boosting model (XGBoost) in other regression problems39, this model was selected for prediction in this study. Additionally, two other commonly used machine learning models, support vector regression (SVR)40 and random forest (RF)41, were also employed to determine the optimal prediction model for the studied topic.The main objective of this study is to develop an ensemble model that can accurately predict the compressive strength of CCFST under various loading conditions. As depicted in Fig. l is the loss function to measure the error between the model prediction and the true value, and Ω is the regularization term to measure the complexity of the model and avoid overfitting. The loss function is subjected to a second-order expansion of Taylor's formula, which leads to Eqs. , and 499 tests on CCFST columns under eccentric loading Dataset 2) were collected were colFurther, the Pearson linear correlations between the input and output variables were calculated and plotted as shown in Fig. The collected databases were randomly divided into training datasets (80%) and test datasets (20%). It should be noted that all inputs were normalized to the range  in order to avoid scaling effects. During the training process, the grid search method was used to find the optimal hyperparameters, and the tenfold cross-validation method was employed to reduce the deviation generated by random sampling of the training set.For comparison to assess the validity and reliability of the proposed models, random forest and the SVR model were also used for the same training and test sets. Compared to the SVR and RF models, which have fewer hyper-parameters, the tuning process of the XGBoost model is more time-consuming. However, in terms of prediction performance, the extra effort is certainly worth it. The correlation between the predicted results of the three models and the experimental values under different cases is shown in Fig. Figure 45. As shown in Fig. D is the most important design parameter under the current data set. For several other input variables, the characteristic importance of their parameters under the current data set is ranked from top to bottom. In addition, it can be concluded that all the parameters except et, L, and eb, are positive for the bearing capacity, and their increase will increase the bearing capacity.The study of the importance and degree of influence of design parameters on the bearing capacity is an important guide for the design of CFST. For this reason, the Shapley additive explanation (SHAP) method is introduced in this section to analyze the influence of design parameters on the outputThe proposed ensemble model can accurately establish the complex relationships between geometry, material properties, and compressive strength for different types and different loading conditions of CCFST columns.The average relative prediction errors of the proposed models for their test sets are 13.923%, and 13.805%, respectively. The average relative errors are all smaller than those of the conventional SVR and RF models, and the relative errors are all within 15%, which shows a high prediction accuracy. The proposed model can be used as an alternative to the commonly used design codes to estimate the compressive strength of CFST columns.D) has the greatest influence on the compressive strength of CCFST columns, followed by the top eccentricity (et), concrete compressive strength (fc), length of the column (L), bottom eccentricity (eb), and thickness of the steel tube (T). The yield strength of the steel tube (fy) has the least effect. Therefore, designers should pay close attention to the column diameter when designing CFST columns.The results show that, among the input parameters considered in this study, the cross-sectional dimension (et and eb) and the length of the column (L) have negative effects on the compressive strength of CCFST columns, while the other geometric parameters and material properties have positive effects. This information can help designers adjust the selection of parameters in real time to achieve the best combination of design parameters for CCFST columns based on bearing capacity.In addition, the results indicate that the top and bottom eccentricities  to assist structural designers in achieving automatic output of bearing capacity for a given input. Such a tool could aid in understanding load carrying capacity under different parameter combinations in real-time, facilitating the correction and guidance of CCFST column design.


Worldwide, life expectancy and the number of elderly individuals are increasing due to social, health, and technological advancements –3. ThereGiven the potential economic and social burden of these conditions, it is crucial to develop new strategies for proper clinical management . The maiYin et al. conducted a cross-sectional analysis using baseline data from the West China Health and Aging Trend (WCHAT) study, investigating the relationship between various biomarkers and sarcopenia. The authors identified fasting insulin combined with the aspartate aminotransferase to alanine aminotransferase (AST/ALT) ratio as appropriate predictors of sarcopenia, suggesting the use of these biomarkers for early detection. Additionally, He et al. found that higher AST/ALT and lower insulin*prealbumin (INS*PA) product were associated with a higher prevalence of sarcopenia among elderly Chinese participants in the WCHAT study. The authors recommended regular monitoring of AST/ALT and INS*PA as a suitable approach for sarcopenia screening and management, given the affordability and simplicity of these blood biomarkers. Future studies should further explore the relationship between biochemical and metabolic markers and sarcopenia to develop more versatile and user-friendly screening tools.So far, the diagnosis of sarcopenia and related conditions requires assessing muscle mass, muscle strength, and physical performance . One of Veronese et al. conducted a longitudinal cohort study investigating the association of sarcopenia with radiographic and symptomatic knee osteoarthritis (OA). Over a four-year follow-up period, the presence of sarcopenia at baseline was strongly linked to a higher risk of developing symptomatic knee OA, while there was no significant difference in radiographic OA prevalence. Dionyssiotis et al. conducted a cross-sectional study involving hospitalized patients with neurodisabilities and healthy controls, and they observed significantly lower body mass index (BMI) and skeletal muscle index (SMI) scores in neurological patients. Similarly, elderly patients with musculoskeletal disorders exhibited a high prevalence of sarcopenia, and a correlation between sarcopenia and increased BMI has been found in this population  and/or sarcopenia and total, cardiovascular, and cancer mortality. The ABSI value, which assesses the health implications of body height, mass, and waist circumference, was found to be significantly associated with all-cause and cardiovascular mortality. Additionally, the coexistence of higher ABSI values and sarcopenia appeared to contribute to a higher risk of death compared to high ABSI values or sarcopenia alone.In an observational study, Liu et al. within the Research Topic aimed to assess the causality between osteoporosis and sarcopenia using instrumental variables and Mendelian randomization. The results revealed a significant causal effect between osteoporosis and sarcopenia, with severe osteoporosis increasing the risk of appendicular lean mass loss and subsequent reduced lumbar spine bone mineral density . These findings emphasize the importance of addressing both osteoporosis and sarcopenia in the prevention, diagnosis, and treatment of osteosarcopenia, providing valuable insights for patient management.Finally, given the substantial societal burden of age-related osteoporosis and sarcopenia and the evidence indicating their mutual influence, a study by The results of the original studies in the Research Topic highlight the association between sarcopenia and various comorbidities, including neurological and musculoskeletal concerns as well as obesity, which can lead to adverse outcomes and increased mortality risk. Serological biomarkers show promise in the early detection of sarcopenia and should represent a valuable resource for clinical practice, allowing early detection of osteosarcopenia and sarcopenic obesity, and mitigating the progression of associated conditions.By recognizing and diagnosing osteosarcopenia and osteopenic obesity, healthcare professionals can tailor interventions that address the specific needs of these individuals. This includes implementing exercise programs to improve muscle strength, bone density, and balance, as well as adopting nutritional strategies to support optimal musculoskeletal health , 10. ForPahlavani reveals the potential of exercise therapy, particularly exercises with blood flow restriction, in reversing the decreased muscle mass and strength, increased adipose mass, and pro-inflammatory subset associated with sarcopenic obesity. Exercises with blood flow restriction may be recommended for individuals unable to engage in high-intensity strength training due to chronic illnesses and sarcopenic obesity (Pahlavani). Nevertheless, understanding osteosarcopenia and sarcopenic obesity is crucial for providing appropriate management strategies.A comprehensive review by In conclusion, the journey towards a complete understanding of these conditions and their management remains challenging; the studies presented in this Research Topic have provided valuable insights into the complexity of sarcopenia-related conditions and the necessity for early diagnosis and personalized rehabilitation. The findings from the manuscripts included in the Research Topic underscore the importance of developing multidisciplinary approaches in the future. We extend our gratitude to all the participants and contributors to the research projects and the papers included in this Research Topic, with the hope that the information presented will advance clinical practice and inspire further innovative research in the future.SM: Writing – original draft, Writing – review & editing. MM: Conceptualization, Writing – original draft, Writing – review & editing. IK-A: Supervision, Writing – review & editing. YD: Conceptualization, Writing – review & editing.


There is a rising noncommunicable disease (NCD) burden in low- and middle-income countries. Sub-Saharan Africa (SSA) bears a higher burden than the global average with South Africa (SA) enduring the highest regional burden. SA among other southern African countries also bears a high prevalence of HIV and other chronic communicable diseases. Having a perspective on common chronic diseases in the ever-increasing numbers of adult cancer patients in SA will inform our understanding of approaches to better manage them. This commentary reviews regional and national studies and data of low- and middle-income countries and particularly SA on the chronic infectious and NCD multimorbidity burden among adult cancer patients. It also reflects on the considerable health system challenges of managing discordant multimorbidity among adult cancer patients within the SA Public Health System. Despite the critical need to better manage the growing MM burden in general and particularly the high prevalence of discordant multimorbidity among cancer patients, there is a dearth of research into MM management generally and in LMICs particularly. Since the Second World War, medical advances have enabled substantial gains in the management of preventable and communicable diseases, resulting in steadily improving global health and increasing life expectancy. This infectious disease predominance is progressively being superseded by a rising noncommunicable disease (NCD) burden with the transition speed corresponding to the Human Development Index (HDI) of global nations . This isAccording to the World Health Organisation (WHO), NCDs kill 41 million people each year, equivalent to 74% of global deaths with over 80% of NCD deaths due to cardiovascular diseases (CVDs), cancers, chronic respiratory diseases and diabetes, and associated kidney disease . Mental Some 86% of premature NCD deaths (age 30–69 years) occur in LMICs, Sub-Saharan Africa (SSA) bears a higher burden than the global average with SA enduring the highest regional burden . Despite3, but the largest percentage increases are now occurring in LMICs [et al. derived their incidence estimates for the country based on death reports [GLOBOCAN 2020 reports that the global burden of cancer is substantially growing with the cumulative risk of developing cancer by age 75 at 22.6% for males and 18.6% for females . In HICsin LMICs ,23. In Sin LMICs . Bray et reports . SANCR r reports . Since tUnsurprisingly, the high chronic disease burden among global populations has created a perfect storm for multimorbidity (MM), defined as the coexistence in an individual of two or more NCDs  and infectious diseases of long duration. It typically occurs in ageing populations, but the global trend is towards a rapidly increasing prevalence at earlier age onset . In HICsOur own evidence of the high discordant MM burden among SSA patients comes from breast and prostate cancer patients newly diagnosed and treated in tertiary academic public health hospital cancer clinics. Our studies span a single site , multi-SA  site, and a multi-SSA country site  cohort study . We confThe SA quadruple burden of disease has placed an enormous and increasing strain on the country’s under-resourced three-tiered public health system that serves approximately 85% of the population , yet with only 20% of the available healthcare resources ,42. The The current consensus for best practices to manage MM is to focus on MM management at the PHC level, guided by the World Health Organization’s Innovative Care for Chronic Conditions (ICCC) framework . It advoThe United Kingdom National Institute for Health and Care Excellence (NICE) guidelines for MM management call for a re-orientation of care tailored to individual patients’ goals, priorities, and levels of health literacy ,48. It iMore epidemiological evidence characterising cancer and MM burden in SA.Examination of existing policies and best buys, including expert health economic analyses, to determine changes needed to support the development, evaluation, and implementation of various interventions at the community, patient, and healthcare system levels to address the overall burden on the country.Provision of integrated preventative and disease management services, where the patient, as well as the community, are placed at the centre of care.Implementation of appropriate electronic tools and resources to enable ongoing surveillance of the burden of cancer and MM to determine trends and evaluate the effectiveness of interventions; andActivation of community resources and social structures and individuals and patients themselves to actively demand cancer and MM screening/early symptom detection services offered through preventative health services supported by the required policies. These goals are daunting but potentially achievable with effort and coordination across the stakeholder base.Involvement of all available public and private healthcare resources in so-called ‘private-public partnerships’ (PPPs) to enhance healthcare delivery.Despite the critical need to better manage the growing MM burden, there is a dearth of research into MM management generally and in LMICs particularly . Recent


Nearly a billion people depend on tropical seascapes. The need to ensure sustainable use of these vital areas is recognised, as one of 17 policy commitments made by world leaders, in Sustainable Development Goal (SDG) 14 (‘Life below Water’) of the United Nations. SDG 14 seeks to secure marine sustainability by 2030. In a time of increasing social-ecological unpredictability and risk, scientists and policymakers working towards SDG 14 in the Asia–Pacific region need to know: (1) How are seascapes changing? (2) What can global society do about these changes? and (3) How can science and society together achieve sustainable seascape futures? Through a horizon scan, we identified nine emerging research priorities that clarify potential research contributions to marine sustainability in locations with high coral reef abundance. They include research on seascape geological and biological evolution and adaptation; elucidating drivers and mechanisms of change; understanding how seascape functions and services are produced, and how people depend on them; costs, benefits, and trade-offs to people in changing seascapes; improving seascape technologies and practices; learning to govern and manage seascapes for all; sustainable use, justice, and human well-being; bridging communities and epistemologies for innovative, equitable, and scale-crossing solutions; and informing resilient seascape futures through modelling and synthesis. Researchers can contribute to the sustainability of tropical seascapes by co-developing transdisciplinary understandings of people and ecosystems, emphasising the importance of equity and justice, and improving knowledge of key cross-scale and cross-level processes, feedbacks, and thresholds. The well-being, prosperity, and security of over nearly a billion coastal people living in 117 countries are already at risk from degradation in marine and coastal environments , SDG 14 (‘Life below water’) seeks explicitly to ‘conserve and sustainably use the oceans, seas, and marine resources for sustainable development’. Although key milestones were intended to be achieved by 2030, many targets of SDG 14 appear unlikely to be met  How and why are seascapes changing? (2) What can and should society do about these changes? and (3) How can science and society together achieve sustainable seascape futures? While these questions are applicable to many ecosystems and landscapes around the world, they are particularly important for tropical seascapes, which are less documented and less researched than most temperate marine or terrestrial systems . Different policies may be poorly aligned or in conflict with one another and with SDG 14, as in the case of guidelines for small-scale fisheries within the EU  and career stages. While the majority of participants were based at Australian institutions due to COVID-19 restrictions and the preference that we meet in person, the group was considerably more diverse than institutional affiliations would suggest; it included individuals of seven different nationalities with extensive experience working in locations beyond Australia , with Indigenous communities, and with societal partners .Our initial scoping process identified the three challenges discussed above as being of direct relevance to both national and local decision-makers . After a series of smaller-group discussions, we collated suggestions and reduced our list of candidate research priorities to the nine summarised in this manuscript through a process of debate and discussion. Although identifying specific pathways to achieve desirable outcomes was beyond the scope of this manuscript, we compared our findings to future-oriented global frameworks . This was done after, rather than before or during, the process to maintain a level of creativity and independence from existing paradigms during the process and to evaluate external validity after the process.Realising the full potential of research and adaptive management in fostering and co-creating sustainable seascape futures will require a cohesive approach that addresses all three challenges. We identified nine distinct but interlocking research priorities (RPs) that capture what we perceive to be the primary ingredients of the solution. These priorities explicitly consider strategies for navigating the complexity of geographic connections, feedbacks between cause and effect, and cross-scale processes Fig. . They spAddressing the first challenge (changing seascapes) will require new understandings of seascape dynamics and continual updates of knowledge. We identified two key research priorities that help address this: seascape evolution and adaptation RP1), and elucidating drivers and mechanisms of change  requires clarifying the complex interactions among different system components, including, for example, cross-scale interactions, feedbacks, knock-on effects, and interacting thresholds .Addressing the third challenge (how science and society can together improve sustainability) requires research that identifies which capacities must be developed and what actions undertaken at different scales, and by whom, to ensure a just and sustainable future for seascapes. We identified two key research priorities: improving seascape technologies and practices (RP5), and learning to govern and manage seascapes for all . Policymakers, managers, and communities continue to struggle with designing institutions and making decisions that reflect the environmental complexity and human diversity of seascapes. Government departments are often siloed; cumulative assessment, strategic and adaptive planning tools are not always implemented well ; bridging communities and epistemologies (world views) for innovative, equitable, and scale-crossing solutions (RP8); and informing resilient seascape futures, primarily by using models and related methods (e.g. scenario planning) to understand seascape dynamics and provide decision support (RP9). As explained in Table The experience of well-being and its dependence on seascapes varies significantly across individuals and societies. Further research is needed to understand what constitutes well-being; how it changes over time; and how different aspects of human well-being and anthropogenic impacts on ecosystems are inter-related. Both exposure to disturbance and human response capacity are intricately connected to access to resources  is urgently needed, many nations have limited power and capacity to respond effectively to current environmental trends (Barlow et al. We have described nine inter-related research priorities that we regard as central to ensuring the future sustainability of seascapes around the world. These priorities are linked by many important cross-cutting research themes. For example, understanding the interplay of local and regional influences on ecological communities, and the feedbacks between local and regional social, ecological, and social-ecological dynamics, will be critical for efforts to build local resilience to ongoing threats such as anthropogenic climate change, over-fishing, and pollution (Hughes et al. Research agendas are created by people who are embedded within particular cultures and social strata, including both researchers and funders, and the questions that individuals and groups consider to be important or interesting strongly reflect their own values, background, and preferences (Watkins and Harvey There is clearly no single panacea for marine and coastal sustainability, and making better progress towards SDG 14 in the western Pacific will require a complex and challenging series of interventions. Environmental degradation and rising inequality around the world suggest limited success for standard research approaches promoting science as a tool to solve environmental problems. We nonetheless believe that research has critical roles to play in the generation of new knowledge, the expansion and sharing of grassroots innovations (Seyfang and Smith


Owing to their low prevalence, rare diseases are poorly addressed in the scientific literature and clinical practice guidelines. Thus, health care workers are inadequately equipped to provide timely diagnoses, appropriate treatment, and support for these poorly understood conditions. These clinical tribulations are experienced as moral challenges by patients, jeopardizing their life trajectories, dreams, and aspirations.This paper presents an ethical action plan for rare disease care and the process underlying its development.Ethics and Rare Diseases Working Group, which included 3 patient partners, 2 clinician researchers, and 1 representative from Québec’s rare disease association.This action plan was designed through an ethical inquiry conducted by the The plan is structured into 4 components. Component A presents the key moral challenges encountered by patients, which are the lack of knowledge on rare diseases among health care workers, the problematic attitudes that it sometimes elicits, and the distress and powerlessness experienced by patients. Component B emphasizes a vision for patient partnership in rare disease care characterized by open-mindedness, empathy, respect, and support of patient autonomy from health care workers. Component C outlines 2 courses of action prompted by this vision: raising awareness among health care workers and empowering patients to better navigate their care. Component D compares several interventions that could help integrate these 2 courses of action in rare disease care.Overall, this action plan represents a toolbox that provides a review of multiple possible interventions for policy makers, hospital managers, practitioners, researchers, and patient associations to critically reflect on key moral challenges experienced by patients with rare diseases and ways to mitigate them. This paper also prompts reflection on the values underlying rare disease care, patient experiences, and health care workers’ beliefs and behaviors. Health care workers and patients were the primary beneficiaries of this action plan. A disease is considered rare when its prevalence is estimated to be 1 in 2000 . ThroughMoral challenges are experiences that are unacceptable in the eyes of patients because they put their values at stake   were involved in the development of the action plan as members of the Ethics and Rare Diseases Working Group. The action plan is also supported by scientific literature, gray literature from Québec, and semistructured interviews conducted with patients with rare diseases from this province. This action plan introduces an ethical inquiry into rare diseases that is informative, relevant, and potentially informative in other health care contexts [This ethics action plan was developed with members of the rare disease community in Québec, Canada, in accordance with the importance of local contexts for participatory action research . Two biocontexts . The parcontexts .This study first describes the participatory process that underlies the development of an action plan. The overall structure of the action plan was then presented. Subsequently, 4 components of the action plan are described: the key moral challenges encountered by patients (component A), a vision for patient partnership in rare disease care (component B), the courses of action prompted by this vision (component C), and promising interventions that could help address the moral challenges by enacting these courses of action (component D). These components, which emerge from qualitative methods, are presented along with commentaries that reflect the perspectives of the working group.Ethics and Rare Diseases Working Group using qualitative methods. The resulting action plan was supported by insights from an exploratory literature review and a community survey conducted by our team [our team  . Two coding guides were generated. In the first coding guide, which was generated by the first author, primary themes reflected the components of the action plan, which were key moral challenges encountered by rare disease patients (component A), the vision for patient partnership in rare disease care (component B), courses of action (component C), and promising interventions (component D). Secondary themes corresponded to the subcomponents of the action plan . This coFonds de recherche du Québec-Santé, the Tri-Council Policy Statement 2—Ethical Conduct for Research Involving Humans of the Panel on Research Ethics of the Canadian government, and the Helsinki Declaration. The survey respondents provided informed consent before participating in the study. Interview participants were offered $50. Three $50 gift cards were drawn for survey participants. Survey and interview participants were deidentified . Transcripts were anonymized .The study was approved by the Human Subject Ethics Committee of the Montreal Clinical Research Institute (2021-1080). It complied with the Standards on Research Ethics and Scientific Integrity of the As illustrated in Ethics and Rare Diseases Working Group and for previously collected data [Patients with rare diseases experience a plethora of moral challenges in health care. Three challenges stood out as most morally significant for members of the ted data   rather Novel policies and public actions should be implemented to raise awareness among health care workers and promote patient empowerment. Policy development requires more resources than activities that target health care workers and patients. Nonetheless, promising policies include the development of guidelines for rare disease care, creation of accredited clinics, and expansion and promotion of patient partnerships.First, a guideline document addressing the commonalities between most rare diseases could present the common challenges encountered by patients, emphasize the often unusual clinical presentations of rare diseases, and introduce appropriate ethical attitudes to enact with these patients . These gSecond, accredited clinical centers for rare diseases could be created to unite several clinicians, benefiting patient care and interprofessional collaboration. Clinical centers could receive accreditation provided that their health care workers receive proper training on rare diseases and on appropriate ethical attitudes, notably through the above-mentioned educational activities. Despite being resource-intensive, this accreditation strategy would ensure the uptake of appropriate ethical attitudes among health care workers employed in these clinics and favor high-quality care .Third, patient partnerships should be expanded and promoted for policy making and research. Such approaches contrast slightly with the vision of patient partnerships in care. Patient partnership in policy making or research involves integrating patients into management teams or research groups ,51,53 beEthics and Rare Diseases Working Group, gray and scientific literature, and semistructured interviews. More broadly, the article reflects on the values underlying rare disease care and patient experience, in addition to health care workers’ beliefs and behaviors.This paper presents a first ethical action plan for improving the quality of care offered to individuals living with rare diseases. The action plan is articulated around 4 components: the key moral challenges encountered by patients (component A), a vision for patient partnership in rare disease care (component B), courses of action prompted by this vision (component C), and promising interventions that could help address moral challenges by enacting these courses of action (component D). It is intended to serve as a resource and toolbox to help policy makers, hospital managers, practitioners, researchers, and patient associations critically reflect on the key moral challenges experienced by this patient population and on ways to address these challenges. This action plan was supported by insights from the Although this ethical action plan is anchored in sociocultural elements specific to Québec, the ethical inquiry it initiates may benefit other health care contexts and cultures. Hence, future research conducted in Québec or elsewhere could involve the design, implementation, and evaluation of the promising interventions identified in this study. These activities can be developed in collaboration with working groups comprising stakeholders and should be subjected to responsive evaluations. These evaluative processes, which are participatory in nature, aim to assess the value of clinical practices or programs and to identify potential improvements ,115. The