Millions of people are affected by pain-related conditions worldwide. Literature has consistently shown that each individual experiences and perceives pain in a unique manner due to biological, environmental, and cultural factors in which they have been raised. It has been established that biological males and females perceive pain differently and that it may be partially explained by their distinct hormonal profiles since birth, which are only further magnified during puberty. For biological males, high levels of testosterone have shown to increase their pain threshold; and for biological females, estrogen fluctuations have shown to increase pain intensity and perception. However, sex hormones have not been studied in the context of pain treatment or their impact on biochemical pathways involved in pain perception. For this purpose, the transgender community serves as a unique population to investigate the impact of hormone replacement therapy on molecular pathways involved in the perception of pain. The purpose of this review is to explore the biochemistry of hormone replacement in transgender patients who also have other pain-related conditions such as headaches, fibromyalgia, temporomandibular myalgia, and visceral pain. The complex interaction between sex hormones and pain has been widely explored by multiple authors, ranging from basic science studies examining the changes in pain neurobiological pathways and pain-related gene expression modification in patients with different hormonal profiles , to clinAlthough some controversial results have been found, a literature review of published studies implies that estrogens have important effects regulating pain by acting on intracellular receptors, modifying gene expression and G-coupled proteins distributed along the central and peripheral nervous systems . AdditioThe effects of androgens in nociceptive pathways remains unclear; however, the androgen receptor distribution throughout the limbic system and the effects in down-regulation of estrogen receptor expression may be responsible for the accountable clinical differences in pain perception between the two sexes and genders ,9, consiDifferences between hormonal profiles in pain perception have been studied in the biological females and males, frequently assuming androgens as the main masculine sexual hormone, and estrogens and progesterone as the main female hormones. However, very little data has been published about patients with gender incongruence, when the gender identity is inconsistent with the biological sex, often associated with significant distress, giving rise to Gender Dysphoria (GD) , a condiIn this manuscript, the available literature describing the differences in pain perception and pain-related conditions in biological males and females, the transgender population undergoing sex hormone therapy will be reviewed.18 and dopaminergic systems.Several epidemiologic studies have explored differences in pain perception between males and females, reporting greater prevalence of pain in women, as well as lower pain thresholds , increasClassically, epidemiologic studies describing gender differences in pain perception and modulation have been made in biological male and female patients, assuming that men have higher amounts of androgens and women more estrogens and progesterone ,9. HowevSensation of pain is essential for living organisms to distinguish between safe and dangerous stimuli. There are many triggers for this sensation, namely, noxious thermal, chemical, and mechanical stimuli. In addition to the environmental triggers, tissue damage and inflammation may also lead to pain sensation. The endocrine and immune systems in the human body respond differently to such stimuli; depending on the dominant hormones present, some individuals may experience pain to a higher degree than others . In biol11. Testosterone decreases capsaicin receptor-mediated signals in the dorsal root ganglion neurons, suggesting that it is antinociceptive [Testosterone has consistently shown protection against pain in males. Literature has shown that testosterone limits the production of pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α), which in return contributes to major antinociception in males compared to femalesiceptive . Furthericeptive .Literature has shown inconsistent results when considering the effects of estradiol on pain perception in females. Low levels of estrogen have been associated with increased pro-inflammatory response, on the other hand, hormone therapy in biological females has not shown promising results in decreasing the inflammatory response . On the Female sex hormones are especially significant during the reproductive age due to the cyclical pattern that they follow monthly. As mentioned earlier, the fluctuating feature of estrogens makes women more vulnerable to a decreased pain threshold, and as a result, more likely to experience severe pain. This is especially interesting when exploring the levels of hormones during the menstrual cycle and its impact on pain sensitivity. One study by Bajaj et al.  showed tIn females at reproductive age that are not receiving oral-contraceptive therapy or other forms of exogenous hormones, pain is typically at the highest intensity following a sudden drop in estradiol, which typically takes place in the middle (days 13–15) of the menstrual cycle . ConsistSex hormones play a different role in many of the pain-related conditions that affect biological males and females as well as transgender patients. The following sections attempt to explore the role of hormones on pain perception in different patient populations while considering their hormone profiles. Migraine headaches and non-migraine headaches are more prevalent in females compared to males . This coAloisi et al.  studied Temporomandibular joint disorders commonly present with joint pain, crepitus or difficulty chewing and are 1.5–3 times more prevalent in women than in men . PreviouLikewise, it has been observed that estrogen α-receptor polymorphisms contribute to a different frequency of TMDs in the feminine population in both painful and non-painful presentations . SeveralSpecifically for fibromyalgia, data suggesting biological reasons accounting for differences in pain presentation and frequencies between genders have been published. The incidence of pediatric fibromyalgia was reported as being similar between age subpopulations until the age of puberty, after which women show a frank increase in the incidence . SchertzOne preclinical study investigating fibromyalgia in Wistar rats showed that reserpine-irreversible vesicular monoamine transporter-2 (VMAT-2)-induced muscle hyperalgesia and allodynia in those rats. Further, female rats that had undergone ovariectomy experienced nociception to a greater extent suggesting that menopause hormone status makes women more susceptible to pain related to fibromyalgia. Ovariectomized female rats experienced 50% reduction in pain perception upon beginning hormone replacement with 17β-estradiol. After 48 h of administration, all groups experienced reduced hyperalgesia and allodynia that was induced by reserpine. These findings suggest that steady levels of estrogens promote less pain perception in females, while sudden drops and fluctuations are major contributors to the increased pain in females with fibromyalgia .As established in many studies, fibromyalgia is more prevalent in biological females than males. This can be partially justified by the fluctuating estrogen and progesterone levels that cycle every month. Interestingly, however, fibromyalgia remains more prevalent in transgender men compared to transgender women. Levit et al.  explaineIn an experimental model, rats from both sexes were exposed to mechanical colorectal distention and pain perception was measured. It was observed that female rats responded to less intense painful stimuli in comparison with male rats. However, after ovariectomy, female rats showed a decrease in visceral pain sensitivity at 18 days and orchidectomized rats showed an increase in stress-induced visceral pain. Cross-sex therapy with testosterone and estrogens was administered to intact rats of both genders, after which a decrease in pain duration and intensity was noted in female rats, but no such significant difference was seen in intact male rats. The opposite was also true in male rats undergoing estrogen therapy, showing an increased pain sensitivity .Other experimental models have evaluated an increase in pain thresholds following the administration of testosterone, noticing less responsiveness to nociceptive stimuli after the hormone administration ,32. BaseMusculoskeletal pain is very common in women classified as premenopausal or postmenopausal. This may be attributed to the sudden drop in estrogen upon reaching menopause, which later exacerbates musculoskeletal pain and perhaps precipitates many chronic arthralgias and myalgias . A studyConsidering the molecular pathways involved in musculoskeletal pain, preclinical studies have shown that transient receptor potential vanilloid type 1 (TRPV1) is upregulated in biological female rats and in male rats that have received an orchiectomy, which is a procedure that removes one or both testicles. In other words, a lack of or decreased levels of testosterone upregulates TRPV1, which is thought to enhance mechanical sensitivity to pain. This biochemical change is considered to play a major role in pain hypersensitivity in males because testosterone replacement therapy in these rats reduced musculoskeletal pain. However, it did not have a significant effect in females .An interesting finding by Watt showed that females have a protective layer prior to reaching menopause because estrogen seems to block proteinase, which prevents musculoskeletal pain in females. However, this protection is lost following an ovariectomy or upon reaching menopause, which then explains the elevated prevalence of musculoskeletal pain in females and specifically females after menopause . AlthougAlthough not one of the most frequently cited pain-related reasons for seeking medical attention, transgender males and females are both at increased risk of breast pain compared to their biological male and female patient cohorts. In transgender males, chest binding, or compressing the chest tissue, is not an uncommon practice  and is sIn contrast, transgender females complaining of breast pain are more likely to present with hormone-induced tissue changes, such as gynecomastia. In the Aloisi et al.  study, 1It is recommended to biological females to obtain a cervical cancer screening every three years after reaching the age of twenty-one. As a result, this preventative screening is also recommended to transgender men and any patient that has a cervix as the screening can help prevent cervical cancer. Compared to biological females, transgender men tend to experience higher levels of pain during the procedure despite being on testosterone replacement therapy . As estaChanges in pain perception and pain-related chronic conditions have been most frequently evaluated as part of the quality-of-life assessment. In the same way, some authors found that chronic pain is an independent quality of life predictor in biological male and female patients  as in trAdditionally, besides the sex differences in pain perception, the effect of pain on the quality of life is different between genders, as in the Bingefors et al.  study, wAs mentioned earlier in the article, cervical screening is especially painful and uncomfortable for transgender men. As expected, this may lead to many transgender men not seeking out preventative care despite it being necessary and beneficial for their wellbeing and longevity. This population, in return, may experience higher rates of cervical cancer and mortality due to late diagnosis and delayed necessary treatments. Educating providers and informing them about the different experiences due to hormone replacement therapy will allow the providers to be more aware and considerate of patient’s unique anatomy, and thus making the experience more comfortable for these patients.Literature has consistently shown differences in pain perception in biological males and females. Testosterone shows protective factors in biological males and in transgender males receiving testosterone hormone replacement. On the other hand, estrogen fluctuations provide an explanation for the lower pain threshold seen in females. This is especially true in post-menopausal women who experience a great deal of fluctuations. Very few studies have been conducted evaluating changes in pain perception and pain-related conditions in transgender patients. The correlation of hormonal profiles and the epidemiology of pain-related conditions show a similar distribution of headache and musculoskeletal pain, with feminizing hormone therapy tending to increase pain and testosterone use tending to decrease it. This may be explained by the increased CGRP and tryptophan seen as a result of increased and decreased levels of estrogen, respectively. Similar findings for temporomandibular joint disorders and visceral pain are suggested by animal and therapeutic models. Women suffering from ovarian and breast cancer are especially at risk for experiencing pain due to the sudden increases and decreases in estrogen and progesterone. While the mechanisms of pain perception based on sex hormones have yet to be completely understood, there is no doubt that they influence the intensity of pain in the two sexes and as a result affect the prevalence of chronic pain conditions in these populations.


Monkeypox is a virus that was formerly recognized as a rare zoonotic disease but has been noted as an emerging disease of concern where there are significant gaps in knowledge. In 2022, Monkeypox outbreaks are being concurrently reported in numerous non-endemic geographical areas, thus instigating a global wave of public health concern amid calls for urgent action from international authorities. As of the 8th of June 2022, about 1,285 laboratory-confirmed cases were detected in 28 regions across Africa, the Americas, and the European Region .Misinformation is plentiful as Monkeypox virus cases are on the rise. The sensational nature of misinformation results in it being easily distributed and false beliefs perpetuated, further compounding the situation and causing widespread “misinfodemic” . MisinfoThe origin of the Monkeypox virus, both in terms of the “first ever” monkeypox cases and also the origins of this 2022 outbreak, is widely questioned on social media. Both plausible and unlikely scenarios are discussed by a range of public commentators. One false claim is that the virus was manufactured and released intentionally from a laboratory in China. Furthermore, there are clearly unsubstantiated myths linking the Monkeypox virus to COVID-19 vaccination, stemming from the idea that the AstraZeneca vaccine utilized a chimpanzee viral vector. Monkeypox is a pox virus whilst the AstraZeneca vaccine is based on a weakened and altered adenovirus vector that cannot infect humans . In addiMisinformation can drive stigma . Given tvia social media analysis of user behavioral trends. This can aid in exploring major causes of misinformation as well as predict disease outbreaks as seen during the COVID-19 pandemic [However, encouraging the spread of accurate information on social media is not enough to completely counter any harm of misinformation. An ongoing review of social media is necessary to identify evolving trends, new rumors, and key sources of misinformation. Introducing a flagging system for self-reporting suspicious posts related to Monkeypox misinformation can help foster responsible behaviors within the online community. Additionally, research is warranted for understanding the impact of misinformation on disease outbreaks pandemic .Outbreaks of emerging infections like Monkeypox will continue to occur, and the general public will continue to seek information from easily accessible internet resources. Online misinformation leads to unwarranted public concern and may exacerbate the outbreak of emerging infectious diseases due to improper public health guidance. Multi-faceted efforts are warranted between governments, social media platforms, and community leaders in combatting this public health crisis.


Freshwater ecosystems provide major benefits to human wellbeing—so-called ecosystem services (ES)—but are currently threatened among others by ecotoxicological pressure from chemicals reaching the environment. There is an increased motivation to incorporate ES in quantification tools that support decision-making, such as life cycle assessment (LCA). However, mechanistic models and frameworks that can systematically translate ecotoxicity effect data from chemical tests into eventual damage on species diversity, functional diversity, and ES in the field are still missing. While current approaches focus on translating predicted ecotoxicity impacts to damage in terms of species loss, no approaches are available in LCA and other comparative assessment frameworks for linking ecotoxicity to damage on ecosystem functioning or ES.To overcome this challenge, we propose a way forward based on evaluating available approaches to characterize damage of chemical pollution on freshwater ES. We first outline an overall framework for linking freshwater ecotoxicity effects to damage on related ES in compliance with the boundary conditions of quantitative, comparative assessments. Second, within the proposed framework, we present possible approaches for stepwise linking ecotoxicity effects to species loss, functional diversity loss, and damage on ES. Finally, we discuss strengths, limitations, and data availability of possible approaches for each step.Although most approaches for directly deriving damage on ES from either species loss or damage to functional diversity have not been operationalized, there are some promising ways forward. The Threshold Indicator Taxa ANalysis (TITAN) seems suitable to translate predicted ecotoxicity effects to a metric of quantitative damage on species diversity. A Trait Probability Density Framework (TPD) approach that incorporates various functional diversity components and functional groups could be adapted to link species loss to functional diversity loss. An Ecological Production Function (EPF) approach seems most promising for further linking functional diversity loss to damage on ES flows for human wellbeing. However, in order to integrate the entire pathway from predicted freshwater ecotoxicity to damage on ES into LCA and other comparative frameworks, the approaches adopted for each step need to be harmonized in terms of assumptions, boundary conditions and consistent interfaces with each other. These bDespite these benefits, freshwater ecosystems face continuously increasing pressures from human activities, such as pollution from chemicals emitted along product life cycles , which iSeveral authors have considered how to incorporate protecting or restoring ES in decision-making , which rQuantitative decision support tools, such as life cycle assessment (LCA), chemical substitution or chemical footprinting, have been developed in support of assessing and increasing environmental sustainability of products and technologies , which aThe translation of predicted ecotoxicity impacts into aquatic species loss as LCA-metric for damage on ecosystem quality remains challenging, given the large diversity of chemical compounds, the required step to extrapolate from ecotoxicity test data to predicted toxic pressure, the largely unresolved association between the predicted toxic pressure and structural or functional damage in terms of, for example, species loss and altered food web function in the field, and the location-dependent variation in many parameters that influence the outcome of the impact pathway from emissions to change in ecosystem services. For the purpose of comparative LCA, the mechanistic or empirical association between insights from laboratory test data and eventual damage in the field is of interest, given the principle that other impact pathways also aim to characterize damage in the same units. Considering this pathway for chemical pollution highlights various challenges related to disconnects between current approaches and final damage aspects. There may be, for example, within-ecosystem species shifts as function of chemical pressure that would not lead to net species loss or significant functional damage .Damage on ecosystem functioning or even further on ES associated with ecotoxicity impacts are currently not addressed in LCA. This is despite the fact that inclusion of ES in LCA to assess the importance and magnitude of different stressors on ecosystems and their respective services is the focus of several ongoing research efforts . Among tIn another study, An approach that was discussed for overcoming the complexity of assessing ES, which could also be potentially useful in the context of LCA, is the use of ecological production functions (EPFs) to quantify and predict changes between specific ecosystem functions and ES , by linkIn all, despite some emerging concepts to generally evaluate ES in LCA, challenges for including freshwater ES associated with ecotoxicity impacts from chemical life cycle emissions would be valuable for decision support, though remain largely unresolved. In order to quantify ecotoxicity-related damage on services provided by freshwater ecosystems, the main human-valued ES need to be first defined, including their underlying pathways from pressures to species and functional diversity loss in freshwater ecosystems, and finally to damage on ES. The present study aims at addressing this knowledge gap and proposes a way forward to characterize damage of chemical pollution on ES of freshwater ecosystems in LCA. This is done by focusing on three specific objectives: (a) to outline an overall framework for linking predicted freshwater ecotoxicity impacts to damage on related ES in compliance with the boundary conditions of LCA; (b) to present possible approaches for linking predicted ecotoxicity impacts to species loss and functional diversity loss, and finally to damage on ES in LCA; and (c) to discuss strengths, limitations and data availability of possible approaches for each step from ecotoxicity impacts to damage on ES.2Linking chemical emissions via predicted ecotoxicity impacts to damage on ES is not straightforward. When developing the pathway from ecotoxicity impacts to damage on ES, the main link is often from predicted species-level effects to damage on structural biodiversity , further to damage on functional (bio-)diversity loss, and finally to damage on related ES . AlternaIn the present study, we illustrate the broader complexity of the impact pathway for freshwater ecosystems and its connections between ecotoxicity, species loss, functional damage, and ES damage. As starting point, we adapted the Adverse Ecosystem Service Pathway (AESP) conceptual framework  based onIn practice, protection of biodiversity at the ecosystem level still relies primarily on extrapolating ecotoxicity effects at the level of the individual organism. This is based on data from ecotoxicity tests, extrapolated to structural ecosystem properties  and some ES of importance for human wellbeing, whereby current uncertainties in this assessment process are reflected in the magnitude of uncertainty factors utilized in the derivation of environmental quality standards that aim to ascertain sufficient protection even under data uncertainties . HoweverAs shown in In the LCA framework, “ecosystem quality” is one of the main defined areas of protection , with reThe impact pathway from emissions to ecotoxicity impacts expressed at the level of affected species fractions is already covered well in LCA, whereby predicted impacts – expressed as Potentially Affected Fraction of species (PAF) – are extrapolated to damage – expressed as Potentially Disappeared Fraction of species (PDF) on the basis of empirical PAF-PDF associations . This pr3Assessing ecotoxicity impacts on freshwater ecosystems requires looking at the source of damage and the overall framework from emission to ecotoxicity damage on species diversity, functional diversity, and ES. The pathway from emissions to ecotoxicity effects is already covered, for instance, in the global scientific consensus model USEtox, where ecotoxicity effects of a chemical emitted into the environment are assessed by combining factors characterizing environmental fate, ecological exposure, and ecotoxicological effects . EnvironThe scientific literature provides some opportunities that could serve as a starting point for translating ecotoxicity impacts into damage on species diversity, functional diversity, and ecosystem services of freshwater ecosystems in the context of LCA and similar frameworks see . The opp3.1Effects of chemicals on freshwater ecosystem species range from direct acute and chronic toxicity in organisms to many sub-lethal or indirect impacts on behaviour, functional roles, predator–prey relationships, and food web dynamics . If consThree approaches were initially developed to be potentially used as a starting point to translate ecotoxicity impacts into damage on species diversity expressed as species loss. These approaches include the media recovery approach that is based on species richness  recovery after exposure to a toxicant, the mean extinction approach that quantifies the expected survival rate of different species when exposed to a stressor, and the genetic diversity approach that is based on changes in species genetic diversity . The genGenetic and species diversity are fundamental components of assessing impacts on biodiversity . Both arThe possibility that genetic and species diversity influence each other has been acknowledged for decades . A positAnother type of approaches in linking ecotoxicity effect to species loss (i.e. loss in species diversity) consists of the idea to develop and use mechanistic models such as dynamic energy budget models (DEB), population models, and food web models to extrapolate effects at individual species levels to damage at the population level or community level . DEB modPopulation models are another opportunity, which utilizes information on individual species' life history characteristics , thus bringing additional biological realism when predicting damage to populations from data on various endpoints . HoweverFood web models, such as AQUATOX , consideTranslating ecotoxicity impacts into species loss can also be achieved using the principal response curve (PRC) approach. This approach uses data on multiple species responses from controlled experiments, e.g., mesocosms. However, PRC statistics are only feasible for data with repeated measures over time . Unlike In contrast to PRC derived from mesocosm-type test data series, the Threshold Indicator Taxa Analysis (TITAN) approach uses field monitoring data on multiple stressed system to derive species-specific differences in abundance response thresholds given pressure level gradients . TITAN'sThe challenges of most mechanistic models and the empirical approaches are partly conceptual but mostly also related to available data, as highlighted above, including the need to cover a wider variety of species, currently limited coverage of chemicals and different organisms' specific endpoints, which still require attention. Using the SSD approach to cover a broader range of species can bridge part of the data-related gap and with that can help refining some of the models . Further3.2Functional diversity is the variation of traits between organisms . SpeciesAt the community level, estimating functional diversity within a community of species is often determined as a function of differences in individual species traits . That isEcosystem functioning relates to the sum of all processes that sustain an ecosystem through biological activities . ProcessChemical pollution may have a specific impact in ecosystems and their functional characteristics. That is, differences in the match, or mismatch, of chemical modes of action and species traits  determine how chemical exposures affect species and which consequences on ecosystem functioning or to be expected . ChemicaAccording to The function sensitivity distribution (FSD) approach has been proposed to quantify the impact of a toxic chemical on the functioning of an ecosystem by considering function-related endpoints . Its appGiven various concepts and components in estimating functional diversity, The phenotypic diversity model  could also provide a way to translate changes in species diversity into damage on ecosystem functioning. Species diversity directly links phenotypic variance to ecosystem functioning, represented as a change in biomass production in an ecosystem from a toxic pressure. With a focus on species functional groups as the basic unit of the ecosystem, species sensitivity is taken into consideration in this approach .Functional indicators that measure functional effect traits or rates or attributes of processes have been proposed. Such indicators have been proposed, since it is considered difficult to measure ecosystem functions or predict them from underlying structural impacts. On this relationship, it can be reasoned that highly aggregated functional metrics (such as primary productivity) are relatively insensitive as compared to underlying structural impacts. Exploiting the relationship between potential functional indicators that are more directly connected to mechanistic processes can help link species loss to ecosystem function loss by assessing how a change in the state related to processes impact rates of processes within the food web. However, changes in multiple interacting functions at the food web level and across different trophic levels are indicated by processes measured at the food web level, such as the flow of energy through the food web .Combining different functional diversity components, FSD, and functional indicators  can hencAn overview of the features of different approaches that could potentially serve as a starting point for translating damage on species diversity into damage on functional diversity of freshwater ecosystems in the context of LCA is provided in 3.3Damage on functional diversity loss can be linked to damage on related ES as an intermediate step of the main pathway in linking ecotoxicity effects to damage on ES . HoweverFreshwater ES are dependent on freshwater organism interactions and processes . For exaBiodiversity is the variety of life forms, including the variation of genes, species, and functional traits. Biodiversity and ecosystem functioning relationships (BEF) have been studied for several decades , with reSome studies have shown that environmental change may damage ecosystem functioning without affecting species richness by affecting population density and community composition as the community competes for limited resources at one trophic level . HoweverBEF has often been measured without extending to known ES. Likewise, biodiversity and ecosystem services relationships (BES) have often been described without understanding the underlying ecosystem functions . PredictFor example, diverse communities are more productive because they contain key species that greatly influence productivity, and differences in functional traits increase the total resource capture . FurtherMany ES ultimately depend on the variety of life forms . TherefoAccording to Studies directly assessing ecotoxicity impacts on freshwater ecosystem functioning, which could facilitate further translation of functional loss to damage on ES, are rare due to little understanding of biodiversity-ecosystem-function/services relationships and the availability of mechanistic models  to link chemical-induced effects on individual species to ES delivery .The quantitative ecological production functions (EPFs) approach provides quantifiable links from ecosystem functional diversity loss to damage on ES flows  or a dirES conceptual frameworks also offer ways of linking ecosystem functioning loss to damage on the ES. From earlier reviews conducted on ES methods and applications to freshwater ecosystems , most esThe cascade model proposed by Overall, numerous knowledge gaps remain for successfully translating ecotoxicity impacts into damage on freshwater ES, either directly from species loss or through functional diversity loss. This includes (a) the lack of comprehensive and integrated approaches to assess impacts of chemicals and other stressors while taking into account different routes of chemical exposures, (b) the overestimation or underestimation of potential chemical risk on SPUs, which reduces the accuracy of ES assessment, (c) the complexity in analysing ES trade-offs, i.e. protecting one ES resulting in downstream effects on other ES .The challenge of overestimation or underestimation of the risk on SPUs may be addressed in part by generating separate SSDs for different species groups, which uses ecological information on species communities such as functional groups or trait characteristics . This maCurrent methods that link individual elements along the pathway from ecotoxicity impacts to damage on ES delivery  are stil4One of the key problems of ecotoxicity assessments and assessing damage is the need for laboratory-to-field extrapolation, given that stressors studied in applied ecology (such as nutrient enrichment) are addressed based on ecological concepts and field data, whilst stressors studied in applied ecotoxicology are most often relaying on laboratory toxicity data. Whilst there are mechanism-based approaches which could be applied in PAF-PDF characterization of damage, it is key to highlight the final issue that the predicted damage should relate to true damage, that is: that the lab-field extrapolation for chemical pollution impacts is correct. The latter can be judged by analyses of landscape-level ecosystem data. Assessment and management of ES eventually require data-driven insights to recognize ES deterioration upon adding more man-made pressures and improvement upon less man-made pressures. Data-driven insights can be obtained from (bio-)monitoring data, combined with appropriate statistical analyses. The latter should be able to characterize the relative roles of different pressures on ecological metrics, be it species abundance data, aggregated structural biodiversity metrics, or aggregated ES metrics. In an ideal case, the damage predicted by any of the mechanistic models should relate to damage in the field.Generally, the (bio-)monitoring data should cover a number of sites that vastly exceed the number of pressure metrics to avoid the so-called 'curse of dimensionality’. Few sites mean that each added pressure parameter reduces the power of statistical analyses unless sufficient increases in the number of study sites are substantiated. One of the key problems in this respect is the study of chemical pollution through separate exposure or risk metrics for each chemical. The problem was solved by summarizing all chemicals, or mode-of-action subgroups, via mixture toxic pressure quantification .The statistical diagnostic assessments also need to take into account that there are different types of ecosystems , such that the natural conditions are represented in a multitude of non– or minimally disturbed ecosystem types, whereby damage should be considered relative to those different reference states.Regarding the statistical analyses aimed at diagnosing relationships between pressure variables and impact variables, the best 'training' data need to consist of the longest possible data gradients for all pressures , where the covariance amongst the pressures is below a critical level. This can be checked by calculating, e.g., the Variance Inflation Factor, which should be below a threshold above which interpretation bias (in diagnosing probable causes of impacts) occurs .Monitoring-based approaches involve repetitive data collection to determine trends in parameters or endpoints that comprise ES . CharactMultiple stress analyses have been made for various pressure combinations, areas, species groups, and practical aims. Examples are There are global monitoring platform for ES and biodiversity inspired initiatives, such as the Global Biodiversity Information Facility (GBIF) and the Ocean Biodiversity Information System (OBIS) . These aIn the ES field, monitoring can have a different focus. For instance, for recreation fishing ES, monitoring can either focus on the effect of a stressor on the fishery SPU values, on the ways of preserving fishery SPU values, and on the state of the ecosystem in terms of the SPU, i.e., effect-based monitoring . BecauseAn attempt was also made earlier to monitor the ecological status of the aquatic ecosystem in Europe as an indicator of water quality, which involved using ecological status metrics from biological quality elements information instead of raw field monitoring data . Using tFor a holistic understanding of how ES can be influenced by one or multiple man-made pressures, efforts are still needed to further develop the data, statistical analysis frameworks, and tools that combine knowledge of ES monitoring with the status and trends of stressors at different spatial and temporal scales. This is particularly challenging when there is interest in chemical pollution as a spatio-temporally variable pressure next to various other pressures, given that applied ecology and applied ecotoxicology need to be bridged by summary concepts such as 'mixture toxic pressure.'.5To address damage on freshwater ES in LCA associated with toxic chemical emissions along product and technology life cycles, related ecotoxicity impacts need to be linked to damage on species  and functional diversity and finally to damage on ES. This needs to consider approaches that utilize field-based monitoring data with biological realism and align with LCA boundary conditions.For a holistic assessment of the entire ecosystem rather than individual species population, models that consider multiple populations or entire food webs  can helpA trait probability density framework incorporating various functional diversity components can subsequently link species loss to functional diversity loss. However, more data with functional diversity endpoints are still needed before this framework can be operationalized.Quantitative ecological production functions could finally translate damage on species diversity to functional loss and damage on ES, if uncertainty in extrapolating from the relevant SPUs and functions to ES is considered . The chaThe advantage of using EPF-based approaches is that they allow for measured functional endpoints to be further linked to changes in ES delivery. However, identifying endpoints suitable for ecosystem assessment remains a challenge , where fOverall, we highlighted key elements to develop a framework and associated potentially useful approaches for integration in LCA and similar assessment frameworks that link ecotoxicity impacts on aquatic freshwater species to damage on genetic and functional diversity at the ecosystem level, and further to damage on ES delivery. More attention needs to be paid to developing and refining mechanistic damage models with standardized functional endpoints and structures that align with cause-effect chain modelling, such as the cascade model. By providing an overall framework as well as an evaluation of potentially useful scientific and practical approaches, our study constitutes a useful starting point for addressing current challenges in linking ecotoxicity impacts to damage on freshwater ES, either directly from species loss or through functional diversity loss.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Atrial fibrillation (AF) is the most common sustained heart rhythm disorder and is often associated with symptoms that can significantly impact quality of life and daily functioning. Palpitations are the cardinal symptom of AF and many AF therapies are targeted towards relieving this symptom. However, up to two-third of patients also complain of dyspnea as a predominant self-reported symptom. In clinical practice it is often challenging to ascertain whether dyspnea represents an AF-related symptom or a symptom of concomitant cardiovascular and non-cardiovascular comorbidities, since common AF comorbidities such as heart failure and chronic obstructive pulmonary disease share similar symptoms. In addition, therapeutic approaches specifically targeting dyspnea have not been well validated. Thus, assessing and treating dyspnea can be difficult.This review describes the latest knowledge on the burden and pathophysiology of dyspnea in AF patients. We discuss the role of heart rhythm control interventions as well as the management of AF risk factors and comorbidities with the goal to achieve maximal relief of dyspnea. Given the different and often complex mechanistic pathways leading to dyspnea, dyspneic AF patients will likely profit from an integrated multidisciplinary approach to tackle all factors and mechanisms involved. Therefore, we propose an interdisciplinary and integrated care pathway for the work-up of dyspnea in AF patients. This symptom is more common when AF is accompanied by a comorbid disease, such as heart failure (HF) or chronic obstructive pulmonary disease (COPD) Dyspnea is another common presenting symptom of AF. Studies have shown that it can be the presenting symptom in up to two-thirds of patients . This syThe aim of this review is to provide an integral overview of dyspnea in AF. We will discuss the pathophysiology of dyspnea in AF and describe the important role of comorbidities. Next, dyspnea assessment and the efficacy of current AF therapy to provide dyspnea relief is presented and the need for a multidisciplinary approach is highlighted. Since dyspnea and exercise intolerance are closely linked 2.Several mechanisms have been proposed that may play a role in the pathophysiology and perception of dyspnea in AF .Fig. 1Me2.1Intuitive mechanisms for dyspnea and reduced exercise performance in AF are linked to impairments in hemodynamic responses to physical activity. First, the loss of a normal atrial contraction as a result of AF leads to reduced ventricular filling and subsequently reduced cardiac output Heart failure with preserved ejection fraction (HFpEF) also impairs exercise tolerance. Exercise intolerance in AF is strongly associated with elevated left ventricular filling pressure 2.2Additionally, peripheral muscle oxygen uptake may play a role in the pathophysiology and perception of dyspnea in AF. Oxygen transport (VO2) can be described by the product of cardiac output and arterial-venous O2 content difference. Previous studies have shown that blood flow to the legs remains preserved even in severe HF suggesting a peripheral limitation to exercise in these patient 2.3Both the impaired flow and endothelial dysfunction can lead to increased exercise pressor reflex (EPR) activity in AF 2.4Healthy individuals rarely have a ventilatory limitation to exercise 2.5The emotional state of a person also modulates dyspnea. Anxiety, anger and depression can increase symptoms of dyspnea out of proportion with regard to the cardiorespiratory dysfunction 3Comorbidities are common in AF and their relevance increases in patients with dyspnea, because many of these comorbidities affect the success of AF management Cardiovascular disease. HF is highly prevalent among AF patients  Non-cardiovascular comorbidities. Besides cardiovascular comorbidities, several non-cardiovascular comorbidities contribute to dyspnea. COPD is present in up to 23% of AF patients In conclusion the clinical relevance of comorbidities is higher in patients with AF and dyspnea. Since comorbidities are highly prevalent in dyspneic AF patients, dyspnea could be used as a diagnostic clue to systematically search for concomitant conditions in AF patients, since assessment of comorbidities is crucial to adopt the most ideal treatment strategy. In addition, an accurate evaluation of symptom burden, symptom-rhythm correlation and effect on the functional status of AF patients is also of importance.4(Supplement Table 1). Importantly, both scales assess symptoms during an AF episode, possibly underestimating the illness burden in paroxysmal AF in the absence of such episodes. Numerous other questionnaires are currently used for AF research purposes only (Supplement Table 1) but these questionnaires were not specifically designed to assess dyspnea as a main symptom or address all the different domains of dyspnea There is a need for adequate assessment tools for dyspnea, since dyspnea assessment in daily clinical practice is usually subjective and self-reported. The most frequently used classification scales, the European Heart Rhythm Association (EHRA) classification Supplement Table 2, we propose some requirements for dyspnea measurement in AF patients which could be incorporated in such a mobile health tool.Burden of dyspnea should not only include severity but should also assess time spend with dyspnea, which requires gathering information on both severity and frequency preferably by a prospective repetitive longitudinal momentary assessment. Future questionnaires should therefore include dyspnea specific (sub)scales that are easy to apply, provide sensitive and valid information regarding all domains of dyspnea and that are responsive to intervention, or dyspnea should be systematically assessed by momentary assessment tools [51]. In 5Current guidelines recommend the simple Atrial fibrillation Better Care holistic pathway, which includes both symptom management and comorbidity optimization next to anticoagulation therapy 5.1Importantly, not all dyspnea is always directly related to AF episodes [52]. In patients with paroxysmal AF, the temporal relationship between AF paroxysms can be interrogated during history taking. In patients with persistent AF, cardioversion may be used to restore sinus rhythm and test for dyspnea relief to assess symptom-rhythm correlation. However, the current approach of symptom assessment around rhythm control by electrical cardioversion (ECV), once before ECV and once within 1-month follow-up, may be suboptimal and rarely identified a symptom-rhythm correlation [53]. Although studies on dyspnea improvement with rate or rhythm control strategies are scarce, rhythm control by catheter ablation has been shown to reduce dyspnea at rest and on exertion, which is in line with the overall beneficial effect of catheter ablation on arrhythmia-related symptoms [54].5.2There is some evidence that targeting cardiovascular risk factors and comorbidities also provides dyspnea relief in patients with AF. De With et al.[55], showed that optimizing blood pressure, improving HF treatment and improving the overall cardiovascular risk profile improves quality of life and dyspnea in patients with both AF and HF. Several observational trials [56–58] similarly showed that AF symptom burden and symptom severity scores declined significantly more with aggressive risk factor management and weight reduction in those with obesity. The greater the reduction in weight, the more effect on AF symptoms was achieved [56].In addition, increasing number of studies reveal a central role for regular exercise in the primary and secondary prevention of AF [59]. For example, exercise-based cardiac rehabilitation has been associated with 26% lower odds of AF progression and cardiorespiratory rehabilitation programs aimed at increasing peak metabolic equivalents significantly reduce symptoms in AF patients, even after adjusting for weight loss . This highlights the potential for cardiac rehabilitation in this specific group of AF patients, although randomized controlled trials are required to build the evidence required.Though there are no studies on the effect of treating lung diseases or psychological disorders on dyspnea in AF, it seems reasonable to treat both comorbidities since they are associated with increased dyspnea symptoms in AF patients. Anxiety and depression are common and treating those diseases reduces AF symptoms over time Optimal pharmacological and non-pharmacological treatment of COPD may improve dyspnea sensation and AF treatment outcomes Lastly, when interpreting routine investigations in AF patients such as echocardiography, attention should be paid to uncommon but serious causes of dyspnea such as (chronic thromboembolic) pulmonary hypertension.6(Supplement Table 3). In the previous paragraphs we described how a symptom based approach could have a positive effect. Although not yet proven effective, to optimally implement this and to improve dyspnea assessment and management in AF patients, we propose a multidisciplinary integrated care pathway.In many AF clinics a stepwise approach is used; AF is first treated within a rhythm control approach before the patients without symptom-rhythm correlation and persistent dyspnea are referred to multiple other specialists resulting in a fragmented and burdensome patient journey. Moreover, current guidelines do not specifically focus on the assessment and management of dyspnea in AF patients 6,1The increasing prevalence of multimorbid AF patients necessitates a multidisciplinary and integrated care approach. In such a team multiple specialists work together to assess patients’ needs and to unravel the different components that contribute to the feeling of dyspnea. An example of such an integrated care approach is given in Designing such multidisciplinary teams can be challenging since not all medical specialties  are readily available in every health care setting. Also, simultaneously assessing patients might carry the risk of overdiagnosis and increase health care costs. However, studies in chronic airway diseases have shown that such a strategy can improve quality of life [68]. Identifying comorbidities can potentially prevent overtreatment of AF which is deemed to fail if dyspnea can be attributed to the presence of other co-morbidities. Additionally, early identification of risk factors and comorbidities might also prevent complications at a later stage.7Although several large national and international guidelines  recommend assessment of symptom burden, a practical guide and standardized care pathway for the management and assessment of dyspnea in AF patients is currently lacking. While the organization of management within a multidisciplinary integrated care approach seems attractive, robust clinical trials assessing the added value of such an approach as well as trials assessing the effects of dyspnea care (improved assessment/management) on patient outcomes are required to finally implement them in clinical practice. Additionally, the effect of cardiopulmonary rehabilitation programs and the relative impact of exercise, risk factor management and patient education remain unclear and require further study.8Dyspnea is present in up to 66% of AF patients, particularly if AF is accompanied by comorbidities. AF-related as well as comorbidity-related mechanisms can contribute to dyspnea, which may explain the variable symptom-rhythm correlation and incomplete response of dyspnea to rhythm control interventions in dyspneic AF patients. To manage dyspnea in AF patients, we propose an integrated care approach, in which all AF and concomitant comorbidities are targeted within an multidisciplinary team. Further studies are required to evaluate the benefit of such a multidisciplinary integrated care approach to manage dyspnea in AF patients.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Recent evidence suggests that soil-transmitted helminth (STH) transmission interruption may be feasible through community-wide mass drug administration (cMDA) that deworms community members of all ages. A change from school-based deworming to cMDA will require reconfiguring of STH programs in endemic countries. We conducted formative qualitative research in Benin, India, and Malawi to identify barriers and facilitators to successfully launching a cMDA program from the policy-stakeholder perspective.We conducted 40 key informant interviews with policy stakeholders identified as critical change agents at national, state/district, and sub-district levels. Participants included World Health Organization country office staff, implementing partners, and national and sub-national government officials. We used the Consolidated Framework for Implementation Research to guide data collection, coding, and analysis. Heat maps were used to organize coded data and differentiate perceived facilitators and barriers to launching cMDA by stakeholder.Key facilitators to launching a cMDA program included availability of high-quality, tailored sensitization materials, and human and material resources that could be leveraged from previous MDA campaigns. Key barriers included the potential to overburden existing health workers, uncertainty of external funding to sustain a cMDA program, and concerns about weak intragovernmental coordination to implement cMDA. Cross-cutting themes included the need for rigorous trial evidence on STH transmission interruption to gain confidence in cMDA, and implementation evidence to effectively operationalize cMDA. Importantly, if policy stakeholders anticipate a cMDA program cannot be sustained due to cost and human resource barriers in the long term they may be less likely to support the launch of a program in the short term.Overall, policy stakeholders were optimistic about implementing cMDA primarily because they believe that the tools necessary to successfully implement cMDA are already available. Policy stakeholders in this study were cautiously optimistic about launching cMDA to achieve STH transmission interruption and believe that it is feasible to implement. However, launching cMDA as an alternative policy to school-based deworming will require addressing key resource and evidence barriers.Trial registration This study was registered in the U.S. National Library of Medicine Clinical Trials registry (NCT03014167).The online version contains supplementary material available at 10.1186/s41256-022-00281-z. Soil-transmitted helminths (STH) are a group of intestinal worms that affect an estimated 1.5 billion people annually who primarily reside in low- and middle-income countries (LMICs) . CurrentEarly evidence suggests that it might be possible to interrupt transmission of STH early using community-wide MDA (cMDA), as opposed to school-based MDA –9. Many For programs to successfully make this transition, it is important to understand factors that influence the launch of cMDA for STH transmission interruption . PreviouThe purpose of this study is to identify policy-level determinants (facilitators and barriers) of launching cMDA across three heterogeneous contexts in Benin, India, and Malawi. This evidence is necessary for identifying best practices for rollout of cMDA as part of larger STH transmission interruption programs, or other newly launched community-based public health campaigns.This qualitative study is embedded within the DeWorm3 Project, a hybrid type 1 implementation-effectiveness trial evaluating the feasibility of interrupting STH transmission using cMDA , 17–19. DeWorm3 trial sites include Benin, India, and Malawi Site selection is described in more detail in the DeWorm3 trial protocol . In BeniKey policy stakeholders—including MOH, Ministry of Education, WHO and other implementing partners such as non-governmental organizations (NGOs)—play an important role in shaping, adopting, and scaling up new NTD programs and policies. Stakeholder mapping workshops were conducted in each country to identify individuals who were considered critical STH change agents in each country at the national, state/district, and sub-district levels. Stakeholder maps included 52 individuals in Benin, 137 individuals in India, and 54 individuals in Malawi. Purposive quota sampling was used to select interviewees from the stakeholder maps across stakeholder “levels”, including WHO country offices, implementing partners, and national and sub-national government personnel in each country . We aimeIn 2018, we conducted individual interviews with STH policy stakeholders in Benin, India, and Malawi, before the rollout of cMDA in conjunction with the DeWorm3 Project. Data collection and analysis were informed by the Consolidated Framework for Implementation Research (CFIR), a meta-theoretical framework of 38 constructs that provides a typology for characterizing potential determinants (both barriers and facilitators) to implementation from the perspective of individuals involved in implementation . We idenData were transcribed in the local languages, where applicable, and translated into English. Transcriptions and translations underwent quality assurance reviews to ensure accuracy and any discrepancies were referred to the original transcriber or translator for revision. Participant names were removed from transcripts but the stakeholder level  was included. Atlas.ti 8 qualitative software was used to store and organize the transcripts. A group of five coders based in Seattle, United States; Vellore, India; and Cotonou, Benin engaged in coding the data. All coders were trained using a standardized analysis plan. Data were analyzed deductively using an a priori codebook drawing from 24 CFIR constructs across all five domains, three CFIR constructs that were duplicated to specify if they were relevant to STH or other NTDs (LF), and five additional codes (non-CFIR) that we hypothesized influenced the implementation of cMDA , their response was designated as a strong (dark blue) or moderate (light blue) facilitator. Where the individual indicated that a construct makes the introduction of cMDA difficult , their response was designated as a strong (dark orange) or moderate (light orange) barrier. If the individual indicated that a construct could be both a facilitator and a barrier or was neutral (no evidence of positive or negative influence), it was designated as mixed (grey). Heat maps were visually assessed for patterns across stakeholders, stakeholder levels, constructs, and sites. Facilitators and barriers were identified by noting patterns that were cross-cutting across individuals, constructs, and/or countries and via thematic organization and analysis of coded data.A total of 40 respondents participated in this study Table . These Sengaging participants, engaging leaders, design quality and packaging, and intervention complexity influenced this theme by highlighting opportunities and best practices for strong sensitization campaigns to support rollout of cMDA  before and during cMDA to overcome myths related to MDA Based on their experiences with other cMDA programs for LF, stakeholders in India and Benin expressed concern that adults may reject cMDA for STH if they perceive themselves to be low risk for infection. Thus, stakeholders believed previous MDA awareness materials and social mobilization tools could be leveraged from other campaigns to overcome this challenge.intervention complexity, Fig. We need to sensitize massively like going to the churches... and Mosques. As you know [in District] most of the people are Muslims, so we need to target those areas. We also need to make sure that the local leaders know this issue and we need to tell them that wherever people have gathered…it is also their responsibility to let the people know what government intends to do in their area.—Malawi #8 (District)Policy stakeholders in India and Malawi believed tailored sensitization to specific community sub-groups would make cMDA more complex to deliver Policy stakeholders across three countries believed existing school based and LF MDA resources could be used to support the launch of cMDA Policy stakeholders noted that one reason why cMDA for STH is a priority for the health system is that it is a challenge that can be addressed with tools at hand, without the need to develop new technologies or innovations.tension for change). In Benin, several stakeholders believed children were still at risk of STH morbidities under the current standard of care, and thus STH programs need to be community wide In Benin and India, several policy stakeholders believed it was important to pursue STH transmission interruption and launch cMDA for STH as a part of existing maternal and child health agendas Policy stakeholders compared the human resource requirements of school-based MDA to cMDA, highlighting school-based deworming leverages teachers to distribute drugs, whereas in some settings CDDs would need to be recruited and trained to deliver cMDA. National-level stakeholders in Benin and Malawi did not believe there would be enough CDDs readily available to deliver cMDA for STH with high-coverage While school-based MDA programs do not guarantee financial incentives to teachers to deliver deworming, policymakers in Benin and Malawi believed launching cMDA would require additional monetary incentives for CDDs or other health workers involved Further, stakeholders in India and Malawi believed cMDA would present complex challenges to the CDD workforce that may make it difficult to launch the program with high coverage Policy stakeholders in Benin and Malawi were concerned that launching cMDA could overburden the existing health workforce and strain resources In India, most National and some sub-national policy stakeholders were concerned that the health workforce would not immediately accept launching a new cMDA program if it increased their workload Policy stakeholders were similarly concerned that supervisors may not be able to provide adequate supervision during implementation, should cMDA for STH become standard of care. Supervision was of greater concern to higher level  stakeholders compared to district stakeholders who are typically responsible for local supervision National-level policy stakeholders in Benin and Malawi were concerned that cMDA for STH would not be successful over the long-term without support from NGOs, donors, or other external organizations that choose to champion the potential policy change.available resources, Fig. India is very well placed because it has its own resources, it is not donor dependent… There is a benefit to it also but there is also a slip side to it because it’s your own money…I know in countries like Nigeria, Ethiopia, obviously it’s hugely… donor dependent…the Governments do not have money of their own so the prioritization may also depend upon what priorities of donors are…and that does not necessarily have to be country driven always, we know that.—India #1 (Implementing partner)In contrast, in India, resources were not perceived to be a major barrier, as national-level policymakers highlighted a sense of growing autonomy and reduced donor dependence .Policymakers noted that the limited number of donors and partners supporting NTD programs globally might compromise the ability for programs to test and scale up innovative approaches to cMDA delivery. National-level policy stakeholders in India highlighted WHO and funders would need to continue to be engaged in research and implementation, following launch of a cMDA program.cosmopolitanism, highlighting opportunities and challenges for coordination between the MOH and other ministries, non-ministry partners, and other collaborators In Malawi, partnerships between the MOH and other ministries may need to be formalized prior to launch of a cMDA program. This includes creating administrative structures to link ministries and designate lead ministries for launching cMDA. A challenge that several stakeholders at both national and sub-national levels in Malawi noted is a lack of formal information-sharing systems and supervisory structures to help the MOH effectively collaborate with other ministries, like the Ministry of Education Fig. .We need Health is not the responsibility of the Ministry of Health alone; it is a multi-sectoral issue, and which requires the participation of almost all ministries. The treatment must not be done by the Ministry of Health alone. We must involve the Ministry of Education, Interior.—Benin #6 In contrast, policy stakeholders in Benin and India did not mention cross-ministry or partner coordination as obstacles to the introduction of cMDA for STH. Stakeholders in both countries did, however, highlight the importance of launching cMDA as joint initiatives across ministries Fig. .Health iknowledge and beliefs about cMDA and evidence strength and quality, Policy stakeholders in each country had strong positive attitudes towards launching cMDA driven by the belief that it could potentially eliminate STH transmission The policies that we have currently they are school-based. And whatever information is in that, there are mostly school based and obviously it needs to change to cater for the community element. We would want to see if [cMDA] is successful or not. If it’s successful that’s where policies need to change because the research is there to guide policies makers.—Malawi #7 (District)Stakeholders indicated that there is a dearth of evidence related to STH and transmission interruption. The evidence base will need to be strengthened before proposing new shifts in policy. Policy stakeholders prioritized clinical trial and cost-effectiveness data to inform potential updates to STH policy. Stakeholders in all countries also pressed that evidence about implementation and effective delivery of cMDA were necessary to launch cMDA (CFIR construct Policy stakeholders overall were encouraged by new cMDA clinical trials and were optimistic about incorporating evidence into future policies. Indian stakeholders were the most optimistic in terms of acknowledging potential pathways for scaling up a cMDA policy, while also acknowledging complexities with sustaining new programs Fig. . StakehoThis study used formative qualitative research among policy stakeholders to identify the perceived barriers and facilitators to launching cMDA for STH transmission interruption in Benin, India, and Malawi Table . FacilitStakeholders in all sites identified adaptive community sensitization as one of the most important determinants of successfully launching cMDA programs, due to its role in preparing communities. Without proper sensitization, cMDA could fail to achieve the coverage needed to stop STH transmission, potentially delegitimizing the program early in its implementation. The importance of community sensitization is well known in the MDA literature. For example, in the Greater Mekong Subregion, policymakers and scientists in a formative qualitative study on malaria elimination identified community engagement and sensitization as a priority for addressing the negative impact of rumors and misconceptions on future uptake of MDA . A systeOpportunities to leverage existing MDA campaign infrastructure were perceived to be an asset for launching cMDA; economies of scope might be achieved if existing infrastructure could be utilized to expand deworming. However, policy stakeholders across sites noted that health workers were overstretched and that existing human resources may not be able to absorb a cMDA for STH program. A qualitative evaluation of cMDA for STH in Kenya found that community health volunteers and community members similarly identified health worker-workload and capacity as challenges to delivery . Our stuLaunching successful cMDA for STH is reliant upon leveraging external funding that currently supports school-based deworming programs. One concern amongst stakeholders in Benin was the cost of drugs needed for cMDA in the future, should drug donations ultimately be halted. NTD policy stakeholders have observed this challenge in other settings; for example, onchocerciasis programs targeting disease elimination in Africa have often had setbacks due to inadequate domestic funding. Programs continue to need partnerships and financial support to achieve elimination . Cost anPolicy stakeholders in Malawi described a lack of intra-governmental coordination and collaboration in standard of care school-based MDA. In contrast, stakeholders in Benin and India highlighted opportunities for joint intra-government initiatives to support launch of cMDA. A study of Bihar’s school-based deworming program highlighted the importance of collaboration between health and education departments: where infrastructure was shared, the program achieved higher coverage and reduced overall program costs .Policy stakeholders also stressed that any future policy changes need to be grounded in rigorous trial evidence about STH transmission and implementation evidence such as cost-effectiveness, not simply driven by political momentum. For example, a triple drug regimen for LF moved rapidly from evidence to policy due in part to the availability of both clinical trial evidence and acceptability studies , 29. FurThere are several strengths of this study. This study included a sample of policy stakeholders from three countries before implementing a multi-site randomized clinical trial. This enabled our study team to engage with policy stakeholders and understand their perspectives on cMDA prior to study launch. Our study team used the CFIR from end-to-end, from data collection to analysis, and previous systematic reviews have demonstrated a dearth of studies using the CFIR in such a comprehensive manner . FurtherThis study also has several limitations. Policy stakeholders knew that cMDA would soon be implemented in certain geographic areas by the DeWorm3 Project and, as a result, their responses may have been affected by social desirability bias. Further, policy stakeholders may have been hesitant to disclose major challenges of launching cMDA, due to concerns related to future funding or external support. To preemptively address these concerns, policy stakeholders were told prior to interviews that their responses would not impact policy decisions or funding. Also, because each site tailored the individual interview guides to account for local implementation contexts and cultural differences, there may be differences in how questions were asked across sites. Lastly, several transcripts were not coded using double coding, and biases related to the interpretation of the data are possible.This formative study applied the CFIR to describe perceived barriers and facilitators of launching cMDA for STH transmission interruption, from the perspective of STH policy stakeholders in Benin, India, and Malawi. Policy stakeholders noted several challenges, primarily human and financial resource constraints that need to be accounted for should future STH for cMDA be launched in routine NTD programs. However, findings indicate that cMDA for STH was broadly appealing to policy stakeholders because it can leverage routine health program resources and contribute to improved maternal and child health. These findings indicate that policy stakeholders largely support launching cMDA for STH and are cautiously optimistic that it might effectively interrupt STH transmission. Continued communication with policy stakeholders will provide the opportunity to understand how perceptions of cMDA for STH may change as stakeholders are engaged in implementation.Additional file 1: Appendix 1. COREQ Table


Monoamine oxidase (MAO) activity is reduced in cigarette smokers and this may promote the reinforcing actions of nicotine, thereby enhancing the addictive properties of cigarettes. At present, it is unclear how cigarette smoking leads to MAO inhibition, but preclinical studies in rodents show that MAO inhibition increases nicotine self-administration, especially at low doses of nicotine. This effect of MAO inhibition develops slowly, likely due to plasticity of brain monoamine systems; studies relying on acute MAO inhibition are unlikely to replicate what happens with smoking. Given that MAO inhibition may reduce the threshold level at which nicotine becomes reinforcing, it is important to consider this in the context of very low nicotine content (VLNC) cigarettes and potential tobacco product regulation. It is also important to consider how this interaction between MAO inhibition and the reinforcing actions of nicotine may be modified in populations that are particularly vulnerable to nicotine dependence. In the context of these issues, we show that the MAO-inhibiting action of cigarette smoke extract (CSE) is similar in VLNC cigarettes and cigarettes with a standard nicotine content. In addition, we present evidence that in a rodent model of schizophrenia the effect of MAO inhibition to enhance nicotine self-administration is absent, and speculate how this may relate to brain serotonin systems. These issues are relevant to the MAO-inhibiting effect of cigarette smoking and its implications to tobacco product regulation. Cigarette smoking is a serious health concern, with nicotine dependence contributing to premature disability and death due to the toxic properties of cigarette smoke. However, while it is clear that nicotine is the primary addictive component of cigarette smoke, the full nature of the addiction and the biological underpinnings are still a matter of debate as there are over 7,000 chemicals in cigarette smoke . MonoamiBrain imaging studies document a decrease in brain MAO in chronic cigarette smokers, with a roughly 30–40% inhibition . Both isDespite the evidence that cigarette smoking leads to a decrease in MAO activity, some studies suggest that low MAO activity may also promote smoking. An association between MAO gene polymorphisms consistent with lower MAO-A activity leading to an increased likelihood of smoking has been reported . In a sein vitro assays, but it is unclear whether the identified MAO inhibitors in smoke can account for this. Maybe all of the relevant MAO-inhibiting substances in cigarette smoke have not yet been identified, possibly because they are not captured in smoke extracts, or maybe the known MAO inhibitors interact in a more than additive manner to inhibit MAO. As discussed below, it is also possible that these studies have not been of a sufficiently chronic nature to allow the effect to develop. The possibility must also be considered that MAO inhibition in cigarette smokers is an effect of metabolic products of the constituents of cigarette smoke or the production of some endogenous MAO inhibitor caused by smoking, and therefore MAO inhibition in cigarette smokers will not be fully explained by studying smoke extracts.Despite the MAO-inhibiting effect of cigarette smoking being known for more than 25 years, the mechanism by which this occurs is still not clear. Several chemicals in cigarette smoke have been identified that inhibit MAO , but it in vitro assays  that are not present in cigarette smoke. in vivo MAO inhibition by CSE. Possibly the most compelling differences between self-administration of nicotine and CSE is reported by in vitro, evidence of in vivo MAO inhibition was not provided. Furthermore, the impact of the increased self-administration of CSE compared to nicotine alone appeared to occur more rapidly than what has been observed with MAO-inhibition. Also, compared to nicotine alone, CSE did not increase responding for nicotine on a progressive ratio schedule of reinforcement, in contrast to what has been reported to MAO inhibition. If CSE inhibits MAO and MAO inhibition promotes nicotine self-administration (particularly at low doses of nicotine), then CSE should support self-administration to an extent greater than nicotine alone. Indeed, some studies have shown that CSE produces a greater effect on nicotine self-administration than can be explained based solely on nicotine content, though none of these studies document Intracranial self-stimulation (ICSS) can be used as another approach to examine the interaction between nicotine and MAO inhibition on reinforcement . In thisThe results of studies on the effects of MAO inhibitors on nicotine self-administration in rodents lead to the hypothesis that mice in which the MAO-A gene has been deleted should show enhanced nicotine reinforcement at low doses of nicotine. While no studies reported to date have examined the effect of reduced MAO-A gene expression on nicotine self-administration, one study  has examSeveral studies have found that MAO inhibition with tranylcypromine or other MAO inhibitors increased nicotine-evoked locomotor activity in rats and mice . InteresOf particular relevance to smoking dependence, Individuals with neuropsychiatric disorders or chronic pain have a greater incidence of smoking than the general population  raising Individuals with schizophrenia also smoke at a much higher rate than the overall population . During These data may also help to provide some insight as to the mechanism by which MAO inhibition increases nicotine self-administration, as it appears to be disrupted in the MAM rats. MAO inhibition would be expected to increase baseline extracellular levels of monoamines, particularly dopamine and serotonin with MAO-A inhibition in rats. Given the role of dopamine in drug self-administration, including the self-administration of nicotine, it is tempting to speculate that increased dopaminergic tone could result in a shift of the nicotine dose-response curve. While this could explain a potentiation of low-dose nicotine self-administration, it is harder to explain why increased dopamine tone would also shift the descending limb of the dose-response curve at higher doses. Additionally, as the MAM model of schizophrenia is thought to have elevated dopaminergic tone in the baseline state, it would be difficult to explain why MAO inhibition does not impact nicotine self-administration in this model . This complexity may involve heterogeneity of brain dopamine systems, with different DA systems mediating the ascending and descending limbs of the dose-response curve. For example, the heterogenous population of dopamine neurons in the ventral tegmental area with different inputs and projection fields are differentially parts of circuits involved with reward or aversion . As noteCigarette smoking causes inhibition of MAO and, based on preclinical studies, MAO inhibition causes an increase in nicotine self-administration at low doses of nicotine. Nicotine and tobacco regulatory policy needs to weigh all factors promoting the use of nicotine and tobacco products, and MAO inhibition appears to be one of those factors requiring consideration. With current nicotine regulatory policy focusing on the potential of reducing nicotine levels in cigarettes to below an addictive level (FDA Tobacco Product Standard for Nicotine Level of Combusted Cigarettes), one of the critical questions for regulating nicotine and tobacco products pertains to the threshold dose at which nicotine becomes addictive. In this context, the preclinical observation that MAO inhibition significantly reduces the threshold dose supporting nicotine self-administration in rodents under specific conditions cannot be ignored. Setting allowable nicotine levels to the lowest possible level may reduce the likelihood that MAO inhibition could maintain nicotine reinforcement and continued use. As current clinical research has used VLNC cigarettes that propose inhibition of MAO similar to what occurs in standard cigarettes, trials of VLNC cigarettes should already account for MAO inhibition. However, monitoring MAO- inhibiting activity of new products would ensure against significant increases in MAO-inhibiting activity that might further alter sensitivity to low doses of nicotine do not occur. Further, non-cigarette tobacco products cannot be assumed to have the same threshold for nicotine reinforcement given that the level of MAO inhibition produced differs across products. Additionally, an interaction between MAO inhibition and the use of nicotine and tobacco products may vary substantially across different sub-populations of smokers; surprisingly, the impact of MAO inhibition on nicotine self-administration was absent in a rodent model of schizophrenia. Although this observation argues against MAO inhibition promoting nicotine use in individuals with schizophrenia, it does highlight the point that the relationship between MAO inhibition and tobacco use is not constant across populations and needs to be addressed in subpopulations with particular vulnerability to nicotine use, such as individuals with depression or chronic pain, and this could be considered in the context of regulatory policy.Cigarette smoking results in inhibition of brain MAO activity, though it is currently unclear which elements in cigarette smoke account for this MAO inhibition and how it generalizes to other tobacco products. While there is no direct evidence that MAO inhibition contributes to tobacco dependence in human smokers, experiments utilizing nicotine self-administration in rodents document that chronic MAO-inhibition increases self-administration of low doses of nicotine. The mechanism by which MAO inhibition promotes self-administration of nicotine in rodents is not yet clear, but chronic adaptations of serotonergic systems may be involved. Given that certain populations may be particularly vulnerable to smoking and tobacco dependence, e.g., individuals with depression, schizophrenia, or chronic pain, it is possible that smoking-induced MAO inhibition may contribute to the high incidence of smoking in these populations. Tobacco regulatory policy needs to consider how nicotine interacts with other chemicals in tobacco products, including the potential for MAO inhibition produced by cigarette smoke, to moderate the public health impact of potential policies.JW and AS conducted the experiments presented in the manuscript. All authors contributed to the development and writing of the manuscript.


Legacy—what one leaves behind and how one hopes to be remembered after death—is an unexplored and important dimension of decision-making for people facing serious illnesses. A preliminary literature review suggests that patients facing serious illness consider legacy when making medical decisions, for example, forgoing expensive treatment with limited or unknown clinical benefit to preserve one’s inheritance for their children. To date, very little is known about the conceptual foundations of legacy. No conceptual frameworks exist that provide a comprehensive understanding of how legacy considerations relate to patient choices about their medical care.The objective of this scoping review is to understand the extent and type of research addressing the concept of legacy by people facing serious illness to inform a conceptual framework of legacy and patient treatment choices.This protocol follows the guidelines put forth by Levac et al, which expands the framework introduced by Arksey and O’Malley, as well as the Joanna Briggs Institute Reviewer’s manual. This scoping review will explore several electronic databases including PubMed, Medline, CINAHL, Cochrane Library, PsycINFO, and others and will include legacy-specific gray literature, including dissertation research available via ProQuest. An initial search will be conducted in English-language literature from 1990 to the present with selected keywords to identify relevant articles and refine the search strategy. After the search strategy has been finalized, 2 independent reviewers will undertake a 2-part study selection process. In the first step, reviewers will screen article titles and abstracts to identify the eligibility of each article based on predetermined exclusion or inclusion criteria. A third senior reviewer will arbitrate discrepancies regarding inclusions or exclusions. During the second step, the full texts will be screened by 2 reviewers, and only relevant articles will be kept. Relevant study data will be extracted, collated, and charted to summarize the key findings related to the construct of legacy.This study will identify how people facing serious illness define legacy, and how their thinking about legacy impacts the choices they make about their medical treatments. We will note gaps in the literature base. The findings of this study will inform a conceptual model that outlines how ideas about legacy impact the patient’s treatment choices. The results of this study will be submitted to an indexed journal.Very little is known about the role of legacy in the treatment decisions of patients across the continuum of serious illness. In particular, no comprehensive conceptual model exists that would provide an understanding of how legacy is considered by people making decisions about their care during serious illness. This study will be among the first to construct a conceptual model detailing how considerations of legacy impact medical decision-making for people facing or living with serious illnesses.DERR1-10.2196/40791 Legacy—what one leaves behind and how one hopes to be remembered after death—is an unexplored and important dimension of decision-making for people with serious illness. Reflecting on one’s values and legacy when living with a serious illness can provide a heightened sense of dignity, purpose, and meaning, as well as improvement in depressive symptoms and quality of life -3. Such Based on a preliminary literature review and previous research , we are To date, little research has been conducted on the concept of primary legacy, despite a wealth of scholarship on bereavement and other secondary and tertiary legacy activities. The extant literature on primary legacy typically examines interventions that might include the creation of a legacy document, such as dignity therapy or life review, or how various material artifacts, such as Physician Orders for Life-Sustaining Treatment (POLST), can be created and used, and their impact on patients’ understanding of their illness and preparation for death. We note, in particular, the foundational contribution Boles and Jones  offer inHowever, how patients define legacy, what it means to them, and how that meaning informs medical decisions are not well understood. A preliminary literature review suggests that people facing serious illness such as cancer consider legacy when making medical decisions, for example, forgoing expensive treatment with limited or unknown clinical benefit to preserve one’s inheritance for their children ,26. Yet,The objective of this scoping review is to inform a conceptual framework of primary legacy and patient treatment choices by understanding the extent and type of academic discourse, addressing the concept of legacy by people facing serious illness. This scoping review will examine the conceptions of primary legacy as it relates to medical decision-making, excluding literature discussing secondary legacy.We conducted a preliminary search of MEDLINE, the Cochrane Database of Systematic Reviews, and JBI Evidence Synthesis, and identified no current or in-process systematic reviews or scoping reviews on the topic of legacy and treatment choices of patients. This scoping review will describe the current literature base and identify research gaps. The results will inform a conceptual model of legacy and medical decision-making that will guide future research.This protocol follows the guidelines put forth by Levac et al , which eThrough preliminary literature reviews, the research questions this scoping review seeks to answer are (1) how is legacy conceptualized by people facing serious illness? and (2) how is legacy conceptualized during medical care decisions by people facing serious illness?This review will follow the population, concept, and context framework put forth by the Joanna Briggs Institute ,34. The Our preliminary literature review confirms that the concept of legacy is discussed across various disciplines. Given the multidisciplinary sources of evidence, we want to ensure comprehensiveness in literature sources and will include a variety of relevant literature databases. We will explore several electronic databases, including PubMed, MEDLINE, CINAHL, Cochrane Library, PsycINFO, and others, to be informed by the subject matter expert (SME) librarian. We will also hand search the gray literature to identify highly relevant sources, such as reports, and evidence-based legacy programs. Gray literature sources include dissertations (to be accessed via ProQuest) and letters to the editor. We will include empirical articles written in English from 1990 to the present. This time period was chosen in consultation with an SME expert to reflect significant shifts in the provision of hospice and palliative care that provided multiple treatment options for people facing serious illness . Our incInclusion criteriaPopulationPeople with or facing serious illness, such as people with a known family history of disease or people who have experienced a health scare, with a priority focus on historically underserved or vulnerable populationsConcept/study focusArticles that discuss, directly or indirectly, how people want to be remembered after their own death (primary legacy)Articles that discuss how people consider legacy when making treatment choicesStudy designsEmpiric studies, conceptual scholarship, and opinion pieces. Priority focus on studies with relevant qualitative componentsLiterature sourcesPriority sources include peer-reviewed books and journal articlesLegacy-specific gray literature—reports, white papers, etcEvidence-based legacy programs are includedTiming of search1990 to the presentLanguageEnglishExclusion criteriaPopulationClinicians and care team membersCaregivers only (studies that include both patient and caregiver perspectives will be included)Note: Population limitations may not be relevant for conceptual or humanities piecesConcept/study focusArticles discussing the legacy of another person after their death (secondary or tertiary legacy).Articles focusing on legacy as a component of bereavementStudy designsNone. Lower priority focus on intervention effectiveness and feasibility studiesAfter conducting a preliminary exploration of the academic literature, noting search terms associated with highly relevant articles, and consulting a university SME librarian, we have designed a preliminary search strategy. An initial search will be conducted in English-language literature from 1990 to the present with selected keywords to identify relevant articles and refine the search strategy using MEDLINE/PubMed, CINAHL, PsycInfo, SocialWork, AnthropologyPlus, Web of Science, ProQuest, and Embase databases. We have limited this time window on the guidance of an SME librarian to reflect substantial cultural changes in the United States in end-of-life care. After the search strategy has been finalized, piloted, and conducted, we will undertake a 2-part study selection process. In the first step, 2 independent reviewers will use an electronic abstract screening tool for abstract and full-text review to assess the eligibility of each article based on predetermined exclusion or inclusion criteria. Discrepancies regarding eligibility will be resolved by consensus or consultation with a third team member.After completing the abstract review, 2 team members will review the full text of articles identified as potentially relevant using the same dual approach, noting reasons for exclusion. Relevant study data will be extracted, collated, and charted to summarize the key findings related to the construct of legacy. To further seek completeness, we will examine the reference lists of highly relevant papers and hand search the gray literature for potentially relevant articles. We will describe the literature flow using the PRISMA  literature flow diagram ,37.Based on the preliminary table of charting elements adapted from Gilfoyle et al , we willFor each study included in the review, we will conduct a dual nonindependent review, in which one reviewer will abstract data, and a second reviewer will check for accuracy and completeness. We will use the data abstraction tool developed by the reviewers. A preliminary list of the data to be abstracted is shown in Publication detailsAuthorYears of data collectionYear of publicationCountry of originPublication typeWhether publication is open accessStudy characteristicsFunderResearch questionDisciplineAims/purposeMethodological designStudy population and demographics Disease stateDisease progressionSample size and response rateRecruitment approachStudy context Methods Intervention type (if applicable)PerspectiveFrom what perspective is research presented? FindingsDefinition of legacyWhat terms and keywords do the authors use to define legacy?Legacy concepts/constructsWhat concepts or constructs are included?Theoretical frameworksWhat theoretical/epistemological frameworks inform this study?Care contextWhat care context does the study examine?Treatment choicesHow is legacy considered in treatment decision-making?Material and social artifactsWhat items, values, or types of artifacts do people leave behind for the purposes of legacy?Social milieuWhat aspects of a person’s social milieu are discussed?Practical steps in creating a legacyHow is legacy discussed in terms of people’s labor?Legacy tensionWhat types of tension regarding legacy are discussed?How death relates to legacyWas type and manner of death discussed as impacting or contributing to legacy?Social personhoodHow is social personhood discussed in the context of legacy? Author conclusionsWhat recommendations are made by the author?Study limitations/applicabilityWhat are the limitations in study design, population, or approach that limit interpretation applicability for the scoping review?After abstracting data, the team will review the data and identify themes related to the research questions. We will report findings using a combination of tables and diagrammatic representations. Narrative summaries will accompany each result, describing how the results relate to the research questions, including any unexpected or particularly notable findings. We will comment on any gaps observed in the literature base, research needs, and implications for practice. We will synthesize the findings into the final conceptual model.As put forth by Levac et al , consultThis scoping review consists of reviewing and collecting data from publicly available materials and as such does not require ethics approval.This study will identify how people facing serious illness conceptualize legacy, and how their thinking about legacy impacts the choices they make about their medical treatments. We will describe our literature flow using the PRISMA flow diagram . We willThis study is funded by the National Cancer Institute. We began this scoping review in February 2022 and plan a manuscript submission in late 2022 or early 2023 to an indexed journal.This paper describes the protocol for a planned scoping literature review. Very little is known about the role of legacy in the treatment decisions of patients across the continuum of serious illness. In particular, no comprehensive conceptual model exists that would provide an understanding of how legacy is considered by people making decisions about their care during serious illness. This study will include a scoping review of major research databases to develop a conceptual model that can inform future studies and interventions that investigate the role of legacy in medical decision-making. This scoping review protocol adheres to Levac et al’s  guidelinThis scoping review contains important strengths. It is embedded in an established health research partnership and will include the involvement of coresearchers from multiple sites with diverse expertise in the analysis and interpretation stages. This scoping review includes multiple reviewers for all phases of identification and selection. This scoping review has a priority focus on historically underserved or vulnerable populations. This scoping review is limited to English-language articles published from 1990 to the present; translation of non-English language articles is not feasible for this review. This represents a potential limitation and may result in some missed articles. However, although the formal literature search is a limited time period, we intend to include seminal or highly relevant articles identified through hand searching. We also intend to prioritize the inclusion of research with participants who are non-English speakers.This study will be among the first to construct a conceptual model detailing how considerations of legacy impact medical decision-making for people facing or living with serious illness.