Advanced therapy medicinal products (ATMPs) are a heterogeneous class of medicinal products that by offering the potential of cure represent a paradigm shift in the approach of many life-threatening diseases. Although a common regulatory framework for ATMPs has been established in the EU, the health technology assessment (HTA) and financing decisions remain local. The aim of this article is to present an integrated analysis of the current status of the value judgment of ATMPs and the integration of ethical evaluation in the HTA process. It has been identified that approaching the specificities of ATMPs in terms of market access will require a broadening of the definition of value to be able to systematically capture elements of value not traditionally considered. Outcomes modelling will play an important role in the pricing and reimbursement of ATMPs, providing a way to bridge the gap caused by the absence of data from clinical studies or real-world data. Given the nature and disruptive consequences of ATMPs the assessment and adoption of these medicinal products raises important ethical questions, both at a policy and at society level that should be properly addressed. HTA can be made more transparent and reliable, and simultaneously promote robust and accountable decision making, by turning explicit the value judgments implicit in HTA. Ultimately, there should be no core conflict between ethical requirements and HTA in a scenario where the goal is to promote equity and access of patients to truly innovative therapies such as ATMPs, while assuring the sustainability of healthcare systems. Advanced therapy medicinal products (ATMPs), are a heterogeneous class of medicinal products that includes products based on genes , cells  and tissues  . ATMPs mThese novel highly complex therapies need to be addressed differently when compared to traditional medicinal or biologic products in their development, manufacturing, or administration process, with emphasis in the establishment of batch consistency, product stability and product safety and efficacy through pre-clinical and clinical studies .Particularly, they are also expected to bear a higher risk potential compared to other biological medicinal products such as tumorigenicity, cell differentiation and patient integration .A legal framework has been established in the European Union (EU) governing the regulation of all medicinal products for human use, including ATMPs. A consolidated regulatory framework for ATMPs was introduced by Regulation 1394/2007/EC of the European Parliament and of the Council of 13 November 2007 on ATMPs and amending Directive 2001/83/EC and Regulation 726/2004/EC. This regulation provides specific regulatory principles for the evaluation and authorization of ATMPs and filled a pre-existing regulatory gap by subjecting these innovative products to the general EU pharmaceutical legislation [The ATMPs regulation defines three specific types of medicinal products, including gene therapy medicinal products, somatic cell therapy medicinal products, and tissue-engineered products, all of which meet one of the definitions of medicinal products established . AdditioATMPs often target rare diseases and can be designated as orphan medicinal products in the EU. In this region, in order for a product to qualify for orphan designation, the prevalence of the disease addressed must not be superior to 5 in 10,000 people .In the ATMPs product development, to achieve the market access, developers need to first have a clear understanding of the markets and their reimbursement requirements before initiating clinical studies, namely to have a clear understanding of the market environment for the target indication, the disease burden, the target patient type, the alternative treatments already available, the reimbursement profiles of alternative products and the reimbursement policy of the relevant payers . AdditioIn the EU the marketing authorization for a new medicine via the centralized procedure involves a series of quality and clinical reviews by the EMA. Following marketing authorization, HTA bodies or payers on a country-by-country basis will undertake a review of the clinical evidence prior to conducting the economic review. While for the EMA the focus of the clinical review is assessing the quality, efficacy and safety of the product, the clinical review undertaken by HTA bodies/payers will focus on assessing comparative effectiveness against an existing therapeutic alternative or the best supportive care. The size of the incremental clinical benefit acknowledged is then used as a basis for the economic analysis, together with cost considerations. Finally, before patients can have access to the new therapy, a decision to include the therapy in any formulary is usually made at the local level, is subject to budget impact considerations, and may change periodically according to budget cycles .Despite the centralization of the marketing authorization process, the reimbursement process is greatly fragmented across countries and even across regions of a given country. Therefore, there are significant variations in pricing and reimbursement frameworks among the five largest EU countries , that is, the Big 5EU .The EUnetHTA  HTA definition states that: “Health technology assessment is a multidisciplinary process that summarizes information about the medical, social, economic and ethical issues related to the use of a health technology in a systematic, transparent, unbiased, robust manner. Its aim is to inform the formulation of safe, effective, health policies that are patient focused and seek to achieve best value” .Currently, the HTA procedure is considered a standard policy tool for informing decision makers who manage the entry of new medicinal products, medical devices, and other technologies in health systems, namely, through pricing and reimbursement .However, individual EU HTA agencies have adopted different priorities and methods, linked to their health system funding model and the weighting of economic/budget impact versus broader clinical or societal impact. This variation across HTA decision making is perhaps more visible when considering access to ATMPs than to conventional therapies. Some HTA bodies show more willingness than others to admit new types of evidence beyond randomized controlled trials, or to consider economic models that include extrapolating longer-term benefit from limited existing data.Affordability is vital to the sustainability of healthcare systems, however, budget impact analysis can pose a challenge to rewarding and promoting innovation such as ATMPs. On one hand, the focus of the analysis is typically the healthcare budget isolated, and savings in the social care budget  are not adequately captured in the benefits assessment. On the other hand, the time horizon of the analysis is often 1–2 years, which implies that long-term benefits, such as in the case of ATMPs, are also inadequately captured .Over the years, the assessment of price and reimbursement for innovative therapies has shifted towards value-based models , 9. HoweJørgensen and colleagues identified the pricing, reimbursement and market access considerations most relevant for ATMPs in the Big 5EU. The clinical benefit is measured in comparison to a suitable comparator. This comparator can differ between countries, since clinical practice may be different in different settings, which raises the need to perform indirect comparisons .In the Big 5EU, the only country that links the cost per QALY specifically and methodologically to pricing and reimbursement is the United Kingdom. In Germany, cost-effectiveness analysis is not commonly used, which means comparative efficacy and budget impact remain the main decision-making criteria for pricing and reimbursement .Other factors, such as the contribution to gross domestic product (GDP), involvement of patient advocacy groups as well as ethical, equality, and equity considerations can also impact on the final decision on a country level .Despite their significant therapeutic potential, ATMPs face specific pricing and reimbursement challenges. ATMPs have high manufacturing costs, which will demand a high target price to achieve commercial viability. Their incremental benefit claims can cover a longer horizon than is supported by clinical trial data at launch since ATMPs may potentially provide life-long benefits.Also, ATMPs require complex interventional procedures for their administration and are therefore likely to be restricted to centers of excellence . AnotherOften clinical studies evaluating ATMPs may also be more dependent on surrogate outcomes instead of clinical outcomes, which poses additional challenges to the assessment .Outcomes modelling will play an important role in the pricing and reimbursement of ATMPs. In therapeutic areas with a high unmet need it may be considered not ethically justifiable to randomize patients to receive placebo as a control, when an efficacious alternative is already available. In these cases, single-arm trials may be performed, which provide a lower grade evidence from the payer perspective, as they only allow an indirect comparison with the standard of care, which adds additional challenges to the pricing and reimbursement negotiations. Additionally, the timeframe of a clinical trial does not allow to capture long-term benefits, which means that an important part of the value proposition is not documented, such as in the case of the curative treatments of some ATMPs.Outcomes modelling is a way to bridge the gap caused by the absence of satisfactory data from clinical studies or real-world data. Therefore, for many ATMPs, indirect comparisons and extrapolations become particularly relevant. They allow data comparison from different sources where direct comparisons are unavailable. Indirect comparison is particularly relevant for ATMPs in two situations: in cases where the comparator in the pivotal trial does not reflect the standard of care in the country in question, or in cases where ethical considerations demand the performance of a single-arm study. This methodology offers a way to use data from other studies or observational sources such as meta analyses and registries to estimate the comparative effectiveness of the new treatment .In terms of market access solutions, risk sharing agreements between the manufacturers and payers are a way to reduce the uncertainty related with the lack of long-term data at launch. It is important to note that these schemes require regular patient follow-up and are often associated with significant clinical and administrative burden, which has limited their implementation .Ultimately, the demonstration of effectiveness and comparative effectiveness of ATMPs in the long term will need to be complemented by the collection and subsequent analysis of real-world evidence .In a market economy, the value of an economic good can be regarded in two ways: what individuals are willing to pay for it (a demand-side view) or what individuals have to trade off to obtain it (an opportunity cost or supply-side view) . CurrentGarrison and colleagues characterized the challenges for traditional approaches in assessing the value of one-time gene replacement therapies and proposed a health economic rationale for a higher value-based cost-effectiveness threshold (CET). It is generally recognized that ultrarare, health-catastrophic conditions should be assessed against a higher CET .The administration of a one-time dosing with potential lifelong benefit creates new challenges for payers to adequately reward the manufacturers of such innovations with an adequate return on their investment. The measured value and financing of pharmaceutical products have been traditionally strongly influenced by the duration of treatment. Economic value is usually defined in terms of health gained, that is QALY plus cost-offsets evaluated over the defined time horizon. Yet, conveying appropriate value in the long term for one-time therapies is problematic since this usually requires extrapolation from small clinical trials of short duration .The ICER  has debated a range of up to $500K per QALY for ultra rare diseases but has informed it will still publicize the base-case value-based price at a CET of $150K per QALY gained. In the United Kingdom, the National Institute for Health and Care Excellence (NICE) has defined gene therapies as “highly specialized technologies” that should be subject to a much higher, yet variable, threshold up to £300K ($390K) per QALY depending on the magnitude of the QALY gains .A recent special task force (STF) of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) specified, “Health plan coverage and reimbursement decisions should consider cost-effectiveness analyses, as measured by cost per QALY, as a starting point”. It further recommended that elements of costs and benefits not usually included in cost-effectiveness analysis that affect individual well-being  may be relevant for some health plan decisions. Still, more research is needed on how best to measure and include them in decision making .The potential elements of value identified in the ISPOR STF, in this broader perspective were divided into three categories: (1) core elements of value ; (2) common but consistently used elements of value ; (3) potential novel elements of value  .Jena and Lakdawalla reinforced the importance of several other elements in this assessment: health equity (related to severity of disease), caregiver burden, and family spillovers (in terms of the negative effect on the well-being of family members) .Jönsson and colleagues also proposed that these wider benefits should include disease severity, age of onset, lifetime burden of illness, socioeconomic impact, and possible spillovers from the initial innovation .It seems clear that value will need to be considered differently for ATMPs. Additional elements of value  should then be considered in the evaluation of these products .“Ethics is nothing but a technology to make a particular set of  problems manageable and controllable” . BioethiThe fundamental principles of bioethics and biolaw include the respect for life in all its forms, and the quality of the environment, to ensure the maintenance of life and vital processes, with a constant commitment to transparency and the spreading of knowledge involving biological and medical sciences .Thomas Beauchamp and James Childress proposed in the book Principles of Biomedical Ethics, Principlism and its four principles. These principles are: autonomy, beneficence, non-maleficence and justice. The key characteristic of this model is the equal value of each principle: they are always valid and binding unless they are in conflict and it is not established if one takes priority over the others .Regarding ATMPs, though genome editing consists of a general process, it is important to highlight that the ethical implications of gene editing are not just about the process, but instead are directly related to the purpose for which it is used .From the perspective of bioethics, the use of gene therapy appears to be closely related to several challenging factors, such as economic difficulties, particularly with regards to wealth distribution, political and cultural conflicts, as well as the scarcity of studies evaluating the impacts of the use of gene therapy on human health. These aspects raise both clinical dilemmas and legal issues .In general, clinical research on genetic diseases raises scientific and ethical concerns, that include specific ethical procedures for genetic research, collection, storage and access to genetic materials, aims of the use of genetic information, the definition of the time of archiving genetic material in biobanks, informed consent and confidentiality issues and concerns specific of pediatrics .In terms of marketing authorization of ATPMs, the fact that conditional approval takes place at a stage that is still part of the research phase adds complexity to the ethical questions raised .Also, in the case of ATMPs, when a product is autologous (originated from the same patient), the question of the ownership of the product can be posed, namely whether the developer or the patient are the righteous owners of the product .When pediatric patients are affected by rare diseases, difficulties double as children should be considered ‘twice orphan’, and randomized controlled trials, considered as the standard in research design, are even more unfeasible due to the smaller number of patients. It becomes ethically problematic to propose a control arm  for a study aimed to establish the efficacy of a new product .When considering ethics in the scope of gene therapy, the concept of changing the DNA of an individual, even to cure a fatal genetic disease, differs from more traditional therapeutic solutions such as surgery, medicinal products, among others, and can raise several concerns .Hunt proposed in 2008 a list of topics for discussion Table .Table 1TCurrently, there are still many uncertainties about the side effects of gene therapy, despite the scientific and technological advances. Moreover, the lesser-known effects, such as long-term expression of the introduced genes, the lack of control of the expression of these genes and genetic modification of germ cells, are not known .The resource to real world evidence can be considered paramount in gathering the information needed for the approval of ATMPs. In this scope, patient registries provide highly valuable but also sensitive data, and thus, demand patient privacy protections and a detailed understanding of the ethical and legal implications of proprietary use of medical data .Crucial ethical issues receiving great interest by the scientific community, as demonstrated in the regulatory framework, the literature and EU projects, are genetic aspects, data protection issues, confidentiality and the handling of biological samples .An important issue raised is the legitimacy of sharing patient data from different countries from the ethical point of view. This practice is increasingly widespread in the case of rare diseases and particularly challenging when these data are from pediatric patients and include genetic data. Notably, no specific ethical reference on the use of ATMPs for pediatric rare diseases is available in the current EU regulatory framework .An important note is that curative therapies, such as ATMPs, have the potential to eliminate the need for long-term management and provide longer term increases in quality of life. Still, it is not known whether curative therapies are valued more highly by society than treatments that offer the same “total” health gains through marginal gains over many years and/or patients .As highlighted by Rodriguez-Monguio and colleagues, the societal value of orphan drugs can be outlined by several ethical constructs. Considering that society wishes to maximize total net benefits, aligning with a classic utilitarian doctrine, aiming to maximize utility for the greatest number of individuals in society, the cost–benefit ratio of rare diseases may be positioned less favorably to receive public funding as it would in an egalitarian approach, that aims to maximize equality of all individuals. The aim of achieving an egalitarian outcome may be grounded on attaining a determined threshold of health, an overall prioritization of the worst off, or amount of resources for each individual. Therefore, an egalitarian doctrine could offer a better foundation for public funding for orphan drugs development and treatment coverage for rare diseases. Otherwise, the rule of rescue, or the capacity to intervene if a therapy becomes available, may also offer a defense for funding rare disease treatments with public funds .Globally, the ethics of the resource distribution to subsidy orphan drugs has been discussed but not agreed upon in the literature. Currently there is no societal consensus on whether the size of the patient population, in itself, can act as an admissible factor in employing separate measures of effectiveness and economic evaluation  for the approval and reimbursement of orphan drugs. Some authors argue that the special status argument for public subsidy and reimbursement of orphan drugs does not stand up to critical assessment, while others have highlighted the importance of using economic evaluation, political debate, and social dialogue to ensure distributive justice to orphan drug development and access .Orphan drugs are often for treatment of life-threatening diseases, which emphasizes ethical imperatives for timely access to orphan drugs. Therefore, the right to life may be conceived as the right to health. On the other hand, the Universal Declaration of Human Rights, proclaimed by the General Assembly of the United Nations in 1948 established the right to life that was codified in the European Convention on Human Rights (1950). Additionally, the right to the “highest attainable standard of health” was first predicted in 1946 in the Constitution of the World Health Organization .Considering the important specific ethical questions that are raised for orphan medicines and ATMPs, further discussion is required at a societal and policy level to assure that these questions are analyzed and taken into consideration in the policies and decisions made in terms of the HTA of these innovative medicinal products.First, it should be noted that for any new technology developed, ethical issues are raised .Ethics is recognized as a crucial element in HTA since its conception, however, ethical issues are still not frequently addressed explicitly in this area . PerhapsAccording to EUnetHTA, the ethical domain involves “an understanding of the consequences of implementing or not implementing a health care technology in two respects: with regard to the prevailing societal values and with regard to the norms and values that the technology itself constructs when it is put into use” .Hofmann and colleagues proposed a shift from an externalist conception of value judgments that considers value judgments as added to the results of HTA to an internalist one that recognizes and openly addresses value judgments as they arise within the HTA process .In fact, the HTA process itself can raise relevant ethical issues. These include questions about the ethical consequences of the choice of endpoints or comparators, and whether there are any ethical concerns in the economic evaluation .Even though the clear distinction between facts and values remains philosophically difficult to defend, it is present in the current concept and use of HTA, namely, in the distinction between assessment and appraisal, between systematic review and personal preferences, between scientific judgments and social judgments .By definition HTA will include the collection and analysis of evidence from research in a systematic and reproducible way to be used for decision-making purposes by elaborating “assessment” reports . “AssessIn the end, there is no incompatibility and the appraisal process may remain deliberative, while the assessment can remain descriptive .Several articles published by Hofmann and colleagues since 2005 have defended a better integration of ethical analysis in HTA . HTA canTurning explicit the value judgments implicit in HTA, for example in the framing of the research question, as well as in the appraisal stage, by weighing the information provided, can make HTA more open, transparent, and reliable, and also promote robust and accountable decision making .ought to be distributed . This aspect has direct implications on resource allocation decisions.Several value judgments are made in the economic analysis of HTA. The quantification of societal preferences for the distribution of health gains has always played a crucial role in health economics. Nevertheless, the implicitly assumed desire (preferences) to maximize health in economic evaluations may not correspond to how the majority of the people in a society think health On the other hand, cost-effectiveness analyses assume that “a QALY is a QALY,” equally weighted across individuals which consists in a quasi-egalitarian value judgment, that may be questionable in some circumstances and correcting for this aspect is not straightforward .Also, the technical development of cost-effectiveness analyses also comprises important value judgments, namely through the methodological options that are made at different steps during the analysis. These relevant decision points include the choice of perspective, the target population, and the outcome measure .Another important value-based choice in the economic evaluation process is related to the outcome measure used in the cost-effectiveness ratio. The LYG and QALY gained are the two most often used outcome measures. Since the valuation of health states varies between those who experience a health state directly and those who do not, consequently the outcome of the cost-effectiveness analysis will differ depending on whose values are used .As Hofmann and colleagues pointed out, value judgments are greatly present in the appraisal process that will consider the outputs of the assessment, and in the decision making procedures. Today, some EU countries have created explicit processes making use of multi-stakeholder consultations. Therefore, the definition of the appraisal and the assessment-appraisal border, and likewise the organization of the appraisal process, requires a series of value judgments, such as who should perform the appraisal, who should be involved and how should stakeholders participate in the process. Also, in the appraisal process a judgment is performed on the relative importance of a series of factors that differ from appraisal to appraisal. These factors could include namely, burden of disease, effectiveness, cost-effectiveness, budget impact and extent of individual responsibility. Yet, it is important to highlight that these aspects are valued differently by the different stakeholders involved in appraisal committees, namely patient representatives, health professionals, policy makers, payers, academic researchers, industry members, care givers, citizens, etc. Different stakeholders will make different value judgments with regards to the above-mentioned aspects, which will have an impact on resource allocation .A value judgment should not be understood as a “bias”, and in fact value judgments are found in all levels of what is regarded as the scientific endeavor of HTA . In sum, value judgments are not at all alien to the HTA process .In spite of the fact it remains uncertain how far HTA bodies should go in stating what is right or wrong, they clearly possess a central responsibility in bringing to light the diversity of socio-ethical issues that may affect individuals and society, particularly issues related to equity, transparency, social justice, and impact of technologies on marginalized groups.The ethical principles implied suggest that decisions regarding the allocation of scarce resources must be based on fair, transparent, and nondiscriminatory criteria that enable individuals in a society with a particular health need to receive appropriate healthcare services .Since there seems to be no agreement on how to better approach the crucial elements of equity, the value assumptions and judgments made during a HTA should be explicit, making transparent the ethical framework underlying the economic analysis .Contrasting with clinical and economic assessments, that aim to correctly elucidate and predict the outcomes of a technology using empirical data, ethical analysis will look for ethical values and use philosophical theories to justify reasons for implementing a technology. Hence, other approaches must be used to face ethical issues in HTA, in which HTA experts may not necessarily have specialized knowledge and skills .Hofmann and colleagues developed in 2005 a checklist of thirty-three ethics questions that provided a starting point for the systematic integration of ethics into the HTA process and created the basis for developing similar sets of enquiries .Notwithstanding the advances made so far in the development of ethical frameworks for HTA, there is still no clear agreement on the scope and particulars of a practical method to address ethical aspects in HTA .There is a variety of theoretical approaches available for HTA bodies to analyze values, ethics, and social dimensions of new technologies. Three broad methodological approaches to the introduction of ethical and social issues into HTA reports are available: (1) seeking expert advice from bioethicists and social scientists, (2) conducting qualitative and/or quantitative primary research, and (3) performing secondary research that includes published literature on social and ethical issues. At the HTA agency level, consultative mechanisms have also been recommended as a form of informing on research priorities and helping address the perceptions and expectations of lay members or representatives of stakeholder groups .In terms of the means for integrating ethical and social issues into HTA reports, bioethics expert advice may be sought and integrated into the HTA report, alternatively a specific group of experts may be mandated to produce a stand-alone report that complements the HTA report. In both these scenarios, ethics experts act as consultants. Some issues or principles can be generalized, however, country specificities are relevant, and analyses performed in one country or region may not be applicable in others. Thus, HTA agencies benefit from using local social scientists and ethicists who could become familiarized with the local HTA aims, methods, and constraints .Legault and colleagues identified on HTA literature relating to the barriers to the incorporation of ethics in HTA nine ethical approaches: principlism, casuistry, coherence analysis, wide reflective equilibrium, axiology, the socratic approach, the triangular model, constructive technology assessment and social shaping of technology .For the purpose of ethical evaluation based on the concept of a human person four principles have been identified: “a. the defense of human physical life; b. the contextual exercise of freedom and responsibility within the decision-making process; c. the safeguard of the therapeutic principle, according to which the human person has to be treated as a whole; d. the principles of sociality and subsidiarity, for which public and private authorities are called to help all persons in need” .The EUnetHTA Core Model described the three steps of the Triangular model .The first step of the Triangular Model is an in-depth study of all factual data concerning the technology, including its components, origin, purpose and consequences. The second step will be the ethical/anthropological analysis, in which the four evaluation principles mentioned above are applied to the case. Although not explicitly specified, it may be assumed that the analysis will comprise the evaluation of the consequences of the technology for the human being. The third step is the normative level and the ethical/anthropological analysis will lead the final ethical evaluation that normatively will determine a given real-world choice .Globally, the differences between the different approaches identified are primarily related with their disciplinary foundation . Their complexity can be observed in the particular characteristics of the ethical assessment originating from their differing disciplinary foundation .Assasi and colleagues also identified multiple guidance documents for the incorporation of ethical considerations in HTA, varying in their philosophical approach, structure and comprehensiveness.This group noted ethical guidance documents have been designed for different purposes throughout the HTA process .The ethical guidance documents identified frequently promoted the combination of normative reflection with descriptive approaches to the analysis of values and preferences of different stakeholders. However, the nature of the proposed procedural approaches varied considerably. They ranged from the approaches that advised on a general way of thinking about how to approach the assessment of ethical issues in HTA to those that provided analytical tools or case studies to aid users to understand a particular ethical analysis method .The barriers to the implementation of ethical analysis in to HTA, originated from the very nature of ethical analysis itself are, as identified by Assasi and colleagues: the diversity in the types of ethical analysis proposed and their complexity and the difficulty of applying ethical analysis in such a way as to obtain concrete outcomes , 28.Notwithstanding the advances achieved in this field, the majority of the HTA agencies apply ad hoc solutions in terms of the integration of ethics analysis in HTA and few systematically included ethicists in the procedure. Therefore, although the consideration of social and ethical implications of health technology is an unambiguous part of the HTA process, it is still not systematically performed, and the methods available for assessing ethical implications of health technology could be further developed .In summary, to fully integrate ethics in HTA, several methods have been developed which may be useful for emphasizing ethical value judgments in the HTA process. At a higher level, the value base of a new technology can be considered as important as its evidence base and core values may be elaborated for HTA, namely universal access, freedom of choice, and quality care. Additionally, high-level reflections on the general values of health care  and its philosophical foundations, such as equity, equality, maximization of health or preferences or social values are required and should be more transparently used .Currently, several innovative gene therapies in development will address the underlying root cause of genetic diseases. This curative potential represents a paradigm shift in the approach of many life-threatening diseases.In terms of the marketing authorization of ATMPs, a harmonized regulatory framework has been established in the EU. However, it will be important to promote consistent methods for conditional approval based upon the coverage with evidence or risk sharing. Subsequently, after the new treatment is made available for patients, it will be important to implement the appropriate arrangements for the collection and submission of supplementary real-world evidence and perform the corresponding review of the new evidence collected.In terms of HTA the decisions remain at local level, which by itself is a source of inequality between EU citizens, namely in terms of access to the latest potentially lifesaving therapies, such as ATMPs.ATMPs, may offer one-time, potentially curative treatments but, due to their characteristics, they will come to the market without solid evidence of their long-term effects and with a high price. These factors create important challenges for their reimbursement and adoption.It seems clear that in an environment of limited healthcare budgets and increased scrutiny over the value preposition of any new product, it will be critical for developers to adopt an economic perspective early in the product development, from the pre-clinical stage, to ensure market access and long-term market viability.It has been identified that one way to approach the specificities of ATMPs in terms of market access would imply broadening the definition of value to be able to systematically capture elements of value not captured in the QALY.It seems critical to reach a consensus on how to appropriately reward value created by these new therapies that will allow to incentivize the appropriate risk taking and investments by their developers.It appears has a logical solution that higher cost-effectiveness thresholds would support a higher value-based price and consequently a more appropriate reward for developers.To achieve this purpose, it will be necessary to develop new methods that more truthfully capture the value of ATMPs that may cure and not just treat a particular disease.Traditionally, HTA bodies have implemented higher cost-effectiveness thresholds for rare and life-threatening diseases. This is assumed to be in line with the wishes of the citizens of each country to agree to pay more for health gains in these particular situations. However, this willingness to pay will surely be further defied with the approval of more one-time gene therapies that are currently under development.Several financing programs have been considered to address concerns about value and affordability, namely outcomes-based agreements, to reinsure payers regarding the effectiveness and long-term effects issues. However, even if the proposed costs for ATMPs are set inside the range of the cost-effectiveness thresholds defined, payers may not have the financial capability to support the access to these emerging groundbreaking products and assuring the affordability for these products since the early development is crucial.An element that cannot be left aside from this discussion is the current growing role of patients in influencing the policy decisions taken and early patient engagement is key to attaining market access goals.Globally, in the EU, in a setting where the equity between countries is promoted, access and equity in the field of ATMPs should be pursued. Policies should promote the equal access of EU citizens to the new innovative and potentially curative treatments. For this, the implementation of innovative approaches is required to assess the true value and fair price of ATMPs, assuring affordability and equity.We are currently in a time of profound societal changes occurring in relation to healthcare technology development due to the emergency of groundbreaking therapies such as ATMPs. The HTA and market access decisions made in the scope of ATMPs raise important ethical questions and have important effects and consequences in society and therefore it is imperative that they are also assessed from an ethical perspective. In this context, HTA bodies have a greater responsibility to inform payers and the public on the reasons for the financing decisions made. For this, an effort should be made to make the ethical dimensions of HTA more transparent.A complex aspect to face is the question of how to address value judgments in the scope of HTA. As it has been argued, value judgments are at the core of HTA, being an intrinsic part of the entire process.It should be emphasized that to promote the ethical analysis in HTA, experts from different arenas such as HTA and bioethics, as well as health care professionals and patient representatives, should cooperate to further develop the methodology of reviews of normative ethical guidance to support evidence-based financing decisions. Particularly, for this integration to occur reliable methods should be used.Ultimately, it should be accepted that even if it is not possible to agree on one procedure and approach in ethics applied to HTA, it is always possible to find a set of questions that are relevant in handling value judgment issues with respect to HTA.The assurance that solid ethical standards are followed is intrinsic to science and research. On another perspective, science relies on social agreement and legal frames. Ideally, there should be no core conflict between ethical requirements and HTA in a scenario where the ultimate goal is to promote equity and access of patients to truly innovative therapies such as ATMPs, while assuring the sustainability of healthcare systems.


During the last 15 years, VITO has established an infrastructure for biobanking a collection of biological samples from the general population in Flanders (Belgium). This biobank was set up to contribute to future, yet unspecified, research questions in the field of environment and health. Biobank@VITO is a population biobank in which bio-specimen including human peripheral blood, cord blood, and blood derivatives , urine, hair, nails, exhaled breath condensate, saliva DNA, and human breast milk collected from non-diseased populations are preserved. Currently, the biobank stores about 70,000 samples from 7,700 individuals. These biospecimen were collected since 2002 in different human biomonitoring studies comprising European , national , Flemish  campaigns), and local  well-defined and ethically approved research projects. Participants to the surveys included different age groups  and were representatively selected with regard to gender, age class, residence, and/or socioeconomic status (SES). In each campaign, samples were stored in the Biobank@VITO. The registration, preservation, and management of the samples in the biobank were done in a qualitative and uniform manner which guarantees the traceability of all samples. The samples in the biobank have an extended information backbone on the lifestyle, environment, and health status of the donor. The biological samples in the biobank are an invaluable archive that can be used to address specific policy and research questions in the future, to test old samples with new technology and according to the latest methods and insights or to measure newly identified pollutants in old samples looking for long-term trends. Flanders is generally considered to be one of Europe's economic top regions with an extensive transportation network and intensive industrial activity. At the same time, Flanders is one of the most densely populated areas of Europe. Exposure to traffic or industrial emissions remain an important factor for adverse human health effects. Also lifestyle, diet, socio-economic, or physical exercise have been shown to have an impact on the health of the population. All these issues clearly illustrate that the relationship between environmental quality, socio-economic living conditions, individual behavior, and public health is a very complex one. As a response to this and to the societal challenges, human biomonitoring data and auxiliary personal information are collected and used as science based evidence to underpin measures for safeguarding environmental quality and to minimize the adverse effects of environmental stressors. In 2003, the Flemish government voted the Decree on Preventive Health Care as a legal recognition of environmental health in which the Flemish government imposes itself to perform human biomonitoring (HBM), i.e., the measurement of potentially adverse chemicals in human matrices such as urine or blood. In order to achieve a structured and coordinated approach for human biomonitoring in Flanders, the Flemish Centre of Expertise on Environment and Health was founded by the Flemish government . The Center is the main driving force behind the Flemish Environment and Health Studies, FLEHS. Human biomonitoring is the core of the programme on which several research projects are engrafted. Internal concentrations of a broad range of environmental chemicals and/or associated health effects are monitored. Exposure biomarkers provide information on the internal exposure to chemical substances and effect biomarkers provide information on the biological consequences of the presence of these chemical substances in the human body.For over 15 years, a large number of human samples  have been collected in the Flemish general population and have been analyzed for the presence of environmental chemicals or their metabolites. This allowed to estimate population reference values  of exposure to both well-established and new or emerging chemicals . In eachThis paper describes the mission, the objectives, the management, and the sample collections of the population biobank hosted at VITO.Human biomonitoring in the general population is an intrinsic part of the Flemish approach to science based policy-making in the field of environment and health. The monitoring programs of the Flemish Centre of Expertise for Environment and Health comprise now already a large number of chemicals. However, due to the rapid progress of technology and predicted increases in production volume of chemicals over the next 30 years, we expect increased exposure through environment and use of consumption products and people will come into contact with ever more and new foreign substances. As a result, additional relevant research or policy questions may arise in the future. Therefore, as part of the FLEHS programme and on request of the Flemish authorities, it was decided to build a human biobank in which samples are stored for potential use in the future.Since 2002, biobank samples were stored in a biorepository. The human samples originate from members of different age groups from the Flemish population that were invited to participate in the studies according to a randomized two stage recruitment strategy and that gave permission to take and store their samples in the biobank. A large number of human biological samples including blood and blood derivatives, urine, hair, nails, exhaled breath condensate, saliva DNA, and human breast milk samples have been collected over the years, resulting from the activities of the Flemish Centre of Expertise for Environment and Health and a number of other biomonitoring activities. The samples are well-documented in terms of individual exposure to environmental chemicals and related health status. Additionally, extensive information on lifestyle, personal characteristics, food consumption, individual risk perception, etc., is available from self-assessed questionnaires at the time of sampling. In this way, the samples are invaluable for new knowledge acquisition in the field of environment and health. In order to preserve this potential optimally for the future and to be able to serve for further research, a well-developed biobank is necessary.Biobank@VITO aims at setting up a professional, state-of-the-art biobanking structure in which the focus is put on collecting samples of the general population. The goal is 2-fold: (1) provide a facility where the collection of human samples, gathered over the last two decades, are stored under state-of-the-art circumstances; (2) provide a professional storage facility for future (prospective) biomonitoring initiatives in Flanders and elsewhere. Both objectives are implemented with attention to respect the privacy of the participants [GDPR  compliant] and ethical aspects.The biobank allows additional biomarker measurements to expand past and ongoing studies. Supplementary biomarker analyses (both biomarkers of exposure and biomarkers of effect) can be carried out at a later time in an existing cohort of which much information is already available. This saves a lot of costs and work as no new recruitment and sampling should be organized, and maximum use can be made of the questionnaire data and measurements that are already available in the database.With appropriate storage of samples, retrospective analyses of samples from years or even decades ago can be performed using state-of-the-art analytical technology to assess internal exposure and associated biological effects.Following time trends requires different campaigns that are spread over time. The biobank allows screening of new and emerging chemicals in various matrices, once appropriate biomarkers are developed. For these new biomarkers, samples from the past can then be analyzed to check the level of these substances in the body x years ago and to assess how levels evolve over time. These analyzes can be performed on pooled samples as well as on individual samples. Such time trends can best be followed up in reference populations.By repeating biomonitoring campaigns at regular intervals, human exposure to pollutants over time can be monitored and policy measures can be evaluated .Increasingly, results of prospective cohort studies are used in environmental health research. Repetitive sampling in the same individuals is extremely powerful to unravel the often very subtle and complex relationships between environmental  stressors and potentially adverse health effects. Follow-up studies allow people to be monitored during successive cycles with a specific pre-defined goal in order to study health effects in the longer term (years). Therefore, questionnaires and additional examinations  can be scheduled at regular intervals as well as requesting personal health data from registers. By submitting samples to the biobank at each of the successive cycles, new research hypotheses can be tested afterwards.in utero) for several years or even decades. Prospective cohorts like the 3xG study, or the various newborn cohorts of the FLEHS cycles  the detection of novel effect biomarkers  to monitor the early onset of diseases or (2) the identification of historical exposure that is involved in the onset of diseases later in life The availability of biobank samples in combination with extensive information on the participants allows to design nested case-control studies, and hence offers reductions in costs and efforts of data collection and works more efficiently in case of rare outcomes, expensive measurements, or missing covariates.Since human biomonitoring campaigns involve processing of personal data, the studies were registered at the Belgian Privacy Commission (CBPL = Commissie voor de bescherming van de persoonlijke levenssfeer) until the new GDPR law came into force on 25 May 2018 [(EU) 2016/679]. Following this, the new guidelines on the protection of personal data were applied.In addition, attention is paid to compliance with the ethical code for dealing with biological material . All samNo names or addresses of participants are registered in the Biobank@VITO. All participants, their samples and additional information are pseudonymized by the use of a unique identification code. The key to this code is only known to the field work team that works under the supervision of the responsible medical doctor. All communication with the participants takes place through the latter. The participant can request at any time information about the state of the research and the samples in the biobank, either through the PI or the medical doctor, but only the responsible study doctor can report back to the participant. Each individual can terminate further participation in the study and/or request at each moment to destroy his/her remaining personal samples. The results that are already in the database remain available for the researchers unless the participant explicitly asks to remove all his/her data. The data manager of the field work team contacts the Biobank manager if the consent status of the participant changes. The Biobank manager takes the necessary actions based on the unique identification code. For specific subgroups, permission from the participant was obtained to request personal health data from registers, e.g., data from child care services in the newborn group, data from school health investigations in the adolescent group, etc. This information is requested by the medical doctor, and can be coupled to the central study database on the basis of the unique identification code.The participants are aware of the fact that the analyses that are performed on biobank samples are not communicated on an individual level, since this is explicitly mentioned in the informed consent. However, summary reports of the studies that are performed on biobank samples are communicated via the study websites. Based on these reports, participant can follow the new analyses that are performed. At any moment, a participant has the right to request his/her personal results via the PI or the medical doctor, and this information will then by shared by the medical doctor, either via letter or via telephone, to be able to provide the necessary background information. Also in case of an alarming result for a health parameter that is clearly interpretable, the medical doctor could communicate this result directly to the participant, after discussion and consent by the management board.The human samples are collected, registered, stored, and managed in a qualitative and uniform manner. Procedures for sample collection, sample pre-treatment, aliquoting, primary and secondary sample tubes, temporary storage, transport conditions, and storage method are documented in a detailed manual. Biobank@VITO uses an unambiguous donor identification system which guarantees the traceability of all samples at any time. All samples are uniformly provided with a unique label number. The sample number is linked to a minimal dataset such as the identification code of the participant, collection date, sample type, sample volume, tube code, and sample location. All this information is stored in a database. Since 2015, a computer-based inventory LIMS (Laboratory Information Management System) system is in use for sample registration and management (Labvantage). The inventory enables to identify the location of any sample at all times.Sample types include whole (cord)blood, (cord)blood derivatives such plasma, serum, red blood cells, white blood cells, RNA and DNA, urine, hair, nails, saliva DNA, exhaled breath condensate, and breastmilk. Samples are stored under optimal conditions in storage facilities at various storage temperatures including −80°C, −20°C and room temperature.Continuously efforts are made to improve the quality management system of the biobank in order to be compliant with OECD and ISO guidelines for biobanks , 7 and tThe pre-analytic phase includes the collection, transport and registration of the samples. The different steps are described in detail in a scenario or in a specific procedure (SOPs). The management of material and equipment is described in a SOP and registrations are kept in a database.Samples are stored under the most appropriate condition depending on the sample type and the biomarker to measure. The quality and the stability of the samples is checked on a regular basis and is dependent on the type of sample and the planned analyses e.g., DNA/RNA integrity check, biomarker stability using control samples kept under the same conditions as the actual samples. Samples are stored in small aliquots and freeze-thaw cycles are kept to a minimum. The storage time can be dependent on the quality of samples, on the number of freeze-thaw cycles, on the participants consent or can be a fixed period set by the PI.Freezers and cooling systems are equipped with a computer-based temperature monitoring system for temperature control and an automatic alarm system in case of repository failure. Freezers are centralized in separate rooms that are not shared with other activities.As participants gave donor consent and no broad consent, samples from collections are available for further research within the context of the well-defined research topic that researchers have had the sample donor's consent for. Therefore, novel usage of the samples considering any new research, further uses or new studies, is not possible without first obtaining a new consent of the donor. Supervision on the correct compliance with these terms is the responsibility of the Biobank manager.In addition, Biobank@VITO hosts different samples collections and access to samples is dependent on the reuse policy of the collection's PI. Sample requests addressed directly to the Biobank@VITO will be referred to the relevant PI. As such, new research projects aiming to use samples from the Flemish Environment and Health Study (FLEHS) collections in the biobank have to apply a request to the Supervisory Board of the Centre of Expertise on Environment and Health. Data/sample transfer can only be carried out after approval by the Supervisory Board. Terms and conditions for data/sample request are defined by the Supervisory Committee. For every new analysis on biobank samples, the approval of an ethics committee is required.A large amount of samples have been collected from the general population of Belgium , Flanders  or specific regions . These human biomonitoring studies have different scopes: they often combine specific research questions and policy-based goals, and are financed by different funders, such as the European Commission, the Flemish government, national, or regional organizations. An overview of the type and amount of samples in the biorepository which were collected in different studies is given in On behalf of the Flemish government, the Center of Expertise on Environment and Health has studied the human exposure and health effects of environmental pollutants by conducting 5 years human biomonitoring campaigns in Flanders , 9, 15. The first Flemish Environment and Health Study (FLEHS I 2002–2006) included participants belonging to three different age groups  recruited in eight regions in Flanders with different environmental characteristics. In total, about 1,600 participants per age group participated in the study. The exposure and health effects of ‘classic’ historical pollutants  were measured. Blood and urine samples were collected. Any leftover specimens after biomarker analyses were stored in a biorepository. Saliva and blood samples were collected in a subpopulation of the longitudinal birth cohort of FLEHS I at the age of 10 years (n = 250), (2) 14–15 year old adolescents (n = 200), and (3) adults between 20 and 40 years of age (n = 200). Moreover, adolescents of 14–15 years were recruited in two industrial hotspot areas in Flanders  (n = 200 in each hotspot) (The FLEHS II 2007–2011) biomonitoring campaign aimed to set reference values for a broad range of environmental pollutants in three age groups of the general population . Partici biomonitThe third human biomonitoring program FLEHS III (2012–2015) continued to build on the broad basis of the first and second cycle. Flemish reference values both for historical and recent pollutants were determined in different age groups: pregnant mothers, adolescents of 14–15 year old, adults (50–65 years). Between 200 and 300 study participants per age group were recruited across Flanders. Specific efforts were made for recruitment of participants from different ethnic origin, low income or low education level. Cord blood, blood, urine, and hair samples were collected. In addition, adolescents were studied in one industrial hotspot area . Similar to FLEHS II, additional samples were taken for long-term storage in the biorepository.The fourth campaign FLEHS IV (2016–2020) aimed to recruit 600 adolescents aged 14 and 15 years across Flanders from which 200 participated earlier in the newborn campaign of FLEHS I, 14 years ago. FLEHS IV will examine the exposure to environmental pollutants among young people from the general Flemish population. The study will address present-day topics: environmental exposure and health in Flanders in relation to use of space and eco-behavior related to consumption of locally grown or organic food and housing conditions . New and emerging chemicals were prioritized based on their relevance for assessing exposures from green/gray/blue/agricultural space and eco-behavior. Samples of whole blood, serum, blood RNA, hair, and urine were stored in the biorepository.The 3xG study is a health monitoring pilot study that has been conducted on behalf of the Belgian Agency for Radioactive Waste and Enriched Fossil Materials (NIRAS) and the local partnerships STORA (Dessel) and MONA (Mol) to survey health in relation to life style and environment of children that are born and grow up in 3 Flemish municipalities . The 3xG project is programmed as a long term follow up study for children from before birth until the age of 18 years and was initiated in autumn 2009. The project is carried out by the VITO Health team, Provincial Institute of Hygiene of Antwerp and social scientists of the University of Antwerp and collects biomonitoring data on pesticides, heavy metals, substances in consumer goods and on lifestyle. For this study, urine and blood samples of pregnant women and cord blood samples of their babies were collected, analyzed or stored for later analysis. Monitoring newborns from birth and their long term follow up is used as a sentinel for health of the local population. Early warning and sensitive parameters are collected to reflect potential environmental and life style risk factors and to provide advice for improving health. Special focus is on early warnings for obesity, asthma, allergies, growth, and development and heart and vascular diseases. Presently, 300 mothers and their babies are participating in this study. Cord blood, breast milk, blood, plasma, serum, and urine samples were stored in the biorepository. A follow-up of the children at the age of 7 years is planned in 2019–2020.The objective of the European Seventh Framework Programme COPHES  was to develop a harmonized approach to conduct human biomonitoring in Europe. In 17 European countries, the biomonitoring guidelines and protocols developed by COPHES were tested in a biomonitoring pilot study DEMOCOPHES  , 13. MerBiobank@VITO has its limitations and strengths. Biobank@VITO is a population biobank and hosts a heterogeneous collection of samples from the general population spread across Flanders and over time and covers different ages. As no continuous monitoring program exist in Flanders the characteristics of the collections are completely dependent on the research question of the biomonitoring study. Over the years, samples have always been collected and stored according to most appropriate conditions at that time with regard to the selected biomarkers. Due to progressive insight into storage conditions and technological developments, some issues must be taken into account when reusing these samples. The quality of the samples collected a long time ago might not be useful to perform all type of newly developed biomarker analyses because of the way they were collected/stored at that time and the uncertainty of biomarker stability over time. However, for specific purposes, these samples are still very valuable. Further, biobank establishment, biobanking of human samples and biobank management and maintenance is costly and involves a significant workload. These expenses have to be taken into account in project application and implementation and have a considerable impact on the study budget.However, Biobank@VITO is unique in providing a biological archive of human exposure to environmental chemicals in Flanders. The biobank holds great potential for research on the interaction between health, environment and lifestyle to support policy development in the nexus of environment and health. The biobank is a sustainable platform in which the same human samples can be reanalyzed for new technologically advanced exposure and effect biomarkers. The platform will allow to address specific research questions on population health in relation to environmental factors allowing both prospective and retrospective analysis.All datasets generated for this study are included in the article/GS, VN, and ED designed and coordinated the Flemish HBM studies FLEHS and 3xG. GS, KV, and ED initiated the biobank initiative at VITO. ED, AC, and RV further elaborated the biobank initiative. RV wrote the paper. All authors evaluated and approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Ciguatera is a food intoxication caused by the consumption of primarily coral fish; these species exist in large numbers in the seas that surround the Colombian territory. The underreported diagnosis of this clinical entity has been widely highlighted due to multiple factors, such as, among others, ignorance by the primary care practitioner consulted for this condition as well as clinical similarity to secondary gastroenteric symptoms and common food poisonings of bacterial, parasitic or viral etiology. Eventually, it was found that people affected by ciguatoxins had trips to coastal areas hours before the onset of symptoms. Thanks to multiple studies over the years, it has been possible to identify the relation between toxigenic dinoflagellates and seagrasses, as well as its incorporation into the food chain, starting by fish primarily inhabiting reef ecosystems and culminating in the intake of these by humans. Identifying the epidemiological link, its cardinal symptoms and affected systems, such as gastrointestinal, the peripheral nervous system and, fortunately with a low frequency, the cardiovascular system, leads to a purely clinical diagnostic impression without necessitating further complementary studies; in addition, what would also help fight ciguatera poisoning is performing an adequate treatment of the symptoms right from the start, without underestimating or overlooking any associated complications. Gambierdiscus [35H65NO8 by means of Ultra-Micro methods [Ciguatera fish poisoning (CFP) is an intoxication due to eating contaminated fish with ciguatoxins. Ciguatoxins are lipid-soluble polyether compounds consisting of 13 to 14 heterocyclic rings whose synthesis is associated with various species of dinoflagellates . The maiSphyraena barracuda) and moray eel (Gymnothorax moringa) [On the other hand, CFPs have a great impact on the tourist and gastronomic sector of the Colombian Atlantic and Pacific coast, describing it in the Colombian Caribbean as the main cause of the ciguatera consumption of barracuda meat (moringa) .Seriola zonata , highlights the probability of existence of dinoflagellates that synthesize ciguatoxins in the vicinity of the Departments of Bolívar and Sucre in the Colombian Caribbean, although the species of dinoflagellate that caused the intoxication was not identified [Regarding the first reported case of CFP in Colombia, caused by ingesting the meat of a entified .There is little information on CFP in Colombia and the registration of its dynamics is difficult, given that Colombia is not required to register for the National Public Health Surveillance System—SIVIGILA. For this reason, this review aims to make a survey of the ciguatera register in the Colombian Caribbean and the development of cases recorded when it was possible to find this description.CFP is prevalent throughout the world; it is estimated that there are more than 50,000 cases in the world . In the Prorocentrum emarginatum and Sinophysis microcephala) and, given its floating nature, it represents perhaps the most important vector for the dispersion of these toxic agents on the island [A study carried out by Mancera-Pineda in 2014, where they evaluated the presence of potentially toxic dinoflagellates associated with floating organic material in San Andrés Islas (drif), indicated that drift is an important substrate for dinoflagellates  and brown meat (Gymnothorax moringa) [On the other hand, an ichthyotoxin poisoning event is described in the fishing community of the city of Tasajera, Department of Magdalena. Ciguatera poisoning was diagnosed in seven individuals whose ages ranged from 17 to 53 years (63.4% of the age range of fishermen in the sector), with symptoms of vomiting (100%); muscle pain in the lower extremities ; abdominal spasms (85.7%); diarrhea (100%); numbness and tingling in the face, hands and feet (85.7%); dizziness (100%); and a rash (14.2%); symptoms in most cases disappeared within 8 to 12 days. The main cause of the ciguatera event was the consumption of barracuda  in Colombia [In 2017, Steven and collaborators reported that the highest CFP incidence rates in the Caribbean occur in Antigua and Barbuda ), and the 2003–2013 average projected division rate is 100 to 250 div. moColombia .In the Colombian Caribbean, more than 200 cases of ciguatera have been reported since 1968, without deaths . The symProrocentrum, Ostreopsis and Gambierdiscus, which include toxigenic species related to ciguatera and diarrheic shellfish poisoning  on the Island of Barú, and the same behavior was shown in the study sites; furthermore, findings on Isla de Barú suggest that El Niño may modulate dinoflagellate populations, increasing its abundance compared to neutral periods, especially in species of the genus Prorocentrum [Three seagrasses, ocentrum .Thalassia testudinum, and found seven different dinoflagellates  with a cell density mean of 166 cells/grams dry weight, divided between eight sites  [In 2010, Rodriguez et al. studied the island of San Andres for the dinoflagellates associated with  Acurio) .Gambierdiscus toxicus is the dinoflagellate most associated with the production of ciguatoxins that are the cause of systemic symptomatology [matology . These tmatology .Gambierdiscus that synthesize gambiertoxins. The biomagnification process of ciguatoxins in fish that have been fed with Gambierdiscus sp. have been previously described, establishing an association between the size of the herbivorous fish that habitually feed on this type of dinoflagellates and the concentration of the ciguatoxins, which is species specific [The intoxication is the result of eating herbivorous fish that have fed on the dinoflagellates of the genus specific .Several factors influence the risk of suffering CFP, being more frequent when consuming fish of a large size or high longevity due to the fact that it is more likely that they have a greater accumulation of ciguatoxins given the associations made with these two factors previously . It shouAs for the toxicokinetics of the ciguatoxins, it has been described that ciguatoxins are voltage-gate selective; the intestinal absorption of ciguatoxins is rapid, and it is quickly localized in soft tissues such as skeletal muscle, the heart and the nervous system. Ciguatoxins are transported together with plasma proteins, mainly seroalbumin, and can be found in toxic levels in body fluids such as breast milk and seminal fluid, in addition to their characteristic of liposolubility, making them able to cross the placental barrier and can cause fetal conditions and abortions during the acute phase of the poisoning. After a liver biotransformation, finally the toxin is excreted by bile in the feces .Toxicodynamics consists of an induction to the opening of the voltage-gated sodium channels dependent on ciguatoxins at the level of skeletal muscle, heart cells and mainly peripheral nerves. Once the sodium channels open, an intracellular flow of sodium is generated that causes water to enter the cell and produce edema generated at the level of the white tissues by the toxin mentioned previously. In search of intracellular homeostasis, compensatory mechanisms begin the expulsion of excess sodium internalized in the cell, exchanging it for extracellular calcium to such an extent that the intracellular calcium levels can become so high that they generate increased tissue contraction force muscle .The general signs and symptoms of CFP are as follows: headache, diarrhea, vomiting, osteotendinous hyporeflexia, hives, conjunctivitis, pain and decreased visual acuity. These clinical presentations may vary in the acute, chronic and relapsing phases of the illness .According to the article of Palafox and Buenconsejo-Lum in 2001 , the cliLooking at the first symptoms detected, they frequently appear 4–6 h after toxin consumption, but can occur within minutes with large toxin ingestions or can manifest in 24 h with smaller doses of the toxin [CFP presents a great variety of symptoms and symptomatological patterns, depending on the region where the contaminated meat has been ingested. It is said that the Caribbean areas have primarily gastrointestinal symptoms of the neurological type, whereas the opposite happens in the Pacific ; these dGastrointestinal tract: It is perhaps the most affected and associated with earlier onset; it is characterized by diarrhea, nausea, vomiting, metallic taste, abdominal pain and pain with defecation. The gastroenteritis of infectious origin appears easily; however, they have very nonspecific symptoms that do not usually orient the ciguatera disease with certainty, and can take a long time to disappear, usually between 1 and 2 days after ingestion .Neurological manifestations: Taking into account the pathophysiology of the toxin when producing sodium-channel opening, whereby large intracellular water flow causes edema at the level of the Schwann cells and the axons generate a decrease in the speed of the nerve conduction, and an increase of the refractory phase of the potential of the action, the patients present paresthesia in their limbs that could start from 30 min or days after the consumption of the contaminated fish, being able to persist for months or years. In addition, cases of odontalgias have been reported, so too ataxia, vertigo, allodynia and headache after consumption of ciguatoxins ,30,31.Cardiovascular manifestations: These are the least frequent but the most feared, usually starting 2 and 3 days after consumption . The toxOther manifestations: The most frequent skin conditions of toxic infection are a rash associated with pruritus and are related to acne exacerbations .The main route of exposure of the toxin is orally; there are other ways of transmission, such as maternal–fetal, for which cases of abortions and preterm birth have been reported. In addition to the oral route is the sexual route, by the presence of the toxin in the seminal fluid, causing pain during ejaculation, vaginal burning and pelvic pain; these symptoms may persist for 2 to 3 weeks .The diagnosis is clearly clinical, looking at the recent history of fish consumption, more so if they are species of reefs, and at the subsequent onset of a gastroenteric condition associated with neuropathic symptoms, mainly at the level of the peripheral nervous system. It should always be remembered that the consumption of fish in non-coastal areas does not exclude the diagnosis .The results of general paraclinics, such as a hemogram, arterial gases, and renal and hepatic function, generally yield results in the normal range. Nonspecific alterations in heart rhythms documented in electrocardiogram traces should generate suspicion about the cardiac compromise generated by the ciguatoxins .So far there is no specific paraclinical method for accurate diagnosis of ciguatera in humans. A practical product is commercialized to detect toxins in the meat of the fish to be consumed, called ciguaCheck ,37. In aIt is worth mentioning that the most traditional biological method that is available for use in most care centers, having considerable reliability without being highly specific, is not considered a routine diagnostic method due to its high cost; so, it is not cost effective. From a mouse bioassay, where the rodent was fed contaminated fish meat, it was learnt that one of its main disadvantages is the long observation time of the mice that consumed the contaminated fish meat ,41.Like ciguatera, there is a wide range of toxic infections related to consumption of seafood that are the same or mostly unknown and whose clinical manifestations can be very similar .Tetradotoxism caused by tetradotoxin, which is acquired by consuming puffer fish, is the most fatal marine toxin causing systemic block of the sodium channels, generating symptoms from approximately 20 min up to 3 h after ingestions, rapidly evolving into nausea, vomiting, headache, paresthesia, dysarthria, ataxia, quadriplegia, respiratory failure, coma and death. There is no evidence of an antidote, and treatment consists of limiting or minimizing absorption and treating complications that threaten the patient’s life .The scombroidosis caused by the consumption of fish that have not had a good refrigeration begins a process of decomposition with growth of bacterial colonies activating the enzyme histidine decarboxylase using as a substrate histidine, abundant amino acid in the muscle tissue of reef fish , with thTreatment consists of adrenaline in cases of anaphylactic shock, corticosteroids and antihistamines .Additionally, intravenous mannitol remains the primary treatment consideration for CFP. Mannitol therapy has been recommended for the goal of reducing symptoms  during the acute stage of the illness; it can be used in patients with significant morbidity due to poisoning by ciguatoxins and it is recommended to administer 1.0 g/kg body weight over a 30–45 min period ,48.Clostridium botulinum toxins [Food poisoning of bacterial, viral or parasitic etiology can be triggered by consumption of contaminated fish during the process of handling these foods, often associated with dysentery and fever, and are not related to neurological symptoms. except for botulism caused by intake of m toxins .The clinical management of ciguatera poisoning is symptomatic and supportive; it should be noted that the topic should be known and that it exists so as not to underreport such poisoning. In the following section, a division between acute management and chronic management will be performed .Patients with symptoms such as a skin rash, pruritus and acute gastroenteritis: Medical management is with isotonic intravenous fluids, such as 0.9% saline or Ringer’s lactate, depending on the state of dehydration of the patient; in addition, an antiemetic and an antihistamine can be used .There are case reports in which patients have severe poisoning, defined as alterations in the state of consciousness, presence of cardiac arrhythmias and/or hypotension; in these cases one must start by ensuring the airway is open if necessary, starting mannitol early at a dose of 1gr/kg of weight to pass in 30 min to 1 h and the dose can be repeated. As such, its mechanism of action is not known exactly but it has been speculated that due to its osmotic diuretic effect, it sweeps the ciguatoxins and decreases the axonal edema that causes competitive inhibition with the sodium channels. To begin the said diuretic, one should not wait more than 72 h .In cases of hypotension, supportive medical management with dopamine and anti-shock therapy with volume expanders can be initiated; in case of bradycardia, atropine at a dose of 0.5–2 mg intravenously is useful .As for chronic management, it should be noted that all treatments are aimed at neuropathic therapies, since the predominant symptoms are from the peripheral nervous system; for example, paresthesia, dysesthesia and vertigo; multiple drugs have been studied for these symptoms, and currently they are used with little clinical evidence . It must be said that the management of chronic symptoms could be long term and, in some circumstances, it becomes a challenge for the clinician .Ciguatera poisoning is a disease with great impact on public health, especially in the Colombian coast. The most frequently given advice is not to consume fish weighing more than 2 kg, avoid eating fish such as barracuda and not eating fish parts such as the viscera, brain and gonads, which is where ciguatoxins is mostly accumulated. An invitation is sent to the territorial entities to carry out control measures for the consumption of certain fish; in addition, because this is a medical and environmental alert, the symptoms must be known and an adequate diagnosis of this poisoning must be given, so that CFP does not drastically disrupt our daily life.


Despite significant advances in the treatment of lung cancer, particularly with the evolution of immunotherapies and targeted therapies, the symptom burden is still significant and impact on quality of life for these patients. One-third of lung cancer patients experienced moderate-to-severe symptoms in one study before initial treatment , with siSardaro et al. assessed 80 patients in a prospective study after radiation therapy over a period of 6 months. Their focus was on radiation-induced lung injury (an under-researched topic) and used dyspnea as symptomatic endpoint for lung injury. Parameters of lung volume-dose were strongly correlated with dyspnea, with an increase of 10%. The authors recommended regular assessment of dyspnea to identify early radiation-induced toxicity in the lungs.It is clear that managing symptoms related to lung cancer and its treatments can positively impact on both quality and quantity of life. Hence, in this Research Topic, we have put together six articles that deal with supportive care topics in the lung cancer population. Half of them focus on breathlessness. Yates et al. showed that breathing exercises alongside psychosocial support over 8 weeks was significantly improved in the intervention group in relation to average breathlessness, control over breathlessness and anxiety scores. All these outcomes, however, were secondary outcomes. The primary outcome of “worst” dyspnea, and secondary outcomes for distress from breathlessness, functional status, and depression, did not show an improvement in the intervention group over the control group. This study adds to the limited pool of effective interventions we have to manage breathlessness, and to the consistent literature that breathing retraining and exercises with or without other intervention components can improve this symptom experience. The second trial by Choratas et al. was a small-size feasibility trial of 24 lung cancer patients and 24 of their informal caregivers. The intervention was educational in nature, focusing on teaching patients on aspects of breathlessness and introducing through video clips three interventions, including diaphragmatic breathing, inspiratory muscle training, and the use of a handheld fan. The trial showed that the design of this educational intervention is feasible and suggested improvements in both breathlessness levels and anxiety. However, despite showing some potential effects, a large-scale fully-powered trial is necessary to clarify the effectiveness of this intervention.The other two studies on breathlessness were randomized trials of non-pharmacological interventions. In a multicenter trial of 144 patients, Li et al. investigated the experience of symptoms in lung cancer patients receiving chemotherapy in a longitudinal design from before treatment to cycle one to cycle three and above, using latent profile analysis. Two symptom profiles were identified, including those patients with a “Mild” symptom profile and those with “Moderate-severe” one. During the time of assessment, about 41% of those in the mild group moved to have moderate-severe symptoms, whereas only 2% of the latter group moved to the mild symptom group. Eight symptom transition patterns were observed. This study highlights the changing nature of the symptom experience in this group of patients that needs to be considered in the development of interventions to manage the symptom experience.The study by Zhang et al. used data from 545 patients to develop a survival prognostic model. The best fit for the model (area under the curve = 0.73) included the following variables: age >/=65, TNM stage, lung lobectomy, chemotherapy type and pretreatment hemoglobin levels. The lack of a validation cohort in this study and its retrospective nature are major limitations but if this model is confirmed in future studies it can provide an easily-calculated prediction of survival in non-small cell lung cancer patients.Another study by Molassiotis et al. highlights research priorities in the field from the perspective of nurses and allied health professionals through an international online survey. The development of interventions, particularly around symptom management, were among the most frequently reported priorities, alongside interventions to improve quality of life and healthcare system issues (such as continuity of care or access to care). The list of priorities may be used by funders to stimulate specific research were there are gaps in the evidence and allow for urgently-needed evidence to be developed and subsequently used to improve the care of patients with lung cancer.Some of our observations during the time we edited this Research Topic were about the poor quality of the submitted studies, limited interest in the topic and the narrow focus of studies. The final article of the Research Topic by There is a need for more and better quality studies in the field of quality of life and symptom management in lung cancer. While lung cancer patients will live longer with the recent advances in treatments, the majority will still die from the disease, making quality of life, palliative care and end of life care significant priorities, requiring proactive assessment and management of symptoms, and a multidisciplinary care approach.AM compiled the first draft. PY and JY commented on the draft and had intellectual input. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Down syndrome is the most common chromosomal disorder, associated with moderate to severe intellectual disability. While life expectancy of Down syndrome population has greatly increased over the last decades, mortality rates are still high and subjects are facing prematurely a phenomenon of atypical and accelerated aging. The presence of an immune impairment in Down syndrome subjects is suggested for a long time by the existence of an increased incidence of infections, the incomplete efficacy of vaccinations, and a high prevalence of autoimmunity. Immunologic abnormalities have been described since many years in this population, both from a numerical and a functional points of view, and these abnormalities can mirror the ones observed during normal aging. In this review, we summarize our knowledge on immunologic disturbances commonly observed in subjects with Down syndrome, and in innate and adaptive immunity, as well as regarding chronic inflammation. We then discuss the role of accelerated aging in these observed abnormalities and finally review the potential age-associated molecular and cellular mechanisms involved. Down syndrome (DS) or trisomy 21 is the most common known genetic disorder associated with moderate to severe intellectual disability, occurring in approximately 1 out of every 600–700 live births –6, DS inIn this work, we review how the phenomenon of aging impacts the immune system in DS subjects. We firstly describe clinical features of DS individuals from an immune point of view. We then summarize evidence on immunosenescence in DS subjects and how it impacts both innate and adaptive immunity, as well as chronic inflammation. Finally, we discuss the potentially age-associated mechanisms involved.DS has long been considered as a progeroid syndrome, as individuals with trisomy 21 start to age prematurely and present precociously conditions usually characteristic of the geriatric population –12. The From a biological point of view, the same trend of accelerated aging has been observed with the use of aging biomarkers . The latSignificant evidence has accumulated on the existence of an immune dysregulation in DS, existing from the very beginning of the life of DS individuals. Firstly, it has been observed that DS subjects are characterized by a higher susceptibility to bacterial infections as compared with the general population, with especially a higher incidence of recurrent and chronic respiratory tract ones –25. DS iThis clinical picture recapitulates the increased incidence of infections, the failure of vaccination, and the high prevalence of autoantibodies that can be observed in older people of the general population, supporting here also the concept of DS as an accelerated aging syndrome. This clinical presentation is the reflect of important alterations in immune homeostasis in DS with significant perturbations in all branches of the immune system, some of them being common with the ones observed during immunosenescence and that will be detailed in the next sections.During aging, the immune system shows marked changes which have been gathered under the term immunosenescence –37. TherThe main changes in the adaptive immune system during normal aging occur in the T cell compartment as T lymphocytes appear to be dramatically affected, with a decrease in naïve T cells and an increase in memory ones , 39–41. In DS, studies on immune system have been mainly focused on the T cell compartment Table . DS subjThe thymus is a key lymphoid organ affected by immunosenescence, as it undergoes major changes during aging with a process of involution and shrinking, and a constant decline in the output of newly generated T lymphocytes . In DS sAging also affects the humoral compartment, with reduction in B cell numbers and repertoire diversity . In DS, There are fewer reports evaluating the innate immune system in DS, as compared with the work done on the adaptive one.dimCD16+) in peripheral blood as compared with controls [Regarding the myeloid compartment of the innate immune system, one work has suggested that DS subjects have lower granulocyte counts, lower numbers of myeloid dendritic cells, and higher amounts of pro-inflammatory monocytes  cells , 77. RegAging is characterized by a chronic, low-grade, and sterile inflammation, called “inflammaging,” which has been directly associated with several age-related conditions , 80, 81.Recent works have shed light on the presence of a constant activation of the IFN response in individuals with DS , 87, 89.The chronic pro-inflammatory state observed in DS subjects is likely to greatly contribute to neurodegeneration. Inflammation is indeed considered as an important contributor to neurodegenerative disorders, such as Alzheimer’s disease, which is highly prevalent in this population , 92. ThuAs we have seen above, quantitative and qualitative alterations in all the compartments of the immune system in DS subjects have been well documented. The exact etiology of these alterations is however still debated, and the unanswered question is the following: is the immune system in DS primarily deficient or is it a victim of accelerated aging?On one hand, some observations seem to be in line with the presence of an intrinsic defect , 79, 93.On the other hand, the observed alterations in adaptive immunity in DS appear reminiscent of immunosenescence, with a phenomenon exacerbated with the age of the subjects . For exaThere is a likely possibility that both phenomena of intrinsic defect and accelerated aging are combined, like it seems to be the case in the mouse model of DS (Ts65Dn) . In the Aging is driven by interconnected cellular and molecular mechanisms, which have been gathered under the terms of hallmarks or pillars of aging , 97. TheIndividuals with DS display a spectrum of clinical and biological abnormalities, which are compatible with an important immune impairment. These disturbances are likely caused by the co-existence of two phenomena, with an intrinsic defect and precocious aging on one hand, and a clear phenomenon of accelerated aging on the other hand. The immune dysregulation affects key cell types, both in myeloid and lymphoid compartments, and is associated with a chronic state of inflammation. The dysregulation of immune responses and the inflammatory state are likely to greatly contribute to age-related diseases and especially to neurodegeneration which is highly prevalent in this specific population . Owing t