Chronic obstructive pulmonary disease (COPD) is a major global health problem and is predicted to become the third most common cause of death by 2020. Apart from the important preventive steps of smoking cessation, there are no other specific treatments for COPD that are as effective in reversing the condition, and therefore there is a need to understand the pathophysiological mechanisms that could lead to new therapeutic strategies. The development of experimental models will help to dissect these mechanisms at the cellular and molecular level. COPD is a disease characterized by progressive airflow obstruction of the peripheral airways, associated with lung inflammation, emphysema and mucus hypersecretion. Different approaches to mimic COPD have been developed but are limited in comparison to models of allergic asthma. COPD models usually do not mimic the major features of human COPD and are commonly based on the induction of COPD-like lesions in the lungs and airways using noxious inhalants such as tobacco smoke, nitrogen dioxide, or sulfur dioxide. Depending on the duration and intensity of exposure, these noxious stimuli induce signs of chronic inflammation and airway remodelling. Emphysema can be achieved by combining such exposure with instillation of tissue-degrading enzymes. Other approaches are based on genetically-targeted mice which develop COPD-like lesions with emphysema, and such mice provide deep insights into pathophysiological mechanisms. Future approaches should aim to mimic irreversible airflow obstruction, associated with cough and sputum production, with the possibility of inducing exacerbations. The global burden of disease studies point to an alarming increase in the prevalence of chronic obstructive pulmonary disease (COPD)  which isIn contrast to the large amount of experimental studies on allergic asthma and the detailed knowledge that exists on mediators of allergic airway inflammation ,6, much in vivo animal models to examine more closely pathogenesis, functional changes and the effects of new compounds or treatments. However, animal models have limitations since there is no spontaneous model, and models do not necessarily mimic the entire COPD phenotype. The best model remains chronic exposure to cigarette smoke, since this is the environmental toxic substance(s) that cause COPD in man. However, other substances are also implicated such as environmental pollution due to car exhaust fumes. The present review draws attention to specific aspects of functional and structural features of COPD that need to be realized when interpreting molecular mechanisms identified in animal models of COPD. It identifies important issues related to the ongoing experimental COPD research which may in the future provide optimized COPD diagnosis and treatment.Studying the molecular pathways in human subjects is restricted to the use of morphological and molecular assessment of lung tissues obtained at surgery or performing limited in vitro studies at one single point in time . There iBefore characterizing and discussing the different animal models of COPD which have been established so far, it is crucial to reflect that within COPD, different disease stages exist and that only some of them may be mimicked in animal models. The diagnosis of COPD largely relies on a history of exposure to noxious stimuli (mainly tobacco smoke) and abnormal lung function tests. Since COPD has a variable pathology and the molecular mechanisms are only understood to a minor extent, a simple disease definition has been difficult to establish. However, the diagnosis of COPD relies on the presence of persistent airflow obstruction in a cigarette smoker .A classification of disease severity into four stages has been proposed by the GOLD guidelines based primarily on FEV1 . The staThe presence of airflow obstruction which has a small reversible component, but which is largely irreversible is a major feature of COPD as indicated by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines . It is pIn addition to pulmonary alterations, other organ systems may be affected in COPD . SystemiAn important feature of COPD is the ongoing chronic inflammatory process in the airways as indicated by the current GOLD definition of COPD . There a1 and sputum neutrophilia is more prevalent in subjects with chronic cough and sputum production [Neutrophils play a prominent role in the pathophysiology of COPD as they release a multitude of mediators and tissue-degrading enzymes such as elastases which can orchestrate tissue destruction and chronic inflammation ,23. Neutoduction .The second major cell type involved in cellular mechanisms are macrophages . They caLymphocytes are also involved in cellular mechanisms underlying COPD ,35. IncrDifferent inflammatory cell types have also been characterized in airway tissues. Epithelial neutrophilia has been seen in proximal and distal airways of patients with COPD ,43. The On the basis of the different pathophysiological mechanisms illustrated in Fig. An imbalance between protease and antiprotease enzymes has been hypothesized with respect to the pathogenesis of emphysema . This coOxidative stress arising from inhaled noxious stimuli such as tobacco smoke or nitrogen dioxide may be important cause of the inflammation and tissue damage in COPD. This potential mechanism is supported by clinical reports of increased levels of oxidative stress indicators in exhaled breath condensates of COPD patients -55. AparMany mediators have been identified which may contribute to COPD pathogenesis . As in bA Th2 cytokine that has been proposed to be implicated in the pathophysiology of COPD is IL-13. It is also overexpressed and related to the pathogenesis of the asthmatic Th2 inflammation and airway remodelling process . The effParallel to protease-based and extracellular mediator-based concepts, altered intracellular pathways may also play a role in COPD. MAPK signalling pathways i.e. p38 and c-Jun N terminal kinase (JNK) ,77 seem Previous studies showed an association between latent adenoviral infection with expression of the adenoviral E1A gene and chronic obstructive pulmonary disease (COPD) ,84. It mSince only a minority of smokers (approximately 15 to 20%) develop symptoms and COPD is known to cluster in families, a genetic predisposition has been hypothesized. Many candidate genes have been assessed, but the data are often unclear and systematic studies are currently performed to identify disease-associated genes. Next to alpha1-antitrypsin deficiency, several candidate genes have been suggested to be linked to COPD induction. Genetic polymorphisms in matrix metalloproteinase genes MMP1, MMP9 and MMP12 may be important in the development of COPD. In this respect, polymorphisms in the MMP1 and MMP12 genes, but not MMP9, have been suggested to be related to smoking-related lung injury or are in a linkage disequilibrium with other causative polymorphisms -93. An aThere are three major experimental approaches to mimic COPD encompassing inhalation of noxious stimuli, tracheal instillation of tissue-degrading enzymes to induce emphysema-like lesions and gene-modifying techniques leading to a COPD-like phenotype Figure . These aA variety of animal species has been exposed to tobacco smoke. Next to guinea pigs, rabbits, and dogs, and also rats and mice have been used. Guinea pigs have been reported to be a very susceptible species. They develop COPD-like lesions and emphysema-like airspace enlargement within a few months of active tobacco smoke exposure . By contThe first species to be examined in detail for COPD-like lesions due to tobacco smoke exposure was the guinea pig . DiffereMice represent the most favoured laboratory animal species with regard to immune mechanisms since they offer the opportunity to manipulate gene expression. However, it is more difficult to assess lung function and mice tolerate at least two cigarettes daily for a year with minimal effects on body weight and carboxyhemoglobin levels. Mice differ considerably in respiratory tract functions and anatomy if compared to humans: they are obligate nose breathers, they have lower numbers of cilia, fewer Clara cells and a restriction of submucosal glands to the trachea. Next to a lower filter function for tobacco smoke, mice also do not have a cough reflex and many mediators such as histamine or tachykinins have different pharmacological effects. The development of emphysema-like lesions is strain-dependent: enlarged alveolar spaces and increased alveolar duct area are found after 3–6 months of tobacco smoke exposure in susceptible strains such as B6C3F1 mice . At thesRats are also often used for models of COPD. However, they appear to be relatively resistant to the induction of emphysema-like lesions. Using morphometry and histopathology to assess and compare emphysema development in mice and rats, significant differences were demonstrated : AnimalsRecent work on cigarette exposure in rats indicate that this model also achieves a degree of corticosteroid resistance that has been observed in patients with COPD ,104. ThuGenerally, tobacco smoke exposure may be used to generate COPD features such as emphysema and airway remodelling and chronic inflammation. Although the alterations still differ from the human situation and many involved mediators may have different functional effects especially in the murine respiratory tract, these models represent useful approaches to investigate cellular and molecular mechanisms underlying the development and progression of COPD. As a considerable strain-to-strain and species-to-species variation can be found in the models used so far, the selection of a strain needs to be done with great caution. Animal models of COPD still need to be precisely evaluated as to whether they mimic features of human COPD, and their limitations must be appreciated. Findings obtained from these models may provide significant advances in terms of understanding novel mechanisms involved in COPD.2) is a gaseous irritant which can be used to induce COPD-like lesions in animal models. With daily exposure to high concentrations of SO2, chronic injury and repair of epithelial cells can be observed in species such as rat or guinea pig. The exposure to high-levels of this gas ranging from 200 to 700 ppm for 4 to 8 weeks has been demonstrated to lead to neutrophilic inflammation, morphological signs of mucus production and mucus cell metaplasia and damage of ciliated epithelial cells in rats [2 also leads to loss of cilia and exfoliation of ciliated cells as demonstrated in SO2-exposed dogs using transmission electron microscopy [in vivo and in vitro [Sulfur dioxide  is a another gas that may lead to COPD-like lesions depending on concentration, duration of exposure, and species genetic susceptibility [Nitrogen dioxide  and resistant C3H/HeJ (C3) mice, as well as F1, F2, and backcross (BX) populations derived from them, were acutely exposed to 15 parts per million NO2 for 3 h to determine differences [2 closely resembled C3 mice. Ranges of cellular responses to NO2 in B6:BX and intercross progeny were reported to overlap both progenitor and mean responses of both populations were intermediate to progenitors. Therefore, there were likely two major unlinked genes that account for differential susceptibility to acute NO2 exposure [2 exposure was recently established leading to signs of pulmonary inflammation and progressive development of airflow obstruction [There is also a significant mode of inheritance of susceptibility to NOferences . Signifiexposure . Based otruction .The administration of oxidants such as ozone also causes significant lung injury with some features related to inflammatory changes occurring in human COPD  and thisFurther animal models focus on the exposure to ultrafine particles, silica and coal dust ,139. UltExposure to diesel exhaust particles (DEP) may also lead to chronic airway inflammation in laboratory animals as it was shown to have affect various respiratory conditions including exacerbations of COPD, asthma, and respiratory tract infections . Both thA further toxin is cadmium chloride, a constituent of cigarette smoke. Administration of this substance also leads to alterations in pulmonary integrity with primarily interstitial fibrosis with tethering open of airspaces . A combiEmphysema-like lesions can also be achieved by intrapulmonary challenge with tissue-degrading enzymes and other compounds  Figure . ProteinAmong the different emphysema models, elastase-induced emphysema has also been characterized to be accompanied by pulmonary function abnormalities, hypoxemia, and secretory cell metaplasia which represent characteristic features of human COPD. Recent studies suggested that exogenous retinoic acid can induce alveolar regeneration in models of elastase-induced experimental emphysema  and thatThe mechanisms of emphysema induction by intratracheal administration of elastase encompass an initial loss of collagen and elastin. Later, glycosaminoglycan and elastin levels normalize again but collagen levels are enhanced. The extracellular matrix remains distorted in structure and diminished with resulting abnormal airway architecture . The enlIn general, intrapulmonary administration of tissue-degrading enzymes represents a useful tool especially when focusing on mechanisms to repair emphysematic features. However, the lack of proximity to the human situation needs to be realized since the mechanisms of emphysema induction are clearly not related to the human situation. An advantage of proteinase-based models is the simple exposure protocol with a single intratracheal administration leading to significant and rapid changes. However, extrapolating these findings to slowly developing features of smoking induced human COPD is very difficult since a large number of mediators may not be involved in the rapid proteinase approach. Therefore, these models may not encompass important features of human COPD which may be more closely mimicked by inhalation exposures and it is clear that tissue-degrading enzyme models always represent the picture of an "induced pathogenesis".The genetic predisposition to environmental disease is an important area of research and a number of animal strains prone to develop COPD-like lesions have been characterized -162  gene  and in mA further mechanism to induce emphysema-like lesions is to expose developmentally normal genetically-modified animals to exogenous noxious stimuli such as tobacco smoke. This also allows identifying potential molecular mechanisms involved in the pathogenesis of COPD. Using macrophage elastase (MMP-12) gene-depletion studies it was shown that in contrast to wild type mice, the lung structure of MMP-12 gene-depleted animals remains normal after long term exposure to cigarette smoke . These aIn summary, gene-targeting techniques display very useful tools to examine potential molecular mechanisms underlying human COPD. In combination with inhalation protocols they may identify important protective or pro-inflammatory mediators of the disease.Various other agents have also been characterized to induce airway inflammation injury. In this respect, administration of toxins such as endotoxin leads to a recruitment of neutrophils and macrophage activation with concomitant airspace enlargement ,178.Non-inflammatory emphysema-like lesions may also be accomplished by intravascular administration of a vascular endothelial cell growth factor receptor-2 (VEGFR-2) blocker . VEGF isIn contrast to the variable pathology and different stages of severity in human COPD, currently available animal models are restricted to mimicking a limited amount of characteristic features of COPD. Animal models need to be precisely evaluated based on whether they agree with features of human COPD in order to advance the understanding of mechanisms in human COPD.Based on inhalative exposure to noxious stimuli such as cigarette smoke, the administration of tissue-degrading enzymes or gene-targeting techniques, a number of experimental approaches to mimic acute and chronic features of COPD have been established in the past years. Due to the complexity of the disease, and species-specific differences they are all limited concerning their clinical significance.While the induction of the COPD lesions by tissue-degrading enzymes may appear artificial in many cases, it does not mean that these models are not valuable because they can be used to study many aspects of pulmonary pathophysiology of end-stage emphysema. Cellular mechanisms can be studied efficiently and underlying molecular mechanisms and potential therapeutic approaches can be revealed if the data is extrapolated cautiously.Combined models of inhalative exposure, proteinase-based tissue degradation to produce emphysema and gene-targeting techniques may provide models of COPD which encompass more features of the disease. However, one cannot assume that reproducing COPD with a high degree of fidelity in the animal necessarily means that the model simulates the human condition. In fact, a model that only produces a single pathologic COPD feature may be more useful as long as it produces this feature via a relevant mechanism that allows exploratory research. By contrast, a model producing all kinds of COPD features via irrelevant mechanisms may be less useful. In this respect, validation of models as being relevant is an extremely important issue in the early steps of model development. Animal models should not only assess histopathological features but also attempt to focus on functional features of human COPD such as airflow limitation, mucus hypersecretion, chronic cough and exacerbations, and also on pharmacological features such as corticosteroid resistance or diminished β-adrenergic bronchodilator responses. In conclusion, there are many benefits that can accrue from the development of animal models of COPD, most important of which is understanding of mechanisms and development of specific drugs for COPD.


Recent years have seen a proliferation of do-it-yourself biology (DIYbio) initiatives, consisting of people undertaking a range of bioscience activities outside traditional research environments. DIYbio initiatives, while diverse, exist at the fringes of institutionalised science, which enables them to advance different promissory visions about what science, especially bioscience, could or should become in the future, including how it should be governed. These visions reconfigure conventional delineations of science in politically and normatively loaded ways that can simultaneously reaffirm, contest, and shift the traditional epistemic foundations of science. They put forth alternative science futures in ways that highlight the performative force of promissory visions in shaping not only mainstream but also fringe science activity. DIYbio offers a fruitful lens for understanding how science is currently being reconfigured by unconventional actors to encompass new meanings and domains. It offers a different angle on the wider sociology of expectations engagement with the future as an analytical object, by showing how the future of science is constructed and managed from the fringe. Yet, DIYbio initiatives' promissory visions are also embedded within neoliberal ideals of productive and entrepreneurial citizens, highlighting how the wider socio-economic context constrains the alternative futures manufactured by these initiatives. In recent decades, there has been growing interest and investment in public engagement with science, and professional scientific institutions and research funding bodies have been progressively promoting public involvement as a key part of scientific research. While citizens and publics and so-called lay people have conventionally been positioned as recipients of knowledge and services provided by science professionals, scientific institutions and funding bodies now advocate multilateral engagement, involvement and participation approaches between scientists and citizens . People involved in them generally organise in digital spaces and community laboratories configure science, including how it should be governed, in politically and normatively loaded ways that simultaneously reaffirm, contest, and shift the traditional epistemic foundations of science. While DIYbio initiatives are diverse, their location at the fringes of institutionalised science means that they are generally not strictly bound by professional and institutional scientific conduct norms and standards, enabling them to imagine and practice science differently. They foster alternative promissory futures that scholars should understand in the context of broader socio-economic developments, including the increasing promotion of neoliberal and entrepreneurial citizenship discourses.Promissory visions around DIYbio can offer a different angle on the wider sociology of expectations literature by showing how people outside professional scientific institutions manufacture alternative futures at the fringes of institutionally legitimated science. These futures involve new actors and heterogenous science activities that intentionally move beyond the conventional boundaries of science, highlighting promissory visions’ performative forces in shaping fringe and mainstream science activity. They also highlight the importance of broadening STS scholars’ engagement with the future as an analytical object by looking at how the future is constructed and managed not only by conventional actors at the centre of scientific innovation but also by new unconventional actors located at the margins. In so doing, this paper sheds new light on the shifting and plural meanings of science in the present context in which citizens and publics are increasingly positioned as active contributors to science, but in ways conditioned by governments’ overarching drive to producing active, entrepreneurial, and self-governing citizens.DIYbio is a part of broader contemporary DIY activity, in which people are engaged in a diverse variety of do-it-yourself practices, from making electronics to producing their own food  science’s exclusion of outsiders and alternative kinds of expertise. This sphere has conventionally suppressed epistemological differences and knowledges from the ground, while DIY bio contributes to the expansion of science to include alternative practices and ways of knowing , and often concerning specific emerging technologies or new scientific fields , often create the website content, meaning that it may not reflect members’ general views. Yet, websites are an important way that groups portray themselves to the world in the digital age. The website analysis focused on DIYbio initiatives’ ‘about us’ descriptions, and mission, value, ethics, safety and security statements. These statements are generally formulated to delineate a collective vision that can be used to communicate central beliefs about a group’s distinctive attributes to people both inside and outside the group, indicate expected behaviour standards, and provide a value-based future direction  digital networks. The rest are disproportionately based in Anglophone countries, probably reflecting the exclusion of initiatives without English language websites and the disproportionate representation of white, male and urban people in DIYbio  were conducted to identify further initiatives. Keyword searches retrieved between 12 and 24 pages of search results. Building on a strategy developed by others ScienceBLR public laboratory in Bengaluru, India, initiatives in LMICs, including start-ups and incubators, articulate visions of science directed towards destabilising global power and resource disparities. For example, the incubator Kumasi Hive  in GhanaThese initiatives advance visions around democratised access to science, educating publics, and facilitating non-professionals’ entry into science in ways similar to High-Income Country (HIC) initiatives like Genspace and BioQuisitive. Yet, their key aims centre local community needs – contextualised by socio-economic disadvantage in relation to global inequities in bioscience – as drivers of DIYbio. Initiatives like Kumasi Hive, Hive Biolab, and Connector Ciencia, but also Biomakers lab in Peru, for example, manufacture promissory visions geared towards addressing these inequities, including by fostering not just the development of individual tools but broader bioeconomies.In the context of global economic resource and technoscientific capacity disparities, HICs principally drive the professional and commercial development of new bioscience. Commercially developed biotechnology is often patented and priced in ways inaccessible for low-resource populations, and the direction and distribution of research investment are not properly aligned with global demands. At the same time, regions with the highest disease burdens also have the lowest proportion of biomedical workers WHO, . DIYbio inventors, explorers, daredevils and yes, human guinea pigs. We are true believers and virulent skeptics. We are the crazy people that throw ourselves off of moving band-wagons. … Some will say we’re cheats, line-cutters and outlaws but we just like to trash rule books. The world is already so full of ‘should’ we’re going to fill it with ‘could’. … We have a vision of a planet infected by curiosity and we want it NOW.While Hackstronauts  as a lens to explore the changing meaning of science in the current context, in which people can practice science – including bioscience – outside institutional science in unprecedented ways. Furthermore, it investigated how such practices promote discourses of neoliberal citizenship. Drawing on thematic analysis of DIYbio initiatives’ websites, it focused on DIYbio initiatives’ promissory visions, asking how science is conceptualised and what political and normative visions and contextual factors underlie these conceptualisations.The sociology of expectations literature has documented how new technoscientific developments reflect future-oriented expectations that articulate the future ‘promise’ of science. These expectations have been theorised through the anticipatory concept of ‘visions,’ which incorporate valuations of the kinds of futures various actors see as desirable (or undesirable). These manufactured visions tend to be contested and performative. The envisioned and expected are pluralistic, and they also shape the direction of technoscientific activities in the present. Yet, much of the existing literature has focused on analysing the expectations and visions promoted by professional actors in the technoscientific mainstream. This paper builds on and extends these areas of the sociology of expectations by showing how alterative anticipatory visions of desirable futures are manufactured and performatively enacted by unconventional actors at the fringes of mainstream science.While highly diverse, DIYbio initiatives advance promissory visions expressing desired futures of what science could become, which shape the activities participants undertake, and foreground how science is delineated and stretched to encompass new domains. Most initiatives envision science as a democratised endeavour and aim to widen participation but in ways supporting institutionalised definitions of (participatory) public involvement in science, fostered through links with institutionalised science. In Low- and Middle-Income Countries, this is supplemented with visions to dismantle global inequities around bioscience and enable local communities in under-resourced settings to do science themselves to address local priorities. Some High-Income Country DIYbio initiatives also envision radically alternative futures, advancing conceptualisations and practices that re-erect the epistemic bases of their activities beyond institutionally legitimated scientific procedures to advance political goals challenging conventional power hierarchies. Despite their diversity, DIYbio initiatives’ promissory visions offer an alternative to mainstream science, providing a different basis and sometimes alternate foundation for science and stretching its boundaries to include unconventional actors, practices, and knowledges.These movements also shape how the governance of science, including ethics and safety, is conceptualised. Some DIYbio initiatives, most notably the DIYbio.org network, have developed codified ethics and safety standards that partially reflect institutionalised research governance frameworks, including collaborations with bioethics and biosafety experts, lending credibility for viewing their activities as ethical and safe. Others promote alternative models of self-governance and bottom-up oversight that re-configure governance as a DIY endeavour, including in terms of normative commitments. Even codified DIYbio ethics express commitments to bottom-up oversight. This is part of the construction of promissory futures that re-configure the normative basis of science, framing governance as a bottom-up, community-driven effort that moves beyond and destabilises not only mainstream governance frameworks but also the meaning of what ethical and safe science entails.All DIYbio initiatives included in this study represent science as political and normatively driven. They intentionally blur professional versus community spaces, experts versus amateurs, and scientists versus citizens in ways that offer visions different from the currently hegemonic conceptualisations of what science is or should entail. It is because of their fringe position in relation to institutionally legitimated science that DIYbio initiatives can blur these boundaries and advance alternative visions, and in so doing, re-imagine what science could be. Different DIYbio initiatives have different relationships with and ideas about the role of mainstream conceptualisations of science within DIYbio. While some align themselves with institutional science and credentialed experts, others explicitly reject them and re-frame epistemic authority as arising from elsewhere, such as embodied experience and alterative knowledge practices. DIYbio can thus affirm institutionally legitimated notions of science or shift or even radically undermine them. Yet, they all actively re-envision science, promoting futures with new, unconventional science practitioners, heterogenous activities, and alternative normative directions.Looking at how the fringes of mainstream science envisioned and performatively enacted the future of science enriches the existing sociology of expectations scholarship, which has focused on the technoscientific mainstream. In particular, it expands theorisation of the anticipatory concept of ‘visions,’ and the role of visions in technoscientific developments in ways that are fit to address wider socio-scientific and governance shifts in the present context. DIYbio initiatives’ promissory visions performatively shape the emerging DIYbio sphere, but these visions also shed light on the context in which science is changing to accommodate more active and participatory roles for publics and citizens. Systemic shifts towards multilateral public engagement approaches and the promotion of participatory or DIY citizenship are opening space for new and unconventional re-envisionings of science performed outside the mainstream. While the wider implications of these re-envisionings remain to be seen, they highlight how the futures of science are constructed and contested not only at the centre of scientific innovation but also at the margins by fringe actors who are imagining and performing science in alternative ways. These alternatives exemplify how the meaning of science and who can practice it are currently being re-configured by both conventional and unconventional actors, and they highlight the central role of promissory visions in shaping these re-configurations. In so doing, they also show the importance of broader engagement with the future as an analytical object at the fringes of science.It is also important to direct attention to the wider socio-economic context that is shaping the construction and manifestations of DIYbio initiatives’ promissory visions, and the configurations of science this context promotes. When DIYbio groups frame science as a DIY activity and promote futures where citizens take science into their own hands and govern themselves, they lend support to neoliberal ideals of the entrepreneurial citizen who takes responsibility for their life rather than relying on public infrastructures and government systems to provide and govern for them. This neoliberal framework includes the promotion of citizens’ un-paid labour to facilitate innovation, but the extent to which one can occupy the entrepreneurial citizen position, including the ability to engage in DIYbio, is unevenly distributed due to existing structural inequalities. Indeed, promissory visions of science as a DIY activity are advanced in ways that harness the entrepreneurial, self-governing citizen subject position as part of the future promise of DIYbio. Taking on this subject position relies on individuals being willing and able (including having the requisite spare time and funds) to perform unpaid scientific labour. That DIYbio practitioners today are disproportionately highly educated urban men highlights how the ability to occupy the position of DIYbio practitioner is socially and politically conditioned by questions around who shares, and can engage in, the promise of DIYbio.


In this paper, an efficient and robust methodology to simulate saturated soils subjected to low-medium frequency dynamic loadings under large deformation regime is presented. The coupling between solid and fluid phases is solved through the dynamic reduced formulation  Modeling saturated soils under dynamic loads is of crucial importance when researchers deal with fast phenomena, like landslide propagation. Moreover, the more catastrophic 3D problems should also include large deformations. Despite the importance of both aspects, dynamic saturated problems and large deformations, research focused on these topics at once is limited. One of the main reasons why there is a lack of research in this paramount issue of geomechanics might be that a powerful and useful methodology requires complex hydro-mechanical models including inertial terms coupled with hyper-elastoplastic constitutive models where the deformation gradient acts as strain measure. Moreover, as analytical solutions can only be achieved for few idealized configurations, cutting edge numerical techniques must be considered to attain accurate and robust solutions in real-world problems.The fluid saturated phenomenon has been widely studied in the numerical geotechnical field, where a big range of solutions can be found regarding the formulation considered for the coupled problem (either simplified or complete), the assumptions made with or without accelerations and the numerical techniques used to solve the equations, both in the spatial (mesh or meshfree-based techniques) and temporal dimension (explicit or implicit schemes).w, which has been proved to be successful ),


To support evidence-informed decision-making, we created an evidence gap map to characterise the evidence base on the effectiveness of interventions in improving routine childhood immunisation outcomes in low-income and middle-income countries (LMICs).We developed an intervention–outcome matrix with 38 interventions and 43 outcomes. We searched academic databases and grey literature sources for relevant impact evaluations (IEs) and systematic reviews (SRs). Search results were screened on title/abstract. Those included on title/abstract were retrieved for full review. Studies meeting the eligibility criteria were included and data were extracted for each included study. All screening and data extraction was done by two independent reviewers. We analysed these data to identify trends in the geographic distribution of evidence, the concentration of evidence across intervention and outcome categories, and attention to vulnerable populations in the literature.We identified 309 studies, comprising 226 completed IEs, 58 completed SRs, 24 ongoing IEs and 1 ongoing SR. Evidence from IEs is heavily concentrated in a handful of countries in sub-Saharan Africa and South Asia. Among interventions, the most frequently evaluated are those related to education and material incentives for caregivers or health workers. There are gaps in the study of non-material incentives and outreach to vulnerable populations. Among outcomes, those related to vaccine coverage and health are well covered. However, evidence on intermediate outcomes related to health system capacity or barriers faced by caregivers is much more limited.There is valuable evidence available to decision-makers for use in identifying and deploying effective strategies to increase routine immunisation in LMICs. However, additional research is needed to address gaps in the evidence base. We adopt a rigorous and systematic approach to literature mapping.We map a broad swath of the literature on routine childhood immunisation in low-income and middle-income countries.interactive online map.Our analysis is complemented by an Coverage of intermediate outcomes  in this evidence gap map may be incomplete if studies on these outcomes do not target routine vaccination specifically.Immunisation remains one of the most cost-effective interventions to prevent and control life-threatening infectious diseases. A 2016 study found that for every US dollar invested in vaccination in the world’s 94 lowest-income countries, US$16 can be saved in healthcare costs, lost wages and lost productivity due to illness and death.4In the last few decades, interventions have emerged specifically aimed at strengthening national-level immunisation programmes by addressing delivery constraints. However, even with strengthened routine immunisation programmes, marginalised and vulnerable communities are at risk of being overlooked. Thus, a number of international and national policy frameworks are increasingly focusing on multipronged approaches that provide contextualised solutions to address constraints in delivery of immunisation services as well as behavioural, social and practical barriers faced by caregivers.This study presents an evidence gap map (EGM) of impact evaluations (IEs) and systematic reviews (SRs) measuring the effects of interventions on outcomes related to routine child immunisation. An EGM aims to establish what is known and unknown about an evidence base in a thematic area.EGMs highlight both absolute gaps (an empty cell in the framework), which could be filled with new IEs, and synthesis gaps (multiple IEs but no SRs), which could be filled with evidence synthesis. Furthermore, they can be used to highlight potentially over-researched areas, where the effects of a particular intervention have been evaluated against a range of outcomes (or vice versa) and where additional studies may not be necessary.The objectives of this EGM are to:Present a framework of types of interventions and outcomes related to routine child immunisation in LMICs.Using this framework, map available SRs and IEs by their interventions and outcomes, with a summary of findings provided in this paper.Assess the quality of the SRs falling under the framework.Drawing on the literature on routine child immunisation in LMICs, we developed a theory of change in which we identified key factors—from the perspectives of caregivers and communities, vaccinators, health systems and beyond—that influence whether children receive the full course of routine vaccinations.The theory of change suggests how interventions may be oriented to address afore-mentioned key factors and lead to greater immunisation coverage and better health outcomes . It suggWe included IEs and SRs evaluating the effectiveness of interventions to increase immunisation of children under five in LMICs. Interventions did not have to be expressly designed for the purpose of increasing immunisation rates; rather, we searched for all IEs and SRs that provided evidence on the impact of any intervention on routine immunisation coverage, morbidity or mortality from vaccine-preventable diseases, or any intermediate outcome that precedes them in the theoretical causal chain. There were no restrictions by publication date, publication type/status or language.The EGM includes experimental and quasiexperimental IEs that estimate the causal impact of an intervention, as compared with usual practice or an alternative treatment, by establishing a counterfactual.9To develop the intervention–outcome framework for this EGM, we developed an initial matrix by drawing on the research literature on determinants and constraints related to vaccination in LMICs,This resulted in a framework with 38 unique interventions and 43 unique outcomes. These are each grouped together in a three-level hierarchy of categories. The interventions are grouped broadly by who or what is targeted: caregivers, the health system, non-caregiver community members, the community as a whole or policies and institutions beyond the health system. Our outcome taxonomy has three levels. At the highest level, we divide outcomes into three broad types: (a) those related to behavioural, social and practical barriers faced by caregivers and communities, (b) those related to delivery of vaccination services by formal and informal components of the health system and (c) those related to vaccination coverage/timeliness and health outcomes . Within each of these types are a series of mid-level (broad) categories, and within each of these are specific outcome categories. The inclusion of intermediate outcomes in (a) and (b) allows us to assess the extent to which the evidence base contains insights not only on the effectiveness of interventions in improving vaccination coverage/timeliness and health outcomes but also the effectiveness of interventions in improving their important causal antecedents. The outcomes in category (c) are further divided into more specific categories corresponding to various prerequisites for universal vaccination coverage. The framework also includes seven ‘cross-cutting themes’ that capture possible subgroup analyses  as well as other key features of interest . A sketch of the matrix, showing the first-level and second-level intervention and outcome categories, appears in 10.1136/bmjopen-2021-058258.supp1Supplementary dataMany studies evaluated interventions that included multiple components  and sensitisation meetings with women). We determined that the best approach was to capture all major intervention components for each study. That is, some studies have multiple intervention codes applied to them. In this way, the EGM can be considered a map of ‘instances of evidence’ rather than a map of studies. A study provides an ‘instance of evidence’ when it provides evidence about the impact of a particular type of activity on a particular outcome. Because many studies assess multiple interventions and/or multiple outcomes, many studies provide multiple instances of evidence. While mapping intervention components separately has limitations (see Limitations section below), it is well suited to a literature like that covered in this EGM, where multicomponent interventions are common, but there are few ‘standard packages’ of intervention components that are frequently implemented and evaluated together. This approach also has the advantage of allowing users of the map to easily identify studies that evaluate particular intervention components of interest.This EGM employed systematic methods for search, screening and data extraction, following International Initiative for Impact Evaluation recommended guidelines for EGMs.All search results were screened on title/abstract by a team of trained reviewers. Two reviewers independently screened each abstract. Studies included at the title/abstract level were retrieved for full review. Full texts were also independently screened by two reviewers. All screening disagreements were resolved through discussion.Data extraction was conducted independently by two trained coders using a standard template . For eacWhen our search identified multiple publications resulting from the same study , we counted these as a single study and data extraction for each study drew on all the publications identified for that study.When studies evaluated interventions with multiple components, we coded each intervention separately. While this approach captures important detail about the intervention activities that have been included in IEs, it can also overstate the apparent amount of evidence by ‘double-counting’ studies with multicomponent interventions. Hence, we also conducted an analysis with all multicomponent studies grouped into a single ‘multicomponent’ category, rather than having each component coded individually.For SRs, we conducted critical appraisals using a standardised tool for assessing the quality and systematicity of each review’s search, screening, data extraction and analysis methods . Based oAs the unit of analysis for this EGM is research studies rather than human subjects, there was not a need to involve individual patients. However, to ensure the relevance of our research to a broad array of stakeholders, we engaged an advisory group comprising immunisation experts from the research, practitioner and policy-maker domains. This group advised on the development of our framework, search strategy, data analysis and dissemination plans.A total of 85 countries are represented among the IEs included in the EGM. The regions most commonly represented are sub-Saharan Africa (95 IEs) and South Asia (75 IEs). There is comparatively little evidence from Europe and Central Asia (five IEs) or the Middle East and North Africa (three IEs), with somewhat greater numbers in the East Asia/Pacific and Latin America/Caribbean regions. India is by far the most represented country with 45 IEs. Other South Asian countries are also well represented, including Pakistan (12 IEs) and Bangladesh (9 IEs). Evidence is fairly well-distributed across sub-Saharan Africa, though with some notable gaps. Nigeria is the most represented country with 14 IEs, followed by Kenya (12 IEs), Rwanda (6 IEs) and Ethiopia (7 IEs).The intervention type most commonly evaluated is caregiver incentives and motivation, with 79 IEs and 35 SRs  Because yields nThe most commonly examined specific interventions are material/monetary incentives for caregivers , health system strategic planning  and written or pictorial messages for caregivers , which includes SMS reminders or motivational messages. There is comparatively little work on non-material incentives for caregivers , which includes, for example, community recognition as an incentive to vaccinate. Among interventions to motivate HWs, pay-for-performance schemes are by far the most commonly evaluated .Several evidence gaps are evident. Apart from monetary incentives and pay-for-performance schemes, there is very little evidence on incentives, motivation and informational messages for HWs. There are also significant gaps in outreach to migrant populations  and campaigns to vaccinate refugee populations (no IEs or SRs). We did not identify any IEs or SRs with interventions framed specifically as outreach to vaccine-hesitant groups, although there is some evidence on outreach to vulnerable populations , which may overlap with vaccine-hesitant groups to some extent. Cold chain infrastructure improvements present another notable gap, with only two IEs and one low-confidence SR evaluating such interventions. There is a potential synthesis gap with respect to community HW training and education, for which there are 22 IEs but no medium-confidence or high-confidence SRs.Of the 226 IEs in our EGM, 87 evaluated multicomponent interventions . We findResources and financing in this review met our methodological inclusion criteria). A potential synthesis gap exists on community HW supply and capacity, for which we identified seven IEs but no SRs.By far, the most commonly measured outcome categories fall under vaccination coverage, with 210 IEs and 52 SRs examining 1 of these outcomes . Health Regarding outcomes related to behavioural, social and practical barriers faced by caregivers and communities, some outcome categories are relatively well studied, while others have very little evidence. We identified 18 IEs and 8 SRs that considered caregivers’ attitudes about immunisation. The practical factors that influence caregivers’ opportunities to vaccinate  are also comparatively well studied, with 19 IEs and 5 SRs . In contrast, few studies examine the social processes affecting caregivers’ vaccination decisions  or their readiness to vaccinate .Only two specific outcome categories on the caregiver side of our framework were examined in more than 10 studies: caregivers’ knowledge about immunisation  and retention of vaccination cards  . EvidencRelatively little evidence examines specific outcomes related to delivery of immunisation services . The twoVaccination coverage and child health outcomes are fairly well studied and there are limited evidence gaps or synthesis gaps . One gapOur map identified much more evidence on vaccination coverage than on downstream health outcomes. This pattern likely appears in our map because we only included studies measuring morbidity or mortality if they also measured vaccination coverage—that is, if they provided data that could be used to assess whether the intervention affected morbidity and mortality via immunisation coverage, as opposed to other changes produced by the intervention.Commonly examined interventions such as caregiver incentives and motivation and health system governance, policies and financing are frequently evaluated for their effect on vaccination coverage outcomes. In comparison, most interventions have occasionally been evaluated for their effects of intermediate outcomes that precede coverage in the theoretical chain: behavioural, social and practical barriers faced by caregivers and communities or the health system’s capacity to deliver vaccination services. Some exceptions are (1) sustained sensitisation and education campaigns, which are frequently evaluated for their effect on knowledge of immunisation and (2) formal HW training and education interventions, which have been evaluated for their effects on HW motivation and capacity.We examined included studies for the presence of evidence about themes that cut across our intervention and outcome framework. Many of these themes affect whether the study provides evidence about the effects of an intervention on particular vulnerable populations, either via subgroup analysis or by evaluating an intervention specifically targeted to that population.Evidence patterns are quite similar across equity themes, with attention to each of these themes being relatively rare in IEs . The mosWe recorded whether included studies provided any sort of information about the costs of the intervention, including any form of cost-effectiveness or cost–benefit analysis. Including such cost information is relatively rare: only 37 IEs (16%) and 9 SRs (15%) provide any such information.About two-thirds of the 58 included reviews (39 SRs) received ‘low’ confidence ratings, with the remainder split roughly equally between ‘medium’ (9 SRs) and ‘high’ (10 SRs) confidence ratings.Most EGMs serve two primary purposes.Reflecting the first purpose, this map can serve as a tool for policy-makers and practitioners working in the routine immunisation space to find rigorous evidence to inform decisions about which programmes to implement and how to implement them. High-quality syntheses of rigorous evidence are often the best sources of information on the effectiveness of interventions available to policy-makers and practitioners. Therefore, we recommend consulting the high-confidence syntheses identified in this EGM to inform the selection, design and delivery of interventions to improve immunisation outcomes  behavioural, social and practical barriers faced by caregivers or (b) outcomes influencing the delivery of vaccination services such as the supply and capacity of formal HWs, supply chain management and the use of immunisation data in monitoring and planning. There is likely additional evidence on these intermediate outcomes, but our EGM suggests that it is relatively rare for rigorous quantitative studies to assess them in the specific context of promoting vaccination coverage.In general, our EGM did not identify any glaring synthesis gaps in the form of large clusters of IEs on similar topics but no medium-confidence or high-confidence SRs synthesising the results of these evaluations. However, we note that there are 44 IEs on health provider incentives and motivation interventions, but only one high-confidence SR, which is now nearly a decade old.Among SRs in our sample, the majority (67%) received a confidence rating of ‘low’ based on their methods. The SRs in our sample frequently lacked comprehensive search strategies and appropriate reporting of evidence, particularly with respect to the risk of bias of included primary studies . RecogniOur approach to coding multicomponent interventions presents some limitations. First, it risks overstating the volume of available evidence because the same study can appear in multiple rows in the map. Second, it can potentially distort theories of change. This is because, from looking at the map, it can appear that there is rigorous evidence about the effect of an intervention on an outcome, whereas in actuality there is only evidence about how that intervention affects the outcome as a component in a multicomponent intervention. To address this limitation, we provided an alternative analysis wherein all multicomponent interventions are classified under a single ‘multicomponent’ category .Furthermore, it should be emphasised that our search strategy might have missed studies focused on intermediate outcomes, if assessing impact on vaccination-related outcomes was not a central component of the study. Therefore, these data should not be interpreted as showing, for example, that there is virtually no evidence about how to strengthen capacity among health service administrators. Rather, our EGM suggests that this outcome is rarely considered in the context of vaccination specifically.Our identification of evidence gaps can provide direction for researchers and funders of research about high-priority areas for future investigation. The most glaring gap concerns intermediate outcomes on the capacity of the health system to deliver vaccination services, and on behavioural, social and practical barriers faced by caregivers. As noted above, our EGM results do not necessarily suggest an absolute dearth of evidence on health system strengthening. Rather, we find a lack of specific evidence tying health system capacity to the delivery of vaccination services. Thus, going forward researchers may wish to consider assessing the extent to which improvements in health system capacity lead to improvements in immunisation coverage, by including both as outcomes in evaluations. Specific areas requiring additional attention include: caregivers’ attitudes about health providers, the social and practical factors influencing caregivers’ decisions about vaccination and their access to vaccination services, the supply and capacity of formal HWs and administrators responsible for delivering vaccination services, use of data in monitoring and improving vaccination services and coverage of IPV.Future research should pay greater attention to equity in immunisation studies—as emphasised in WHO’s Immunization Agenda 2030High-quality syntheses of rigorous evidence are often the best sources of information available to policy-makers and practitioners on the effectiveness of interventions. Therefore, we recommend consulting the high-confidence syntheses identified in this EGM to inform the selection, design and delivery of interventions to improve immunisation outcomes , one can consult low-confidence SRs (with appropriate caution) and individual IEs, although it is important not to place too much weight on any individual study. For those deciding to launch an intervention where relevant IE evidence is lacking, we suggest considering whether incorporating an IE of the programme would be feasible.


Non-perennial rivers and streams - those that periodically cease flowing - are critical components of aquatic systems and comprise over half of global river and stream systems. We argue for coordinated, collaborative, standardized, and open efforts to understand their unique biogeochemical behaviour, which is becoming ever more pressing due to pronounced shifts between wet and dry as the climate changes. Rivers and streams are increasingly drying with climate change and biogeochemical impacts may be important. In this comment the authors discuss the challenges to the biogeochemistry of non-perennial rivers and streams, and what can be done to tackle them. These drying rivers are colloquially referred to as non-perennial or intermittent rivers. Such non-perennial systems are sites of dynamic biogeochemical processes and microbial communities as their wetness states shift3. Biogeochemistry ultimately determines the quality of water, which determines what water can be used by humans for drinking water, recreation, and agriculture. Non-perennial rivers transport considerable amounts of sediment and nutrients when flow re-activates, which can significantly impact downstream water quality and ecosystem processes 4. For example, sediment transport is a natural process of river networks, but excess nutrients bound to sediment can decrease water quality  technology are enabling the construction of low cost gages, while high resolution digital elevation models and planned satellite data products will decrease the need for ground truthing sensor data, reducing labor time. The benefits from increased investment in river gages will be amplified by integrating multi-scale observations of water quality and quantity using new technological advances like remote sensing  and increasingly affordable distributed in situ sensor networks  that allow us to gain a higher resolution understanding of longitudinal dynamics within and across river networks12. Additional data collection efforts should adopt open, community-driven, collaborative and standardized operating procedures for the type, frequency, and duration of data collected so as to promote future synthesis.The first major barrier is the biogeochemical and associated microbiome data are even more limited than the hydrologic data from non-perennial rivers. This barrier arises because these data are rarely collected alongside hydrology data at existing gages. Biogeochemical data such as dissolved oxygen, nutrients , or sediment loads are orders of magnitude more limited than already limited hydrological data. Despite their recognized importance, microbial community data are almost entirely constrained to individual studies. Monitoring data largely do not exist, save for scarce public health monitoring of pathogenic taxa. Much of what is known about microbial communities in non-perennial waters is inferred based on environmental or functional  measurements. Incorporating microbial data alongside biogeochemical and hydrologic measurements will yield important insights. The solution is again clear: gages with both hydrologic and biogeochemical monitoring equipment should be placed in non-perennial areas of river networks to begin closing this critical data gap. This solution must include both retrofitting existing gages with additional biogeochemical sensors, as well as outfitting ungaged, non-perennial stretches of river networks. However, as a key point of distinction from our first identified barrier, this data gap is not solely due to a network bias towards studying mid-sized water bodies; it also arises because existing biogeochemical sensors are not always adaptable between wet and dry conditions, and microbiomes do not have readily available sensors to monitor their shifts in real-time. Therefore, we also need adaptation of existing approaches and methods to work in these hybrid aquatic-terrestrial environments. For example, to study how ecosystem metabolism responds to wetting and drying regimes, sensors that can measure oxygen and carbon dioxide levels in both water and air are necessary. The benefit of this investment in infrastructure and methods development would be an increase in our direct measurements of biogeochemical parameters and microbiome shifts, which would allow us to calculate the cumulative impact of non-perennial rivers on water quality.The second major barrier is that concomitant we do not understand how environmental changes—climate change, land use change, and water extraction—will influence duration and frequency of drying, and thus the biogeochemistry and microbial ecology of these rivers. Climate change is shifting precipitation and drought patterns in novel ways, which will have a direct impact on stream drying characteristics that will vary by region8. This shifting baseline creates new scenarios where rivers that have never gone dry before will become non-perennial. To address this, we now must begin to extrapolate beyond current flow conditions into future scenarios. As a solution, more observational data (addressing barriers 1 and 2) can be coupled with experiments mimicking novel environmental conditions. The results of these experiments can be used to improve the ability of ecosystem models to project how newly non-perennial rivers will respond to a changing climate. This information will reduce uncertainty for managers who need to know how changing patterns of streamflow will impact downstream water quality.These first two barriers are compounded by the third, which is that Addressing these three barriers with our proposed solutions will allow us to test hypotheses regarding how flow states will influence the chemistry of exported water, the magnitude of export loads, and the suitability of habitat as an aquatic refuge for organisms when surface water dries Fig. . Testing12. For example, continued support of existing and emerging research coordination networks across the globe  focused on integrating non-perennial systems into river sciences, management, and policy, are valuable mechanisms to leverage the progress we have made in identifying research needs, generate shared knowledge, and create the community of practice that will carry out needed research directions. These emerging scientific networks spanning Europe, Australia, and the United States have synthesized information on the dominant hydrologic behavior of non-perennial rivers, including their global prevalence1, their spatial patterns13, and their temporal trajectories8. However, our understanding of the nexus of hydrology, biogeochemistry and microbiome shifts has been hindered by the barriers articulated herein. As new approaches are developed to integrate various data streams for modeling activities, a centralized database that can link no-flow observations to biogeochemical measurements and microbial data will be a valuable resource. With thoughtful coordination and communication across our global community, we have the opportunity to greatly advance our understanding of the biogeochemical function of currently and soon-to-be drying rivers.Climate change is shifting precipitation patterns across the world, resulting in changes in streamflow. Yet, we do not and cannot predict how these shifts will impact downstream water quality due to limitations in where we collect data, the type and scope of data being collected, and the methods and models we can employ to predict future scenarios. Improving our understanding of the contribution of non-perennial rivers to downstream water quality will enhance modeling efforts, thereby facilitating our ability to predict and manage water quality of both perennial and non-perennial waters that are undergoing rapid environmental change. Thus, expanding the scope of river gage networks to encompass non-perennial systems in all biomes is necessary to fill this knowledge gap. Expanding this network so that biogeochemical and microbial research can be co-located with long-term hydrologic data collection is a critical part of this expansion. To ensure our community can collectively address identified research gaps and management needs, we need new coordinated and collaborative approaches to standardize, manage, and share data


This is a case where artificial intelligence might help level the playing field, for example by creating accessible insights and enabling the large-scale production of high-quality plain language summaries which would truly bring open access to this scientific information. This possibility, combined with the increasing public policy trends encouraging and demanding free access for research supported with public funds, may alter the role journal publications play in communicating science in society. For the field of environmental health science, no-cost AI technology such as ChatGPT holds the promise to improve research translation, but it must continue to be improved (or improve itself) from its current capability.Generative artificial intelligence, popularized by services like ChatGPT, has been the source of much recent popular attention for publishing health research. Another valuable application is in translating published research studies to readers in non-academic settings. These might include environmental justice communities, mainstream media outlets, and community science groups. Five recently published (2021–2022) open-access, peer-reviewed papers, authored by University of Louisville environmental health investigators and collaborators, were submitted to ChatGPT. The average rating of all summaries of all types across the five different studies ranged between 3 and 5, indicating good overall content quality. ChatGPT’s general summary request was consistently rated lower than all other summary types. Whereas higher ratings of 4 and 5 were assigned to the more synthetic, insight-oriented activities, such as the production of a plain language summaries suitable for an 8 Another valuable application is in translating published research studies to readers in non-academic settings. These might include environmental justice communities, mainstream media outlets, and community science groups. Given the number of challenges with writing peer-reviewed research and the follow-on cost and effort in additionally creating plain language summaries (PLS), generative AI may offer scientific researchers a valuable new tool for improving environmental health risk communication and access by the larger constituencies in society.Generative artificial intelligence (AI), popularized by services like ChatGPT, has been the source of much recent popular attention for publishing health research.2 The role of academic researchers in environmental health programs has been tied to not only methods but the essential working relationships for translation to public health action.5 Using an analytic rubric, we explored the use of ChatGPT as an alternative to traditional human expert summarization to support PLS as a form of research translation and provide suggestions for environmental health research translation.However, researchers must balance the potential benefits of generative AI, such as making science more equitable and increasing the diversity and accessibility of scientific knowledge, with potential risks, such as degrading the quality and trust in the research practice. Chatbots can produce convincing but inaccurate text, which might undermine the very trust research translation aims to build.th grade level by one of the authors of each study. The author reviewers were blind to the use of the generative AI as the source of the summarization.Five recently published (2021–2022) open-access, peer-reviewed papers, authored by University of Louisville environmental health investigators and collaborators, were submitted . The PLSth grade reading level and identifying the most important finding and real-world research applications. The majority of these more insight-orientated summaries were judged acceptable for use with the public. Even across this limited collection of studies, there were a few authors who commented that the PLS was still too technical for general audiences. In some cases, ChatGPT’s attempt at simplification removed important detail – for instance, stating wellbeing was associated with cardiovascular diseases (CVD), rather than risk of CVD. Minor inaccuracies around study method interpretations were also observed. In one processed paper the ChatGPT PLS referenced questions about levels of pollution and greenness around the home when the study did not include these questions. Other research has reported ChatGPT created abstracts not always distinguishable from those written by a human expert thus bringing up the need for source disclosure, however medical discharge summaries with automation have been shown to still require manual checking by a human expert where an inaccuracy in a summary report may lead to patient safety issues.7The average rating of all summaries of all types across the five different studies ranged between 3 and 5, indicating good overall content quality. ChatGPT’s general summary request was consistently rated lower than all other summary types. Whereas higher ratings of 4 and 5 were assigned to the more synthetic, insight-oriented activities, such as the production of a PLS suitable for an 82 This is a case where AI might help level the playing field, for example by creating accessible insights and enabling the large-scale production of high-quality PLS which would truly bring open access to this scientific information. This possibility, combined with the increasing public policy trends encouraging and demanding free access for research supported with public funds, may alter the role journal publications play in communicating science in society. Recommendations for future research include the need for rating by community members of paired PLSs and review of a larger number and wider variety of environmental health research study types. For the field of environmental health science, no-cost AI technology such as ChatGPT holds the promise to improve research translation, but it must continue to be improved (or improve itself) from its current capability.There are several critical research needs, especially around inclusion and environmental health justice research.Supplement 1


Fundamental discoveries in the history of science, including research from four Nobel laureates, have identified the pyrimidine nucleotide, nicotinamide adenine dinucleotide (NAD+) as an essential metabolite and the most important cross-kingdom electron carrier. While a wealth of scientific studies in the last century have highlighted the important role of NAD+ in cellular energy generation and redox biology, recent studies have provided evidence for the paramount importance of the non-redox functions of NAD+. Alteration in intracellular NAD+ concentrations is critical in several pathological conditions, including but not limited to neurodegenerative diseases, cancer, diabetes, ischemia injury, dysmetabolic diseases, and inflammatory disorders. Recent advances in our understanding of the biological functions of NAD+-consuming enzymes and the role of NAD+ biosynthetic routes have shown that targeting NAD+ metabolism has very promising potential for therapeutic treatment of infectious diseases. Bacterial resistance to antibiotics is considered one of the greatest threats to human health. Cases of antibiotic resistance are constantly emerging, and the time needed for bacteria to become resistant to newly introduced antibiotics, is getting shorter. Therefore, it is crucial to identify antimicrobials with new mechanism of action to use as therapeutic tools. In this context, modulation of host NAD+ metabolism by the activation or inhibition of key enzymes could influence NAD+ signaling pathways in pathogens and their ability to colonize host cells. Further, the discovery of the enzymes involved in NAD+ turnover in the host during infection could increase our knowledge of bacterial pathogenesis and may be relevant for the development of targeted drug therapies against antibiotic resistant bacteria. However, detailed mechanisms by which NAD+ acts as a regulator and how we can target NAD+ metabolism during microbial infections is still poorly understood.In the current Research Topic, the published papers collectively help to gain some cardinal knowledge on the functions of NAD+ and precursors during infection, and cancer and to find new potential therapeutic targets.Cros et al. demonstrated unequivocally and in agreement with existing data, the advantage to treat bacterial infections with β-NMN compared to other molecules affecting NAD+ metabolism. They also showed that the reduced dysregulated inflammation after the treatment with β-NMN is correlated to reprogramming of macrophages toward an anti-inflammatory pathway. Overall, the promising data presented by Cros et al., confirm the potential therapeutic use of β-NMN in the treatment of bacterial infections and in reducing their deleterious effects.One original paper described the role of Nicotinamide Mononucleotide (β-NMN), a key precursor molecule in the NAD salvage pathway, in reducing inflammation in bacterial peritonitis. Other NAD precursors such as Nicotinamide Riboside (NR) or Nicotinamide have been shown to reduce oxidative stress and inflammation in the heart or to increase the survival rate of mice with lethal endotoxemia or experimentally induced polymicrobial sepsis, respectively. More recently β-NMN administration was effective in reducing the pro-inflammatory cytokine production in an LPS-induced inflammation model. Combining transcriptome analysis and biological assays, Baquero et al. carefully reviewed and analyzed the correlation between NAD+ metabolism and the antimicrobial effects exerted by the intestinal microbiota. The administration of NAD+ precursors synergize with intestinal microbial populations to enhance NAD+ levels in host mammalian cells suggesting that a healthy gut microbiota is strictly necessary for the synthesis of key components used in alternative NAD+ biosynthetic pathways in the host. Baquero et al. highlighted the importance of the microbiota composition and activity when drugs interfering with NAD+ metabolism are used and developed. The cross talk between host and microbiota has been shown in many experimental conditions and should be considered when targeting NAD+ homeostasis in the host. As pointed out by Baquero et al., a correct use of NAD+-boosting compounds accelerating the bacterial metabolism can reduce the persistence of antibiotic resistant pathogens. Finally, they demonstrated that NAD+ availability can influence the growth of bacterial populations producing low-molecular weight antimicrobial agents such as microcin able to modulate the host microbiome.In the second paper Kanayama and Luo demonstrated the close correlation of CD38 overexpression and cancer phenotypes in a stable prostate cancer cell clone. They also observed that while the NAM supplementation failed to restore normal NAD+ levels, it rescued CD38 induced apoptosis and mitochondrial stress. However, they claimed that additional studies are required to confirm the therapeutical implications for NAM treatment in prostate cancer.Among the NAD+ consuming enzymes, CD38 plays a key role in prostate cancer cells since its expression is downregulated if compared to normal tissues. However, a clear role of CD38 in enhancing tumor progression is still lacking. Analyzing oxygen consumption, intracellular NAD+ levels and cell viability via the reprogramming of DNA and histone methylation. These observations demonstrate that IDHs are not only key metabolic enzymes but are also important clinical diagnostic biomarkers for certain tumors as well as potential targets for therapeutic drugs. Huang et al. performed a detailed biochemical characterization of a novel NADP+-specific type III IDH from the eukaryotic microalga P. tricornutum. Among the biochemical properties studied, of interest is the identification of key residues, pivotal for coenzyme binding and specificity. While the IDH studied is derived from a microalga, the data shown provides a better understanding of the catalytic and regulatory properties of this family of enzymes as it affects the metabolism of NAD+ and its functions.Although Isocitrate Dehydrogenase (IDH) is a well-known metabolic enzyme playing a key role in the citric acid cycle, studies have recently evidenced that after mutations in key arginine residues IDH acquires a novel function for which NADP+ instead of NAD+ is the preferred cofactor. Under such circumstances, IDH catalyzes the synthesis of hydroxyglutarate, an oncometabolite that promotes tumorigenesis NAD+ metabolism is a highly interdisciplinary research field with many open questions still to be addressed to improve our knowledge into the various implications of its metabolism and regulatory functions in biological processes. In conclusion, this Research Topic provides examples of how the application of different approaches can benefit the scientific community by providing new insights into the many aspects of NAD+ metabolism.


Clostridium dificile conditions, are less apparent in the absence of interdisciplinary integration.Discoveries of the beneficial effects of gut microbiota have led to efforts to cultivate healthy gut flora to treat disease. The field of ecological restoration specializes on reestablishment of desired species in disturbed ecosystems, which suggests that it may be applicable to microbe restoration in the gut. Common language can lower barriers to interdisciplinary insights. Here I introduce the concept of a “biodiversity dose-response curve” to translate ideas from ecological restoration into research and clinical priorities for fecal microbiota transplantation (FMT). The curve is based on a relationship between ecosystem structure, measured as species diversity found in both nature and gut ecosystems, and ecosystem function, which are the measurable parameters that contribute to ecosystem and human health. I explain why the biodiversity dose-response curve may follow the ecological model of a “rivet-redundancy” relationship, in which the overlap of multiple organisms’ functional contributions to a system mask the impact of initial losses of diversity, but, at a certain level of loss, function declines sharply.  The biodiversity dose-response curve indicates that seemingly healthy individuals may be suboptimal donors; it highlights the importance of recipient diet in FMT success; and it introduces the concept of “passive restoration” into the field of gut medicine. These insights, which may help to explain low success rates of FMT in the treatment of non- Clostridium dificile infection . To dation [CDI , 2, and ion [CDI .The need to cultivate and support beneficial gut microbe communities for human health raises the question of whether preexisting approaches from other areas of science may be of assistance. For example, general ecological models of community assembly lead to predictions for the selection of effective fecal donors . More spC. dificile infection, obesity, and inflammatory bowel disease (IBD), medical researchers, like their peers in ecology, have begun to manipulate the health-related ecosystem benefits provided by beneficial species  plus FMT did not differ after 8 weeks from subjects on UCED alone or FMT alone . HoweverUntil proven otherwise, FMT without consideration of diet can be considered analogous to replanting sensitive species without removing the disturbances that facilitated noxious invaders in the first place . Viewed A widespread failure to place passive restoration  before active restoration  may help to explain a lack of evidence for long-term recipient microbiome changes after FMT in non-CDI diseases. A review of 24 non-CDI FMT research studies identified 19 studies that examined the duration of recipient microbiome changes. Of those, only three monitored recipients beyond 90 days post-treatment: one showed persistent changes for over a year and two reverted to no change after exhibiting an initial difference. Of the 16 studies that monitored for a shorter duration of 14–90 days, initial changes in recipient microbiomes either disappeared or became less significant over time in three studies (Restorationists tend to provide seedling support, such as by watering, for only a short duration of time due to practical considerations. If diet does influence engraftment of healthy microbiomes, research will be required to determine the degree to which short term dietary shifts are sufficient to support engraftment, or whether longer-term “lifestyle” changes before and/or after FMT are necessary. Such studies will require longer-term monitoring than most research on non-CDI diseases to date  as well In summary, the biodiversity dose-response curve identifies factors likely to influence FMT success, beginning with diet as a form of passive restoration, followed by antibiotics or lavage for site prep, and finishing with high diversity donors to ensure sufficient engraftment above the threshold for system failure. These theoretical priorities are supported by early research into the beneficial effects of donor gut microbiome diversity  and reciThe original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The author confirms being the sole contributor of this work and has approved it for publication.


This is a review of the current state of molecular profiling in gastrointestinal (GI) cancers and what to expect from this evolving field in the future. Individualized medicine is moving from broad panel testing of numerous genes or gene products in tumor biopsy samples, identifying biomarkers of prognosis and treatment response, to relatively noninvasive liquid biopsy assays, building on what we have learned in our tumor analysis and growing into its own evolving predictive and prognostic subspecialty. Hence, the field of GI precision oncology is exploding, and this review endeavors to summarize where we are now in preparation for the journey ahead. Comprehensive molecular profiling has evolved over the last decade. The evolution of molecular profiling changed the face of oncology from standard chemotherapy based on histology to personalized therapy. Using immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and whole-genome sequencing, oncologists are able to recognize the genomic drivers of tumorigenesis and provide patients with prognostic biomarkers and targeted therapy options Fig. ; Table 1Molecular profiling using tissue next-generation sequencing (NGS) has become a standard of care practice, and recently, circulating tumor DNA (ctDNA) has emerged as a tool for molecular profiling, a predictor of response to systemic treatment, and a powerful way to measure minimal residual disease (MRD) using less invasive approaches –3.KRAS mutant CRC do not respond to epidermal growth factor rector (EGFR)-targeted agents such as the monoclonal antibodies cetuximab and panitumumab  of the Year . An incr