Drawing on published ethnographic studies of literacy in everyday life to analyse both the symbolic and instrumental meanings of literacy in specific contexts, the author introduces a social practice lens on literacy and citizenship. She explores the pedagogical implications for literacy within citizenship education, particularly in relation to informal learning of “real literacies”, critical digital literacy to distinguish “fake news” and literature as a way of entering someone else’s experiences. UNESCO’s current vision for global citizenship education as nurturing empathy and understanding between peoples implies that literacy providers need to recognise participants as not only consumers, but as co-constructors of texts.Within citizenship education, literacy is often promoted in a narrow functional sense of skills for civic engagement or is used synonymously with “knowledge” to refer to an awareness-raising process around rights. Through an analysis of evolving models of citizenship, this article moves beyond literacy  The relationship between literacy and citizenship is usually seen as a “given” and as unproblematic – including the assumption that literacy is an essential prerequisite for active citizenship. But do we really understand why, when and how literacy is connected with citizenship? All too often, the term “literacy” is used in a metaphorical sense to mean “knowledge” or “learning” , thus obscuring the ways in which reading, writing, constructing and decoding diverse texts may support – or possibly undermine – citizenship. This article sets out to explore the relationship through a sharper lens, starting from the understanding that there is neither only one kind of literacy nor only one model of citizenship.5th Global Report on Adult Learning and Education (GRALE 5)  curricula: “Close to three quarters (74%) of countries indicated that they are developing or implementing policies in relation to citizenship education” (UIL The E 5) UIL  was launrvey UIL  three yeion” UIL , p. 19. GRALE 5 report . His discussion of “true” words centres on the relationship of literacy to citizenship and action: “when a word is deprived of its dimension of action, reflection automatically suffers as well; and the word is changed into idle chatter …” (ibid.).In terms of the interrelationship between literacy and citizenship education, Paulo Freire’s work highlighted the ways in which literacy has been seen as both an obstacle and an opportunity to engage in active citizenship at differing times throughout history, and his work is a key reference both in the port UIL  and in wport UIL , p. 34. Freire has been critiqued by Brian Street for over-stating the importance of literacy within adult education, and thus promoting the illiterate/literate divide.In order to explore how literacy can become a lever for citizenship, I will begin with a historical account of the development of different citizenship models, identifying influences on the changes that have taken place. This is an essential starting point for investigating various approaches to citizenship education, particularly the intended outcomes and purposes. I will then explore where literacy comes into this picture, drawing on a “situated”  meant that the two-way relationship between the individual and the state was relatively straightforward. As Ralph Dahrendorf  that are now pulling apart Williams , p. 209.Writing on “multiple citizenship education”, Heater . His analysis of the tensions between social class and citizenship is based on the idea that citizenship is “a principle of equality” .Significantly, Nussbaum relates this capacity to teaching “involving non-Western cultures” and “internal minorities” , referring in her article on the importance of liberal arts education to Americans as being “tremendously ignorant of other nations of the world” (ibid.). This aspect of citizenship education has particular resonance with the growing policy attention to Indigenous learning, worldviews and knowledges.Martha Nussbaum addressed these issues directly when she made the case for world citizenship education, developing pedagogical principles and curriculum objectives from these cosmopolitan ideas around citizenship Nussbaum . She prothe ability to think what it might be like to be in the shoes of a person different from oneself, to be an intelligent reader of that person’s story, and to understand the emotions and wishes and desires that someone so placed might have (ibid.).Such a stance, she suggests, is not uncritical – similar to when we read about a character in a novel and make judgements about their behaviour and beliefs. This is where education in literature and the arts is important, Nussbaum argues – to begin to understand meanings of speech and writing in the context of “that person’s history and social world” . She highlights the dangers of the “moral imagination” becoming “lazy” through refusing sympathy to “people who look different”. This emphasis on empathy and exercising “the muscles of the imagination”  through reading and discussion points to an important element of literacy education within universities, a pedagogical approach which could be applied to basic adult literacy programmes too.The third capacity essential to world citizenship is what Nussbaum terms “the narrative imagination” . She explains this asglobal citizenship education is to empower learners to engage and assume active roles both locally and globally to face and resolve challenges  set out to link literacy and citizenship. This programme aimedto enable the large number of disenfranchised and passive poor to see themselves as individuals with rights (and duties) upon the state, to position themselves as citizens with legitimate demands for social change and for a life that recognised their claims as individuals regardless of social class, race, and gender differences  relates to the move away from citizenship as based on a unitary identity. Above all, the MOVA programme aimed to facilitate an educational process of critical reflection on society and the individual’s role within that society. But how did this process connect to literacy, as opposed to other kinds of learning within radical adult education?ial” UIL , p. 161.ial” UIL  researchGRALE 5 Executive Summary, the UNESCO Institute for Lifelong Learning (UIL) reports that “[t]here is ample evidence that literacy learning correlates with positive citizenship outcomes” , Oum Fatima’s skill in mental arithmetic and bargaining was legendary. Not only could she switch effortlessly between the several parallel currency units in use … but her ability to negotiate the lowest possible price made her a well-known figure in the derb (quarter). To those of her social class, as well as to those “higher up”, Oum Fatima was a woman of great respect ” (ibid.). Wagner goes on to say that “[w]hether Oum Fatima is illiterate or literate or somewhere in between depends on one’s frame of reference” , commenting that although local educators and policymakers would consider her “illiterate”, people in her neighbourhood “consider her … among the most competent people they know” . What is interesting here – and of particular relevance to discussions on literacy and citizenship – is Oum Fatima’s confidence in engaging with written texts and numeracies, without any formal schooling. This not only demonstrates her knowledge and confidence, built up through her role as an active citizen in this community, but also that she has learned informally how to conduct complex numerical transactions and even how to recognise different written scripts.Turning to another seminal literacy research study, I will now take an “ideological” perspective on literacy Street  through can rather than cannot do – and to recognise the competencies that her neighbours respect. Adopting this perspective on literacy in relation to citizenship education challenges educators to move away from a deficit perspective on learners, to consider instead how and when they engage with literacy practices in their everyday lives. What is of particular relevance to literacy planners is exploring how informal learning connects with formal literacy instruction.Through the lens of an ideological model of literacy – also discussed as a “social practice” or “situated” approach to literacy (and numeracy) – this example challenges the idea of a divide between literate and illiterate, literacy and orality. Instead, Street  proposedfor citizenship. Ahmmardouh Mjaya .In this place, the alternative to signing one’s name on receipt of various development inputs was to give a thumb print. Ms Suya, another participant, described how officials seeing an older woman automatically got out the inkpad – “they grab our hands and make us print using our thumbs” . In this example, the hierarchies of meaning-making are clear and related to identity and status, as Mjaya observes:While the pen symbolized literacy and somehow raised the confidence and status of those who could get hold of it, the inkpad symbolised “illiteracy”, thereby making those who pressed their thumbs on it as a way of signing feel public shame and humiliation .For Ms Awala, learning how to write her name in the literacy class was not just about gaining a functional skill but also around gaining respect from others in the community, particularly from formally educated people. The symbolic meanings associated with literacy here were valued by Ms Awala and her classmates and perhaps drew them to enrol in a literacy class. Though Mjaya’s research revealed that non-literate women also found ways to vote in committees and work as traditional leaders with help from younger educated women who acted as literacy mediators, some older women were keen to be able to perform such tasks involving reading and writing independentlyI will turn now to two recent ethnographic studies to investigate the connection between literacy and citizenship through a social practice lens – though, significantly, neither of them looks at literacy uh Mjaya  explores“I just thought of it. I asked myself how I can liquidate the money, one by one, so it would also be easy for people to understand. Susan taught me at the start what to do … but I wasn’t comfortable, it was difficult to do … so I just did it like this so that if the auditor reads, it’s easy” Millora , p. 147.Mila’s account gives an insight into how she learned to do the accounts “on the job”, through peer instruction and initial support from her colleague Susan, then working out a system that seemed simpler and more straightforward. In contrast to the Malawi extract, this is an example of functional literacy and numeracy skills linked to citizenship and learned in everyday life, “on the job”, rather than in a classroom. Mila has the confidence to “take hold”  are not only diverse and multiple, but also hierarchical – and such research has implications for literacy and citizenship education. Mjaya’s study reveals how everyday life shapes what people take from the classroom – and why they enrol in literacy classes in the first place. In this case, it was the symbolic act of signing with a pen rather than a thumb print, rather than any specific functional literacy skills, which they valued. Through focusing on how people engage with, mediate and learn literacy and numeracy practices in running an organisation, Millora gives insights into informal learning of bureaucratic literacies.Relating these ideas to my earlier review of citizenship education, learning literacy here is very much around social change, empowerment and engaging with new identities. This connects with the concept of global citizenship education as “transformative” Hanemann , and conI will conclude this article by looking at the pedagogical implications of applying the theoretical lenses introduced above to literacy and citizenship. Since it is beyond the scope of this article to review case studies of best practice in literacy programmes, my aim here is to identify some key features and principles that could enable educational providers to strengthen the connections between literacy and citizenship.souk or Mila maintaining her association’s financial records. As educators, we need to find ways of strengthening the connections between classroom and everyday situations where literacy for citizenship plays a role. All too often, programmes have taken a “literacy first” approach  through engaging with “real literacies” – such as learning to read voting slips – but also about using this theoretical lens to investigate the ways in which literacy is shaped by social relationships in everyday life. Thus this article moves beyond literacy for citizenship to considering the ways in which literacy learning can emerge through active citizenship. Introducing the notion of multiple and multimodal literacies can help to broaden and deepen understanding of hierarchies of literacies and languages in relation to people’s multiple and changing identities. Rather than starting from an assumption that people have one dominant identity which shapes their aspirations and rights as citizens, this stance focuses our attention instead on intersectionality and diversity. Significantly, this alternative theoretical perspective on literacy and citizenship raises different questions – including asking whether literacy is and should be a prerequisite for active citizenship.The relationship between literacy and citizenship is often presented unproblematically as being literacy


The aims of this research were to provide a better understanding of the specific evidence needs for assessment of clinical and cost-effectiveness of cell and gene therapies, and to explore the extent that the relevant categories of evidence are considered in health technology assessment (HTA) processes.A targeted literature review was conducted to identify the specific categories of evidence relevant to the assessment of these therapies. Forty-six HTA reports for 9 products in 10 cell and gene therapy indications across 8 jurisdictions were analysed to determine the extent to which various items of evidence were considered.The items to which the HTA bodies reacted positively were: treatment was for a rare disease or serious condition, lack of alternative therapies, evidence indicating substantial health gains, and when alternative payment models could be agreed. The items to which they reacted negatively were: use of unvalidated surrogate endpoints, single arm trials without an adequately matched alternative therapy, inadequate reporting of adverse consequences and risks, short length of follow-up in clinical trials, extrapolating to long-term outcomes, and uncertainty around the economic estimates.The consideration by HTA bodies of evidence relating to the particular features of cell and gene therapies is variable. Several suggestions are made for addressing the assessment challenges posed by these therapies. Jurisdictions conducting HTAs of these therapies can consider whether these suggestions could be incorporated within their existing approach through strengthening deliberative decision-making or performing additional analyses.The online version contains supplementary material available at 10.1186/s12913-023-09494-5. Cell and gene therapies comprise the majority of the products that the European Medicines Agency designates Advanced Therapy Medicinal Products (ATMPs) . While tMany of the assessment challenges relating to cell and gene therapies apply to rare disease treatments more generally, and most of the current cell and gene therapies are for rare conditions. However, in the case of cell and gene therapies the challenges are compounded by the potentially transformational nature of the health gain and the potential long-term nature of the ‘cure’, which is subject to considerable uncertainty.The issue of how HTA bodies are responding to the assessment challenges posed by cell and gene therapies has received relatively lower attention. HTA methods are partly conditioned by the evidence currently available and new methods often imply the need for new types of evidence. For example, the clinical evidence for cell and gene therapies may be sparse in relation to that available for most pharmaceuticals, the economic benefits produced by cell and gene therapies may require additional evidence to demonstrate them and many of the innovative payment models being proposed may require further evidence generation post product launch.In addition, although some of the papers in the current literature argue for a different approach to the HTA of cell and gene therapies, most HTA bodies prefer to use a standardized approach for all health technologies. In this context, the paper by Drummond et al.  argues tTherefore, the aims of this research were: i). to provide a better understanding of the specific evidence needs for assessment of the clinical and cost-effectiveness of cell and gene therapies, ii) to explore the extent that the relevant categories of clinical evidence, economic evidence and evidence post-launch are considered in the HTA processes in several jurisdictions, iii) to identify the issues in the generation and use of evidence that require further discussion and consideration.To achieve the aims above, we undertook i) a targeted review of the literature on the clinical and economic evidence needs for these therapies, and ii) an in-depth analysis of HTA reports from 8 major jurisdictions for 9 cell and gene therapies in 10 indications, together with any associated publicly available documents on managed entry agreements and post-launch evidence requirements.Our starting point for the targeted literature review was the paper by Drummond et al. . We seleGiven that there is already a substantial literature on the assessment challenges posed by cell and gene therapies, including several targeted or systematic reviews , 20–22, For the selection and inclusion of HTA reports in our analysis, we identified HTA evaluation reports for cell and gene therapies from 7 HTA bodies, and one regulatory agency that also performs HTAs, published prior to end of July 2021. The agencies were based in the 5 largest European countries, plus the US and Canada: Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) in Spain, Agenzia Italiana del Farmaco (AIFA) in Italy, Canadian Agency for Drugs and Technologies in Health (CADTH) in Canada, Gemeinsamer Bundesausschuss (G-BA) in Germany, Haute Autorité de Santé (HAS) in France, Institute for Clinical and Economic Review (ICER) in USA, National Institute for Health and Care Excellence (NICE) in England, and Scottish Medicines Consortium (SMC) in Scotland. The agencies selected were also representative of different approaches to conducting HTAs, some using the cost per QALY approach and others relying on an interpretation of the clinical data alone  was checked for accuracy of data extraction by another member of the research team.The checklist has been previously used by Huygens et al.  in a smaWe also conducted a more detailed analysis of the comments made in cases where a particular item was considered, by classifying the comments as ‘positive’, ‘neutral’ or ‘negative’. Positive assessments were those where the HTA body considered that the manufacturer had made a reasonable attempt at dealing with the issue, or where the HTA body recognised the importance of the item in considering the technology. Negative assessments were those where the HTA body felt that the issue had not been adequately addressed, or where it did not recognise the importance of the item in considering the technology. Neutral assessments were those where the committee made no comments either way. These assessments were made by two members of the research team, with a consensus being reached in cases where there were any differences of opinion.The findings were discussed by a small group consisting of academic researchers, payers, patient representatives and pharmaceutical industry personnel, prior to drafting a paper for submission to a peer-reviewed journal.In total 38 papers were selected for detailed review based on their title and abstract, plus 8 reports from HTA bodies and related organizations. The main issues relating to the use of evidence were as follows.Although the main focus of most of the papers reviewed was the economic evidence needs, several also discussed issues with the underlying clinical evidence for cell and gene therapies , 23, 24.Many cell and gene therapies are approved based on accelerated approval pathways, which allow for trials to be powered on surrogate, rather than final, endpoints. Where surrogates are used, they need to be validated, to show that they are closely linked to the final outcome of interest. This would usually be demonstrated through a meta-analysis of randomised controlled trials in the same indication .However, in the case of cell and gene therapies, many of which are for rare conditions, these high standards of validation are difficult to achieve. It may be necessary to relax the requirements for validation to consider the partial exchangeability of evidence across treatment classes or other patient populations. It may also be necessary to accept that although the outcome measure used is not a true surrogate for the final outcome, it may have prognostic value for an outcome of importance to patients, carers or payers .More generally on the appropriate selection of endpoints, the Institute for Clinical and Economic Review (ICER) evaluation framework for assessing single or short-term therapies (ICER-SST), has recognized the importance of patient-centric outcomes, such as daily function, chronic pain, physical activities, goal attainment, which could be relevant in many indications for cell and gene therapy, although they are rarely included in clinical trials .Economic evaluations rely on an estimate of the relative treatment effect between the new treatment of interest and the current standard of care. However, for cell and gene therapies there is a high preponderance of single arm uncontrolled clinical studies, either because the patient population is small, or because of the practical difficulties or ethical concerns in randomization due to the potential of cure offered by the new therapy.Therefore, it may be necessary to construct a comparison arm by using a historical or synthetic cohort. This was the approach followed in the economic evaluation of voretigene neporvovec (Luxturna) for inherited retinal disease. However, when using a non-randomized comparison it is important to adjust for any confounding factors . In the Target trial emulation is gaining traction as a two-step methodological approach, useful in situations where there is dearth of comparative evidence , 30. WhiThe problem of small patient populations for rare diseases is a feature of both randomized and non-randomized clinical studies of cell and gene therapies. One review found that 47.2% of gene therapy clinical trials enrolled fewer than 20 patients and that the median size of trial populations was 213 patients . The HTASmall sample sizes greatly increase the uncertainty around clinical effect size, and also mean that any heterogeneity in the patient population is hard to analyse. With larger sample sizes heterogeneity in clinical and cost-effectiveness can be explored by defining and comparing sub-groups of the patient population, but this may not be possible with small patient numbers. In terms of subgroup data, performing post-hoc analyses without prior specifications is not appropriate, but they have been reported for some gene therapies assessed by EMA, and were found to be hypothesis generating instead of confirming . An issuAnother major consequence of accelerated marketing approval for cell and gene therapies is that the length of the available clinical studies may be short at the time the HTA is conducted, and hence extrapolation to long term endpoints will be required. This means that there is often considerable uncertainty about the nature of the survival curve (for the outcome of interest) for cell and gene therapies, and how this should be modelled. This issue is magnified in HTA evaluations focusing on young, compared with older, patients .Some assessments of cell and gene therapies use mixture cure models, as was the case for axicabtagene ciloleucel (Yescarta), where the key assumption is that of the proportion of patients cured . In the Most of the papers reviewed discussed the economic evidence requirements implied by the features of the diseases treated by cell and gene therapies, or the effects of those treatments.Several papers noted that the conditions treated by cell and gene therapies are life threatening or seriously debilitating. There is some evidence that individuals place a higher value on health gains for people whose health is at a lower level . TherefoInsurance value relates to the notion that individuals place a value on therapies being available in the future, even if they are unlikely to need them. It has been argued that when the treatment is for a serious disease, the insurance value is likely to be higher . Some paIt is often the case for rare diseases that currently no active treatment options exist. Although the definition of “unmet need” is heterogenous across countries, lack of an effective available therapeutic option is often, together with disease severity, a key qualifier for high unmet need, which constitutes a background for the value assessment of cell and gene therapies , 39. ThoMany cell and gene therapies have been described as ‘transformational’ in terms of the increases in length or quality of life they produce . As in tMany cell and gene therapies have curative intent, although the evidence does not currently exist to show that they provide a ‘cure’ . It has However, to date there are no published estimates demonstrating the value of this.Although there is currently no evidence that cell and gene therapies provide a cure, many of them have a treatment effect of long duration. It has been argued in the literature that this adds value in that it provides patients the opportunity to benefit from other treatment advances in the future . Option The value of therapies to carers and the family, in the reduction of the emotional stress of seeing a close relative or friend suffering from a serious disease, or the time spent in providing informal care, is widely recognised but rarely quantified in HTAs . Many ceWhen a drug with a new mechanism of action is discovered, it may facilitate the development of other therapies that will deliver benefits to future patients. Given that gene therapy is in early stages of development, it is likely that the level of scientific spillovers could be extensive. However, this has yet to be demonstrated . Some HTThe choice of discount rate typically has a profound effect on the cost-effectiveness of cell and gene therapies, given their high up-front cost and potentially long-term benefits. Arguments have been made for a lower discount rate for gene therapies, on the grounds that the social rate of time preference might be different for investments made collectively by society, that benefit future generations . HoweverAlthough there are well-accepted methods for characterising uncertainty in economic evaluations, the main uncertainty with cell and gene therapies is the long-term durability of the clinical effect. It has been suggested that it might be useful to conduct a series of scenario analyses for long-term effect that decision-makers could contemplate . A critiUncertainty has also been referenced with respect to ancillary medical costs of administering cell and gene therapies, treating complications, providing follow-up care, and to patients and their families out-of-pocket expenses to travel to administration sites and to stay there for follow-up monitoring .Overall, based on the literature review, we concluded that the issues raised in the Drummond et al. paper were still valid and representative of the current literature.Some of the long-term uncertainties can only be resolved by further data collection post-launch. Several of the papers reviewed stressed the importance of managed entry, or market access agreements for cell and gene therapies, either because of the high cost of these products and/or the uncertainty over their clinical effectiveness , 6. ThesOutcomes-based agreements can be on the population level and dependent on the results of an ongoing prospective clinical study, such as a randomised trial, or on an ad hoc post-marketing observational study. They can also be on the patient level and dependent on a patient registry that is established as part of the agreement. The collection of evidence post-launch is critical to the outcomes-based agreements and can raise several challenges in study design, data collection and analysis. For example, one of the barriers identified for the implementation of outcome-based spread payments is reaching an agreement on financial terms while considering 12-months budget cycles and the possible violation of corresponding international accounting rules . BecauseThe key question is how to collect reliable data on outcomes while still making the process manageable. Three approaches can be observed in the literature. First, data on outcomes can be obtained from clinical studies that are still ongoing at the time market access is granted. This is one of the approaches used to support the reimbursement of drugs on the Cancer Drugs Fund in the UK . SecondlFinally, the literature has identified additional procedural and organizational challenges , from asIn total 46 HTA reports were reviewed, covering 9 cell and gene therapies, one of which  had indications for use in two different patient populations , relapsed or refractory b-cell acute lymphoblastic leukaemia (ALL). Given the different timing of market access for a given technology in different jurisdictions, the list of cell and gene therapies identified was assessed by a maximum of 7 HTA bodies  to a minimum of one single assessment . None of the therapies had been assessed in all 8 jurisdictions.Table The full data extraction for all the HTA reports is given in Appendix Overall, the consideration of the key aspects of the clinical evidence by the various jurisdictions was high. Given the clinical evidence considered in HTA reports of cell and gene therapies typically relies on the pivotal clinical trials used to gain – usually accelerated – regulatory approval, there is high consistency in the consideration of clinical evidence related challenges across the different HTA bodies. For example, the use of a surrogate endpoint was discussed in 70% of the reports, the use of a single arm trial in 85% and the extrapolation to long term outcomes in 78%. The sample size of the clinical trials considered ranged from 18 (Strimvelis) to 436 (Imlygic), with a follow-up from less than 12 months (Glybera) to up to more than 4 years in the case of Zolgensma. The short duration of many of the trials motivates the frequent need of extrapolation of treatment benefit in the long term.Taking the example of Kymriah for relapsed or refractory DLBCL, in all 6 reports analysed the use of a single arm trial and the reporting of adverse consequences and risks was discussed, together with the unanimous recognition that the therapy was not for a paediatric population. However, the fact that the therapy was for a rare disease and for a serious condition was only explicitly considered in 3 and 5 jurisdictions respectively, reflecting different judgments made by the HTA bodies of what constitutes rarity or seriousness of a disease. All agencies but G-BA considered objective response rate as the main endpoint to assess the effectiveness of the intervention, without discussing its surrogacy validity. Depending on the timing of the submission and repeated assessments, the sample size of the clinical trial considered was between 99 and 167, with a median observation time up to 40 months. A matched-adjusted indirect treatment comparison was needed to determine the comparative effectiveness of the treatment, relying on the SCHOLAR-1 cohort in DLBCL . HoweverAlthough more open to judgment and interpretation, the more detailed analysis of comments indicated that the items to which the HTA bodies reacted positively were the indication that the treatment was for a rare disease and that it was a serious condition. The items to which they reacted negatively were the use of unvalidated surrogate endpoints, single arm trials without an adequately matched alternative therapy, inadequate reporting of adverse consequences and risks, the short length of follow-up in clinical trials and the methods for extrapolating to long-term outcomes see Fig. . AlthougTable As in the case of the clinical evidence considerations, the details of the full data extraction are given in Appendix As compared with the clinical evidence considerations, there was much more variability in the extent to which the various elements of economic evidence were considered  was published in January 2022 . The objThe individual-based agreements in Spain and Italy rely on data collected through drug registries and provide enough data on patient response to identify non-responders (for purposes of determining clawback payments) and to inform staged payments. However, the data collected through these registries are not incorporated into a wider programme for real world data collection and do not normally provide enough data to assess clinical outcomes or the impact of therapies on health-related quality of life. The role of these registries in any re-appraisal process is unknown and the data are not normally published.Based on the findings of the literature review and analysis of HTA, it is possible to identify several issues in the generation and use of evidence for cell and gene therapies that require further discussion and consideration However, in discussing these issues it is important to recognise that there are differences between HTA bodies in different jurisdictions in how the clinical and economic evidence should be used. Therefore, any suggestions for improvements need to take account of these country-level differences.To date, most HTA bodies, including those studied here, have not instituted a separate assessment programme or approach for cell and gene therapies, or advanced therapy medicinal products (ATMPs) more generally, although some have supplemental processes for rare disease treatments that are more suited to their assessment , 62. GivIn terms of establishing the validity of the surrogate endpoints, current appraisals of cell and gene therapies are unlikely to meet the highest standards . However, it is still recommended that appraisals of these therapies follow a structured approach to the validation of surrogate endpoints, and justify the adoption based on the prognostic value of the biomarker rather than on the surrogacy value, on relaxed requirements of indication- and treatment- specific evidence of validation, on full or partial exchangeability of evidence across treatment classes and populations. In addition, carefully designed post-launch evidence generation programmes may answer the question of surrogate validity and effectiveness on patient-relevant endpoints, which may be the preferred approach in some jurisdictions. Therefore, it would be useful for HTA bodies and payers to agree standards for long-term patient relevant outcome collection and for validating surrogate endpoints, while acknowledging the challenges posed by small patient populations. Ideally, post-launch evidence generation should be agreed at the time of the HTA, be based on rigorous protocols, and, if possible, enforced by management agreements that make the reimbursement and price status contingent on data collection and the relevant findings.Recruitment to conventional randomized controlled trials may be difficult due to the small target population, and may be influenced by the expectation of sizeable benefits in high unmet-need areas, that strongly enhances the attractiveness of the experimental arm over the standard of care. In addition, there may be operational hurdles, in enrolling patients outside qualified centres, and in the choice of the comparator arm. Although methods for the design and analysis of clinical trials in small populations have been proposed –65,they A high preponderance of pivotal single-arm uncontrolled trials means payers need to find, or assemble, a suitable contemporary historical cohort of patients treated according to standard practice, which can be used to determine the comparative effectiveness of the therapies. A common concern observed in the HTA reports was that ‘standard practice’ could vary across jurisdictions or change over time. Guiding principles for performing such treatment comparisons could be agreed in advance between manufacturers and decision-makers, starting from high-quality patient-level data from reliable and traceable sources; appropriate cohort selection based on matching inclusion/exclusion; suitability of real-world endpoints; fit-for-purpose analytical methodologies. The acceptability of synthetic cohorts or in silico modelling for this purpose should be established. Therefore, it would be useful to agree criteria for when a single-arm clinical study can be deemed acceptable, and guidelines for assembling a matching comparator cohort.Due to the short timeframe of the pivotal clinical studies , long-term benefit and adverse events of cell and gene therapies are not substantiated by trial data and remain largely uncertain at the time of the assessment. Therefore, there is a need to support the assumption of maintained improvement in health or treatment effect in the long-term. It is recommended that current biological knowledge on the pathophysiology of the disease complemented by additional external sources of evidence inform this step. The extrapolation of survival curves is more and more often based on mixture cure models in appraisals of cell and gene therapies, although the plausibility of presence and magnitude of a cure fraction must be discussed at length. Extensive scenario and sensitivity analyses are warranted, given that this parameter may have the largest impact on the cost-effectiveness analyses results.Finally, quality of life measures, although important to patients, are not necessarily considered by those HTA bodies assessing added clinical value, as they are perceived as being subjective. Some countries may need to consider changing their assessment framework to encompass quality of life, although efforts to collect these data in clinical studies also need to improve, as quality of life evidence for cell and gene therapies, and rare diseases more generally, is scarce and often of poor quality . It woulIn addressing the consideration of economic evidence, it is again important to recognise that HTA processes differ quite widely across countries. In those countries that assess the ‘added clinical value’ provided by therapies, economic evidence is not explicitly considered in the assessment process, although the acquisition cost of new therapies is considered as part of the price negotiation. In those countries assessing the ‘cost-effectiveness’ of new therapies, it is possible to discuss how economic value is characterised and whether the definition of ‘value’ should be broadened. It is very rare for countries to switch from one approach to HTA to the other, although France did add the consideration of cost-effectiveness as a supporting approach to its ‘clinical added value’ decision-making procedure. Therefore, in making recommendations for change, it is important to consider how these can be implemented within each of the contrasting approaches to HTA.First, there may be arguments for expanding the HTA process to include the impacts on caregivers and the family. These are important for all therapies, but arguably particularly important in the case of therapies for very severe debilitating illnesses and those affecting children. Within the cost-effectiveness approach this suggests that impacts on caregivers’ quality of life could be assessed and possibly the additional costs imposed on families. If a broader societal perspective were adopted, costs falling on patients and families would be included . In thosWithin the clinical added value approach, consideration of impacts on caregivers and the family could be made an explicit item of value within the ‘clinical’ value, or the composition of assessment committees could be expanded in include patient representatives, who are likely to stress these issues.Secondly, there is broad agreement that cell and gene therapies offer the potential for transformational gains in health. Some jurisdictions following the cost-effectiveness approach do apply a ‘modifier’ to the threshold of the maximum level of incremental cost-effectiveness they are willing to accept in cases where there is a ‘step-change’ in survival and/or quality of life. There could be further examination of whether and how these modifiers are applied in practice and whether they make a difference in the assessments that are performed. It is more difficult to determine how this issue would be explored in those jurisdictions using the ‘added clinical value ‘ approach, other than comparing the decisions across a range of technology appraisals. One study comparing the assessments made by NICE in England and HAS in France did find a correlation between the level of QALYs gained and level of ASMR awarded . PerhapsThirdly, the application of discounting, within the ‘cost-effectiveness’ approach is critical in the assessment of cell and gene therapies, with their high ‘up-front’ costs and potential long-term benefits. It was noticeable in the analysis of HTA reports that where discounting was applied, the effect of differential discount rates was not explored in many cases. Given the sensitivity of the cost-effectiveness estimate of cell and gene therapies to the discount rate, a sensitivity analysis could be presented to decision-makers in all cases.Fourthly, insurance value was not considered in any of the HTA assessments examined, probably because no evidence was presented. It is possible that this is a major element of the value of therapies for catastrophic disease and deserves more investigation. However, further research is required to determine whether the insurance value is substantial for these therapies and whether this justifies the application of a modifier within the HTA process.Finally, a major consideration in all jurisdictions was the uncertainty surrounding cell and gene therapies. Conventional approaches for characterizing uncertainty, such as undertaking probabilistic assessment, are not very helpful when considering issues such as the long-term durability of these therapies, which is often completely unknown. Consideration could be given to the more extensive use of scenario analysis, suggested by Huygens et al. , or the Cell and gene therapies, and advanced therapy medicinal products in general, are often characterized by a high level of uncertainty at market launch over their (long-term) clinical and economic impact. Consequently, ad hoc post launch studies to produce real-world evidence (RWE) could be implemented, if they are needed and feasible. These studies can be linked with outcome-based managed entry agreements in the form of coverage with evidence development: initiating these agreements without an appropriate protocol and data collection may represent missed opportunities.If post-launch data collection through an ad hoc study is not feasible, a pragmatic approach to data collection is better, e.g., the one adopted by England through Managed Access Agreements that rely on existing data collection programs managed by the industry, and existing NHS registries/administrative databases.Individual-based agreements rely on existing drugs registries or ‘ad hoc’ data collection on ‘clinical outcome’ indicators. In many cases they do not provide a complete data set to assess the real-world impact of these therapies, but they could serve performance-linked reimbursement agreements, in which payment is made when patients respond to treatment.In general, more transparency on outcome-based agreements and RWE collected through these agreements is needed, provided that the most sensitive data of the agreement  are kept confidential. Transparency would provide better feedback to those who are tasked with data collection, and would enhance the replicability of the agreements negotiated, thereby benefiting the health care community as a whole. Guidance for implementing and conducting managed entry agreements has recently been developed for rare disease treatments, which could form a basis for discussions on MEAs in cell and gene therapy .This research has shown that the consideration by HTA bodies of evidence relating to the particular features of cell and gene therapies is variable. In part this reflects the different approaches used in different jurisdictions. Although it is not possible to reach a complete consensus on which elements of evidence should be considered, several suggestions have been made. All jurisdictions conducting HTAs of these therapies could consider whether and how these suggestions might be incorporated within their existing approach, through strengthening deliberative decision-making or performing additional analyses.Additional file 1.


Staphylococcus aureus  was the most common pathogen isolated. A previous treatment failure  was the main reason for a switch to a long-acting antibiotic. Most patients were successfully cured with DBV . A source control was performed in most patients with a favourable outcome (80.4%), while MRSA was prevalently isolated in people with an unfavourable outcome (57%). While a higher percentage of success was found in people who received three doses of DBV 1 week apart (92.3%), a higher rate of treatment failure was recorded in cases of when the DBV cycle was composed of less than two or more than four doses (27.8%). Conclusions: DBV has shown to be effective as a treatment for OA infections. The most favourable outcome was found in patients receiving three doses of DBV and with an adequate surgical management prior to antibiotic treatment. Although a rigorous administration schedule does not exist, DBV is a viable treatment option in the management of OA infections.Background: Approved for acute bacterial skin and skin structure infections, dalbavancin (DBV) has gradually acquired over the years a role as an off-label treatment for several infections caused by Gram-positive bacteria even in other anatomical sites. Osteoarticular (OA) infections are one of the most difficult-to-treat infections and, since the absence of recommendations, clinicians use different and heterogenic DBV dosing schedule regimens for the off-label treatment of osteomyelitis, spondylodiscitis, and septic arthritis. Our aim is to systematically review the current literature to describe DBV administration schedules and their outcome in OA infections. Methods: According to the 2020 updated PRISMA guidelines, all peer-reviewed articles regarding the use of DBV in OA infections were included. We conducted a literature search on PubMed and Cochrane Controlled Trials. Results: A total of 23 studies and 450 patients were included, prevalently male  and diabetic . Overall, 280  osteomyelitis, 79  spondylodiscitis, and 29  septic arthritis were considered.  Staphylococcus aureus (SA), coagulase-negative staphylococci (CoNS), enterococci, and streptococci [S. aureus (MRSA) and non-VanA MDR enterococci [Dalbavancin (DBV) is a long-acting parenteral lipoglycopeptide LGP. It was first approved by the Food and Drug Administration (FDA) in 2014 for acute bacterial skin and skin structure infections (ABSSSI), DBV has gradually acquired over the years a role as an off-label treatment for several infections caused by Gram-positive bacteria . DBV carerococci ,6.DBV has a long half-life of around 14 days and high plasma protein binding (approximately 93%) . The is Staphylococcus aureus is the pathogen most frequently involved in bone and joint infections, followed by CoNS, enterococci, and streptococci [Osteoarticular (OA) infections are one of the most difficult-to-treat infections due to the reduced penetration of many antibiotics into bone and joint structures, and the challenge of eradicating bacteria embedded in the biofilm state ,12,13. Bptococci . Due to ptococci , and sevptococci ,16,17,18However, despite its proven effectiveness for OA infection treatment, DBV is approved only for ABSSSIs. The current recommended regimen for the treatment of skin and soft tissue infections consists of a dose of 1500 mg, which may be administered as a single infusion of 1500 mg or fractionated into two doses of 1000 mg and 500 mg, respectively, 1 week apart . To the Our methods meet the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) updated guideline for systematic review stated in 2020 .All randomized clinical trials (RCTs), prospective studies, retrospective studies, case series, or case reports published in peer-reviewed medical journals, regarding the use of DBV in bone and joint infections were included. We excluded articles regarding other antibiotics, non-osteoarticular-related infections (including prosthetic joint infections and hardware-related osteomyelitis), or papers in which data, regarding the use of DBV in bone and joint infections, were included in a wider database, and, therefore, impossible to extrapolate. Also, we excluded articles published in non-English languages, pre-print or ahead of print analysis, pre-clinical studies , reviews, systematic reviews, metanalysis, short communications, letter to the editor, and commentaries.An electronic search was employed to find the published articles which reported OA infections treated with DBV through the United States National Library of Medicine, PubMed (last accessed February 2023), MED-LINE (last accessed February 2023), PubMed Central, PMC (last accessed February 2023), and the Cochrane Controlled Trials (last accessed February 2023). References for this review were identified with the following research terms combination: “Dalbavancin” AND “Bone” OR “Bones” OR “Osteoarticular” OR “Osteomyelitis” OR “Spondylitis” OR “Spondylodiscitis” OR “Arthritis” OR “Joint” OR “Joints”. No time window was applied to the search.A team of six resident doctors in Infectious and Tropical Diseases of the University of Brescia, Italy, read the abstract of each scientific work and independently selected the articles according to the established criteria . A Professor in Infectious and Tropical Diseases of the University of Brescia, Italy (EQR), revised the included and the rejected papers. Then, the selected papers were equally distributed among each resident doctor in order to assess for eligibility by reading the full text manuscript. Each resident doctor read, collected, and synthesised the data for the articles assigned using a detailed database. Afterwards, a random reassignment of the articles was carried out and each doctor reviewed the data collected by colleagues. Disagreements were resolved by a joint discussion supervised by the Professor in Infectious and Tropical Diseases.For each selected article, we collected information regarding the number of patients treated with DBV for OA infections, their demographic  and anamnestic  data. Focusing on infections, we reported the involved bones or joint, and the diagnostic tools performed to assess the diagnosis . The aetiological data, comprehending the type of sample, the results of the cultures and the resistance profiles, if any, were collected. The need of previous surgical intervention or a previous course of antibiotics and the reasons for any antibiotics-switches, were reported. We collected the scheme of DBV used , and the eventual concomitant use of other antibiotic treatments. Furthermore, we reported on the outcome at the first evaluation after treatment and at the end of the follow-up period. Eventual drug adverse events and changes in patients’ quality of life (QoL) were collected. Missing or unclear data were reported as “non-available”. During the process of collecting data, we merged the pathogens which were outside the spectrum of DBV into a comprehensive category named “Other”. At the same time, we uncollected data regarding the use of uncategorizable drugs, such as caspofungin or metronidazole (used each just in one case) and, therefore, deemed irrelevant for the analysis.A total of 109 papers were identified through our search. We excluded two duplicate and two non-English articles. A further 61 analyses were removed as 42 were systematic reviews or non-clinical articles and 19 were pre-clinical studies. Lastly, seven papers were excluded as their abstract did not meet the inclusion criteria. The remaining 37 articles were assessed for eligibility by a full-text analysis. Eleven were excluded as data, regarding bone and joints infections, were impossible to select and three further analyses were removed as no clinical use of DBV was described. Eventually, 23 studies were included as shown in the following flow diagram .Most studies were retrospective non-randomized  and case reports . Only one RCT was present . Regarding the geographic distribution of the studies, 60.9% of the articles were from Europe (14/23). The study characteristics, number of patients, type of infection, aetiologic data, outcome, and the DBV schedule of administration are summarized in Staphylococcus aureus  was the most common pathogen isolated, followed by CoNS , Enterococcus spp. , and Streptococcus spp. . These pathogens were isolated mostly from bone or deep tissues biopsies .A total of 450 patients were included. Considering the available demographic data, patients were mostly male , and with a mean age of 57.2 years old (standard deviation ± 8.4). The most common comorbidities identified were diabetes mellitus , hypertension and other cardiovascular diseases , renal diseases , and malignancies . Six  patients were otherwise healthy. Overall, 280  osteomyelitis and 79  spondylodiscitis were included, mainly involving the lower extremities  and lumbosacral vertebrae . A further 29  septic arthritis were included, as shown in Clostridioides difficile infections were reported. As shown in As regards the treatment before switching to a long-acting antibiotic, a surgical source control of the infection site was frequently performed before the use of DBV . In about one third of the cases no other antibiotics were administered before DBV , while, in case of previous lines of antimicrobial treatment, an anti-Gram-positive molecule was generally mostly used . As shown in The scheme of administration and doses of DBV were fully described in 320 patients (71.1%) as shown Most patients were considered successfully cured after DBV  as most of the patients did not need any other antibiotic treatment after DBV . Treatment failure was recorded in 18.7% of cases  for persistent infection , relapse , or the need to switch therapy . Between the pharmacological failures, we underline that 70.8% of patients who needed surgery after treatment with DBV  underwent a non-conservative intervention, such as amputation. A consecutive antibiotic treatment was prescribed in a few patients, , in seven of them  the chosen molecule had the same spectrum of activity as DBV. Of the available data, follow-up visits within and after a 4 week free-treatment period enlightened a high percentage of clinical success, respectively, of 84.3% (231/274) and 77.4% (212/274) as shown in This systematic review tries to describe the DBV administration schedules and their outcome in OA infections. Bone and joint infections are among the most difficult-to-treat infections, representing a clinical challenge not only for the infectious disease specialist. In this context, the use of DBV is quickly spreading, although there is an absence of specific dosing recommendations and on-label prescriptiveness . To dateS. aureus and, considering only those with a known resistance profile, 47.4% of them were MRSA. The prescription of a long-acting molecule allows the clinician to continue long-term treatment as an outpatient, reducing costs and hospitalization-related complications [Our analysis shows that the main reason for switching to DBV was the failure of a previous antimicrobial treatment regimen. Clinicians should always be aware that, in case of pharmacological failure, an appropriate source control should be considered: the correlation between appropriate bone debridement and a better outcome is widely demonstrated in the literature ,14,45. Iications ,46. As iications , to reduOur results also underline that most of the patients (65.3%) received antibiotics before DBV, mostly with an anti-Gram-positive coverage. On the other side, only a quarter (24%) of patients received co-administered antimicrobial drugs together with DBV: this suggests that DBV is generally considered a reliable monotherapy choice for OA infections . In thisIn our systematic review, 79.3% of patients were successfully treated with DBV, confirming the known efficacy, effectiveness, and safety of this antibiotic in OA infections ,39,48. OS. aureus for 8 weeks [Staphylococcus spp., and Enterococcus spp., at concentrations similar to those achieved in osteoarticular tissues [S. aureus infections [The aim of this systematic review was to describe the administration scheduled regimen and outcomes of DBV in the treatment of OA infections. The rational of Dalbavancin use in OA infections is based on its bone and joint penetration and its PK/PD properties, particularly in relation with renal clearance. Regarding the first topic, Dunne et al.  in a pre 8 weeks ,6. Addit 8 weeks . Further tissues ,54,55. I tissues . With th tissues . Paying fections . The Monfections . At the fections . This anfections . The phafections . In thisConsistently, our results show that the number of favourable clinical outcomes increases with the number of doses, up to three, after which the benefit decreases. The outcome improves as the number of administrations increases within the first three because infections of bone are known to require a high amount of antibiotic for a longer period ,58. On tThe findings of this systematic review should be seen in the light of some limitations. First, this review is mainly based on retrospective studies: only one RCT and three prospective studies were included. Although we have followed all PRISMA statements and guidelines for this systematic review, the protocol was not included in the PROSPERO platform. We know that registration is not mandatory but it ensures an anticipated and clear research plan; therefore, it could be considered another limit in the present analysis. In addition, the inclusion of retrospective studies describing aggregate data makes it difficult to select and analyse data for each individual patient. Furthermore, the heterogeneity of the included studies, each different in its design, provided us with a large subset of data but sometimes incomplete in specific aspects. For this reason, some sub-analyses consider only smaller datasets. In an effort to focus on the DBV dosing schedule and outcomes, we recorded the available data even though data on the specific type of OA infection, such as arthritis or osteomyelitis, were missing. For this reason, the number of patients included is greater than the sum of the different types of infection. In addition, very few data were available on polymicrobial infections, and when present, they were aggregate data. Thus, another limitation of our work is that more microorganisms were isolated than patients, which resulted in the absence of information on polymicrobial infections. Lastly, the heterogeneity of the studies included, in the absence of methods to assess the risk of bias or certainty, in the body of evidence restricted our review to a descriptive analysis. However, to the best of our knowledge, and according to the sources analysed, this would be the largest available collection of data concerning the use of DBV in the treatment of osteoarticular infections.DBV has shown to be effective as a treatment for osteoarticular infections. Adequate surgical management prior to antibiotic treatment proved to be a determining factor in a good outcome in our patient cohort. The most favourable outcome was found in patients receiving three doses of DBV; our systematic review shows that clinicians should be aware in cases of MRSA OA infections and inadequate source controls. The utilization of four or more doses of DBV might not be associated with an improved outcome. Implementation of a test for TDM of DBV in laboratories could allow the best customized timing to be identified for a third dose administration. In the absence of that, attention must be paid to the renal function class for choosing the best distance between the doses. Although the on-label prescription of this new molecule includes only ABSSSI, currently, many specialists choose DBV as a first-line treatment for Gram-positive infections of the osteoarticular. To date, a rigorous administration schedule does not exist; however, DBV is a viable treatment option in the management of OA infections. In light of these considerations, dalbavancin appears to be a promising option for treating OA infections from a clinical, microbiological, pharmacological, and pharmacoeconomic point of view, allowing for an early discharge of the patient owing to its long-term mode of action and contributing to the antimicrobial stewardship program.


Lythrum salicaria. The horticultural plant L. virgatum might further introduce meaningful trait variation by escaping into established L. salicaria populations or by hybridizing with L. salicaria. Although many experiments have focused on L. salicaria genotypes, relatively little is known about L. virgatum ecology. We used a greenhouse common garden to compare traits and flood response of L. salicaria and L. virgatum collected from two sources each in their native range. We tested the hypotheses that these two wetland taxa have comparable responses to flooding (inundation), and that flood tolerance correlated to higher fitness. Flooding produced stronger stress responses in L. virgatum. Compared to L. salicaria, L. virgatum shifted more aboveground allocation away from reproduction, decreased inflorescence biomass by 40% more, and produced 7% more stem aerenchymatous phellum, a specialized tissue that maintains aeration. Despite these more pronounced responses to flooding stress, L. virgatum had higher fitness  than L. salicaria. Overall, L. virgatum differed from L. salicaria in functionally important ways. Lythrum virgatum persisted under flooding and produced more reproductive biomass than L. salicaria under both flooded and non-flooded conditions. However, inundation stressed L. virgatum more than L. salicaria. Lythrum virgatum is likely able to establish into the wetland habitats in which L. salicaria prevails but may possess broader habitat tolerances.Newly introduced trait diversity can spur rapid evolution and facilitate local adaptation in the introduced plant  We sought to compare the little-studied ornamental European wand loosestrife (Lythrum virgatum) to its invasive relative purple loosestrife . Some have assumed the two loosestrifes to be indistinguishable, while others have supported European wand loosestrife as a planting alternative to purple loosestrife. In a greenhouse experiment, we compared the two loosestrifes in terms of ecologically meaningful traits. We revealed similarities as well as important differences that challenge previous assumptions about European wand loosestrife. Our findings are relevant in the applied context of purple loosestrife invasions. European wand loosestrife may contribute an underappreciated store of diversity. High intraspecific variability in introduced plant species can enable rapid evolution in the non-native range. For species that have been introduced repeatedly from multiple sources, high genetic and trait variation within populations is common . A diverLythrum salicaria) is a diverse Eurasian perennial introduced to North America both intentionally as an ornamental and unintentionally through ballast water , might contribute through sexual reproduction to the diversity of invasive L. salicaria populations  gained popularity as an ornamental perennial in North America . Conservationists would benefit from considering them the same species, because any regulations applying to L. salicaria would then also apply to L. virgatum.Another common  America  after gomentally  and in n species . To date species . Such asL. salicaria and L. virgatum to be the same species, L. virgatum’s prevalence in landscaping and in naturalized populations in North America . Native habitats for the two taxa are apparently similar, with L. virgatum described as occupying ‘damp places’ and L. salicaria ‘damp grasslands, banks’  most common in the native range  the two species have comparable flooding response, and 2) that flood tolerance is associated with higher fitness (quantified here as inflorescence biomass) under flooded conditions in both species.The trait diversity ed range . The mose et al. , native e et al. . Lythrumn et al. , 2002, f species —combinedrenchyma  and growrenchyma —suggest L. salicaria, one each from Cornwall and Surrey, UK; were provided by the Millennium Seed Bank Partnership, Kew Gardens. We obtained two L. virgatum accessions, one from Rostock Botanical Garden, Rostock, Germany, and one from Anastasie Fatu Botanic Garden, Iaşi, Romania. Purported species identities of each accession matched identifying traits described by L. salicaria accessions, L. virgatum plants were overall smaller with smaller flowers .We obtained seeds of two different accessions for each species from Europe. All four accessions originally hailed from local natural collections rather than horticultural sources, an important requirement given the unknown origins of many cultivars  died during this time, bringing the total to 15 genets. We cloned genets by planting stem cuttings dipped in rooting hormone  in germination trays. We allowed cuttings at least 20 d to establish, then selected robust individuals to be transplanted into 20 cm diameter × 13 cm tall pots with drainage holes, filled with propagation mix  mixed with ~1% solution of dish detergent  to aid rewetting. Prior to initiation of treatments, these pots were kept in trays and bottom-watered every other day by filling the tray to a depth of ~5 cm (8 cm below the top of the pot).Seeds from all accessions had high survivability (~90%) when germinated in petri dishes on moist filter paper. We transplanted germinants into fertilizer-free propagation mix . We retained four robust genets of each of the four accessions to serve as maternal plants for our experiment. Within accessions, these genets were presumably distinct genotypes, although no information was provided regarding how our source seeds were originally collected. We grew and acclimated genets for about one year in a greenhouse at The Ohio State University  under 16 h/d of light. One salicaria Cornwall mother doubled) × two experimental treatments. This procedure resulted in eight replicates per species (two accessions × four clones) per treatment in each of two blocks . We randomized placement of individuals within replicates.We used a randomized block design with 64 individuals total: two greenhouse rooms × two species × two seed accessions × four genets  across the top of all pots to prevent flooded individuals from floating. All individuals, flooded and non-flooded, received sand to control for any effect this media addition might introduce. We trimmed aboveground biomass to standardize individuals to a similar size prior to the start of treatments. We retained the single largest stem, trimming any additional stems flush to the sand. We trimmed the single retained stem to a height of 30 cm above the sand and removed any lateral branches > 1 cm long. We collected the removed plant material, separated it into vegetative and inflorescence fractions, measured the dry mass (after drying at 60°C), and used these data as model covariates to control for pre-experiment size differences among individuals. We also noted at this time which individuals were flowering prior the start of the experiment. We then nested all 13 cm tall pots within larger ~19 L pots. For the flooded treatment, the outer pots were 28 cm in height and did not contain drainage holes. For the non-flooded controls, the outer pots were holed pots with heights of 24–31 cm. These heights varied due to product availability, but we spread pots of different heights evenly across different replicates and accessions. Nine days after these preparations were completed, we initiated the flooding treatment. For flooded individuals, we lined the unholed outside pots with 2 mm contractor bags  to ensure they were watertight and filled them to a water depth of ~27 cm (14 cm above the top of the inner pot containing the plant). An inundation depth of 14 cm is near the upper limit reported for undation . For nonL. salicaria .We tested Hypothesis 1 by comparing all traits across species by treatments and Hypothesis 2 by testing whether our two fitness indicators  were predicted by our flood tolerance metric (aerenchyma production). To compare how many individuals of each species were flowering prior to the start of the experiment, we used a Pearson’s ΧL. virgatum’s 28% flowering rate did not differ statistically from L. salicaria’s 9% flowering rate . After adjusting for pre-treatment biomass via the covariate, aboveground biomass response to flooding also did not differ between species . By the end of the experiment, the larger L. salicaria consistently allocated more of its aboveground biomass to vegetative growth while the smaller L. virgatum allocated more to reproduction. As a result, L. virgatum was more fit based on our fitness metrics under both flooded and non-flooded conditions. If given more days to grow, our L. salicaria might have reached total fitness comparable to L. virgatum. For consistency, we harvested all individuals at the same time, when the flooded individuals were starting to senesce but potentially before some non-flooded individuals had reached their full reproductive output. The timing of our experiment is however reflected in relevant real-world scenarios. At more northern latitudes, earlier frosts might cut the growing season short. Earlier flowering might allow L. virgatum to thrive in the north, while L. salicaria might be more suited to establishing in all but the most northerly parts of the range. In L. salicaria, the early-flowering strategy predominates in the north . Aerenchyma is a specialized tissue produced under inundation to maintain aeration , suggesting aerenchyma production was a homeostatic response, rather than being adaptive (bolstering fitness) or maladaptive (at the cost of fitness). Other researchers have likewise hypothesized that presence of aerenchyma has not conferred an adaptive advantage to L. salicaria over other aerenchyma-producing Lythraceae species (L. salicaria has shown that stem aerenchymatous phellum functions to maintain overall aboveground biomass, a benefit which increases over the duration of flooding (That prediction was also challenged by our findings regarding another aspect of flood response, production of aerenchymatous phellum on the stem. Aerenchyma had been documented in virgatum  but had L. salicaria might be more advantageous, and is predicted to be increasingly favored as climate change lengthens growing seasons (Longer or repeated inundations might also affect fitness through interactions with flowering time differences. When allowed to grow for longer, the later-flowering pattern of our  seasons  and highL. virgatum was more stressed by flooding than was L. salicaria suggests that, in nature, moisture gradients might structure habitat differentiation between the two species. Such effects would likely operate at a within-ecosystem scale because individual wetlands often span substantial moisture gradients. In the context of invasion, such stratification might indicate L. virgatum would preferentially naturalize into less inundated wetland zones than those occupied by L. salicaria. Other environmental factors surely control establishment and persistence of L. virgatum in nature. For example, specialist beetles incur greater damage on early-flowering genotypes (L. virgatum, especially because it is less hairy. Examining potential interactions with these beetles, which are widely used for biocontrol in the invasive range, should be prioritized (The finding that enotypes  and mighL. virgatum could introduce adaptive novelty into long-established L. salicaria invasions. Future studies should further examine hybridization in nature, although ploidy differences might make hybridization rare and thus difficult to detect. Climate change might provide more chances for hybridization by virtue of lengthened growing seasons, which would extend both flowering and pollinator activity (Lythrum taxonomy largely unresolved. As genetic tools become increasingly accessible, biologists are creating a more generalized understanding rapid evolution in introduced species. This system, for which local adaptation in the invasive range has already been demonstrated, could provide an excellent model.Although the two taxa show important differences, both are adapted to flooded environments and, when found in local proximity, hybridization may be a factor affecting plant habitat tolerances. Studies indicate that hybridization is not only possible (The following additional information is available in the online version of this article –Supporting Information 1. The dataset of all measured traits and experimental design variables.plad009_suppl_Supplementary_DataClick here for additional data file.


The reimbursement of new technologies in inpatient care is not always linked to a requirement for evidence-based evaluation of patient benefit. In Germany, every new technology approved for market was until recently eligible for reimbursement in inpatient care unless explicitly excluded. The aim of this work was (1) to investigate the type of evidence that was available at the time of introduction of 25 innovative technologies and how this evidence evolved over time, and (2) to explore the relationship between clinical evidence and utilization for these technologies in German inpatient care.This study combined different methods. A systematic search for evidence published between 2003 and 2017 was conducted in four bibliographic databases, clinical trial registries, resources for clinical guidelines, and health technology assessment—databases. Information was also collected on funding mechanisms and safety notices. Utilization was measured by hospital procedures captured in claims data. The body of evidence, funding and safety notices per technology were analyzed descriptively. The relationship between utilization and evidence was explored empirically using a multilevel regression analysis.The number of included publications per technology ranges from two to 498. For all technologies, non-comparative studies form the bulk of the evidence. The number of randomized controlled clinical trials per technology ranges from zero to 19. Some technologies were utilized for several years without an adequate evidence base. A relationship between evidence and utilization could be shown for several but not all technologies.This study reveals a mixed picture regarding the evidence available for new technologies, and the relationship between the development of evidence and the use of technologies over time. Although the influence of funding and safety notices requires further investigation, these results re-emphasize the need for strengthening market approval standards and HTA pathways as well as approaches such as coverage with evidence development.The online version contains supplementary material available at 10.1186/s12961-023-01047-w. Health-related technological progress plays an important role in the improvement of health outcomes. Yet new technologies may also bear risks to patients and users , 2. EverNeue Untersuchungs- und Behandlungsmethode, NUB) has been reimbursable in inpatient care unless explicitly excluded by the Federal Joint Committee . When the costs for such NUBs cannot yet be sufficiently accounted for by an existing diagnosis-related group (DRG), hospitals can apply to the German Institute for the Hospital Remuneration System (InEK) for the permission to negotiate one-year, hospital-individual extra-budgetary payments  with health insurers [Fixed supplementary payments entail a uniform national price per case published in the appendix of the DRG catalogue; when a uniform national price cannot be determined, hospitals can still obtain individual  negotiable supplementary payments with a minimum amount of € 600 per case [Once they have been approved for market, the pathway to reimbursement of medical technologies in European health systems generally varies –14. Whilinsurers , 17. Oncinsurers , their aAgainst the background of a lacking requirement for HTA prior to reimbursement and the described financial incentives, it is important for quality of care and value for money to enquire whether the implementation of innovative technologies in German inpatient care is guided by clinical evidence. Previous research on the influence of evidence or funding mechanisms on implementation and diffusion has largely focused on individual technologies –19 or onThe overall aim of this work was twofold: Firstly, we aimed to investigate the type of evidence that was available at the time of introduction of selected innovative technologies in German inpatient care and how this evidence evolved over time. Secondly, we sought to explore the link between the available scientific evidence, such as clinical trials, systematic reviews, or health technology assessment reports, and the diffusion of these technologies.This exploratory analysis consisted of three steps: (i) the systematic identification of scientific evidence regarding the safety and efficacy/effectiveness for each technology, (ii) the description of the available body of evidence for each technology at the time of introduction and its development over time; and (iii) the investigation of the statistical relationship between the identified evidence and the utilization of technologies by hospitals. Additionally, the potential impact of clinical guidelines, funding mechanisms and safety notices  on the utilization of these technologies was investigated based on step (ii), above, to facilitate a more contextualized interpretation.The pool of eligible technologies comprised those for which requested permissions for hospital-individual extra-budgetary payments were granted between 2005 and 2012. This time window ensured the availability of data for at least five years preceding the start of this research in 2018 . Utilization curves for each technology were plotted on the basis of data identified via the respective procedure codes from the DRG statistics dataset. This dataset is made available by the Research Data Centre (RDC) of the Federal Statistical Office and Statistical Offices of the Federal States  upon forInformation sources on funding, recalls and safety warnings per technology are listed in Additional file A systematic literature search was carried out in 2019 in PubMed, Medline (via OVID), Embase (via OVID) and the Cochrane Library. The development of search strategies for each included technology was based on the PICO framework . To define search terms, appraisals by the Medical Service of the National Association of Health Insurance Funds and the Procedure Classification were consulted, focusing on the intervention  and the indication (technology specific search strategies are available upon request). Supplementary searches were performed in the reference lists of included systematic reviews, clinical trial registries, HTA databases and clinical guideline databases 2a Systematic reviews of non-randomized controlled trials2b Prospective non- randomized controlled trials (N-RCT)3 Retrospective controlled trials4 Case-series and other single-arm trials5 Case reports, etc.General inclusion and exclusion criteria based on the PICO framework were developed to select relevant evidence for each technology  and up to 2017 were eligible for inclusion.Evidence was selected in line with the rapid review methods of the Cochrane Collaboration . After dThe selection of evidence identified in trial registries, guideline and HTA-databases, and the process of data extraction and risk of bias (RoB) assessment are described in Additional file For each publication, authors’ conclusions were extracted from abstract and main text and categorized into “positive,” “negative,” “neutral,” or “inconclusive” according to the categorization scheme described in Fig. To explore (a) the characteristics of the available body of evidence for each of the included technologies at the point of their introduction and over time and (b) the potential relationship between evidence and utilization patterns, both a descriptive and a statistical analysis were conducted.Descriptive analysis: The identified body of evidence was analyzed descriptively. Each publication was considered as a separate data point. The recommendations from clinical guidelines, information on funding and safety notices were synthesized narratively for each technology and are discussed in combination with other findings.Empirical evaluation of the relationship between utilization and evidence results: To evaluate whether utilization of a technology over time follows available clinical evidence, a new variable X, “results of available body of evidence” at year t and technology j, was aggregated. The variable incorporates all identified comparative analyses (LoE 1–3) of a technology published up to and including year t, weighted by category of study results  and LoE. The variable depicts the prevailing results of the body of evidence available starting two years before the beginning of utilization in Germany cumulated over all years of utilization until year t. Data for the outcome variable “utilization” is represented by the number of hospital procedures in year t and technology j.Due to the clustered data structure and to account for technology-specific effects, a mixed effects model (multilevel model) for two levels of data was applied , 30. It All searches yielded citation numbers in the four-digit range. The number of publications included in the final analysis LoE 1–4) ranges from two  to 498  Fig. . Additio–4 rangesResults of the searches for grey literature  are presented in Additional file At least one safety notification was identified for 12 technologies in Germany and for two further technologies internationally. The number of safety notifications in Germany ranges from one  to 12 (TAVI). Internationally, TAVI and bioresorbable vascular scaffold in coronary vessels (BVS) are the technologies with the most notifications (74 notifications for TAVI and 48 for BVS). At least one recall was identified for seven technologies in Germany and for six additional technologies internationally.The composition of the body of evidence per technology is shown in Fig. The number of systematic reviews and HTA reports ranges from zero  to 37 (TAVI). The number of systematic reviews is higher than the number of RCTs for most technologies. For some technologies, there were several systematic reviews analyzing the same group of RCTs . More details on study characteristics can be found in Additional file In the first years of documented utilization, the number of available publications is low for almost every technology in the sample. Results from non-comparative study designs (LoE 4) usually dominate the picture. Despite the increasing share of evidence from LoE 1–3 over the course of the observation period  was identified despite high utilization numbers. In fact, for most included technologies there were few RCTs, predominantly with high RoB. A high volume of publications does not necessarily predicate the robustness of the evidence body on the benefit of a technology. Similarly, the availability of multiple systematic reviews of comparative studies (LoE 1a/2a) for the same technology does not necessarily result in information gain. For example, several systematic reviews/meta-analyses on stent retrievers for mechanical thrombectomy in acute stroke were identified in this work, published within two years, and combining the same six RCTs. What is more, findings in systematic reviews are only as robust as the studies included in the review allow.The trend towards higher LoE over time was not always observable. For several technologies, a robust body of evidence  did not materialize for several years or even until the end of the observation period. Across technologies, the number of years and the number of procedures performed before adequate scientific evidence became available varied. The type of FDA approval, which is tied to post-market evidence generation requirements, and could thus have influenced the number and type of available studies , 39, wasA relationship between evidence and utilization could be shown for some technologies, but not all. Up to a point, this was to be expected, as there are many factors that influence the adoption of new technologies in health care organizations that could not be accounted for in the regression model. The available number of alternative technologies, operator experience, user-friendly operation, organizational culture, individual beliefs and preferences of operators as well as patient demand , 43 can The relationship between utilization and funding, as well as the relationship between utilization and safety notifications were explored in a qualitative manner, without clear results. However, this does not fully exclude the possibility that such relationships existed for any of the technologies. This study was not designed to predict what utilization might have looked like if funding had not changed over time from the most insecure (extra-budgetary payments) to more secure types of funding (e.g. adequate depiction in a DRG). For at least one technology, safety notices and restrictions could have strengthened the effect of clinical evidence, but this relationship also proved impossible to evaluate fully with this study design.To ensure quality of care, it is important that reimbursed technologies are safe and effective. The first step towards achieving this is to have regulatory processes in place that only allow such medical devices to enter the market. The changes introduced by the MDR, which took effect in May 2021 , 8, coulThe second step is to assess the comparative effectiveness or even cost-effectiveness of new technologies prior to reimbursement. Every health system needs to balance timely access with certainty on the safety and effectiveness of an innovation, while distributing limited resources wisely. For new technologies that show promise but are not supported by adequate evidence yet, coverage with evidence development (CED) may provide a solution. CED is used by several European countries, such as Belgium, England, France, the Netherlands, Spain, and Switzerland , and hasMoreover, it is important to equip CED programs with the mechanisms to stop reimbursement if the evidence is not sufficient or unfavorable. More broadly, implementing disinvestment approaches that effectively remove low-value technologies from health care provision is both crucial to enable optimal patient care and optimal resource utilization, and  challenging to accomplish. While disinvestment strategies for pharmaceuticals in outpatient care are widely used in European countries , additioThis work has several limitations. Although the sample of included technologies was selected in a systematic approach , it is nThe calculation of utilization is based on procedure documentation available at RDC . The valDue to the rapid review methodology adopted to identify evidence, it is possible that either not all relevant citations were identified, or potentially relevant studies were excluded, e.g., through exclusion of languages other than German or English, and non-availability of full texts. Additional sources for clinical guidelines and HTA reports were chosen from the perspective of the German context; thus, these results are not exhaustive.For feasibility reasons, results per publication were categorized based solely on the conclusions of the authors. This means that the consistency of these conclusions with outcomes reported in the publication results section was not investigated further and the potential influence of spin  has not The aggregated variable representing the body of evidence in the multilevel regression model has the advantage of considering the entire body of evidence available up to the time point of utilization and avoiding distortions, for instance because of a single negative study. However, the disadvantage is that the impact of one single, crucial study, can be underestimated. Furthermore, the consideration and weighting of different study designs reflects a choice based on evidence hierarchies and could be subject to discussion. Finally, other observable  and unobservable factors were not incorporated into the model.This is the first study investigating the relationship between evidence and utilization for a sample of 25 new medical technologies in German inpatient care in a descriptive and empirical manner. The body of clinical evidence per technology often consisted mainly of non-comparative studies; its robustness increased over time for many but not all technologies. A relationship between evidence and utilization could be shown for some, albeit not all, technologies. The influence of funding and safety notices requires further investigation. These results reveal that a re-evaluation of market approval standards and HTA pathways might be warranted.Additional file 1: Appendix 1. Description of included technologies; Appendix 2. Searched sources for evidence; Appendix 3. Inclusion criteria of publications; Appendix 4. Screening of records obtained from registries; Appendix 5. Data extraction; Appendix 6. Risk of bias assessment of RCTs; Appendix 7. Description of the regression model; Appendix 8. Results of the search for evidence per database and screening step; Appendix 9. Characteristics of included studies; Appendix 10. Development of body of evidence; Appendix 11. Results of evidence for technologies in sample; Appendix 12. Recommendations from clinical guidelines; Appendix 13. References.


To summarize the best evidence of emergency target blood pressure management for acute aortic dissection and provide guidance for evidence-based practice of emergency target blood pressure management.  According to the “6S” evidence pyramid model, the evidence of emergency target blood pressure management of acute aortic dissection in various foreign databases and websites of professional associations from January 1, 2010, to August 1, 2022, was retrieved, including clinical decision-making, guidelines, expert consensus, systematic reviews, randomized controlled trials, cohort studies, and case series. Two researchers used the corresponding document quality evaluation tools to evaluate the documents and extracted and summarized the evidence of documents above grade B.  A total of 17 articles were included, including 6 clinical decision-making articles, 5 guidelines, 2 expert consensus articles, 1 systematic review article, 1 randomized controlled trial article, 1 cohort study article, and 1 case series article, forming 36 best evidences, including 9 topics, which are target value setting, management strategy, disease observation, medical history collection, monitoring methods, vasoactive drugs, nonvasoactive drugs, related examinations, and patient education.  The best evidence summarized provides a reference for doctors and nurses in the emergency department to manage the emergency target blood pressure of patients with acute aortic dissection. It is recommended that doctors and nurses in the emergency department follow the best evidence summarized to develop individualized target blood pressure management plan for patients. Acute aortic dissection (AAD) refers to a life-threatening aortic disease . PenetraAccording to the PIPOST  tool, thAccording to the “6S” evidence resource pyramid model , the comInclusion criteria were as follows: The patients were nontraumatic AAD patients aged ≥18 years; the research content was AAD blood pressure management; the types of evidence resources included clinical decision-making, guidelines, expert consensus, systematic reviews, randomized controlled trials, cohort studies, and case series. Exclusion criteria were as follows: the patients were pregnant; the quality of literature was below grade B; articles were published repeatedly or were unable to obtain the full text from; abstracts of the meeting; interpretation or summary of the guide; and updated old guide or expert consensus.This study was independently evaluated by two doctors trained in evidence-based medicine. When the evaluation opinions of the two doctors were inconsistent, the decision was made by consulting evidence-based medicine experts. When the conclusions of evidence from different sources conflict, this study follows the inclusion principle of high-quality evidence first, the latest published authoritative literature second, and then the evidence-based evidence .UpToDate belongs to the top resource of the evidence resource pyramid model, and the evidence conforming to the clinical situation is directly used. The guidelines adopt the AGREE II  (AppraisThe evidence preclassification and evidence recommendation level system 2014)  of Austr4  of AusA preliminary search of 6397 relevant documents, including 2002 duplicate documents, 1233 documents that could not be obtained in full text, 2675 documents with research objects and contents inconsistent with the subject, 465 documents with literature quality below grade B and updated old guidelines or expert consensus, was carried out, and 17 documents were finally included, which are 6 clinical decisions –15, 5 gu(1) A total of five guidelines were included, including the percentage of standardization in each field and the quality evaluation of the guidelines . (2) QuaThrough the extraction and integration of evidence, we finally summarized the evidence from 9 aspects, including target blood pressure setting, management strategy, disease observation, medical history collection, monitoring means, vasoactive drugs, nonvasoactive drugs, relevant examinations, and patient education, and formed 36 best evidence .This study analyzed and recommended evidence from the following three aspects: target blood pressure setting and management strategies; vascular active drugs and other relative drugs; and patient education.Evidence from this study (1–8) indicated that the doctors in the emergency department need to develop initial target blood pressure values, time to reach target values, and target blood pressure management strategies based on individual differences in patients. The initial treatment of AAD is to quickly stabilize the patient's hemodynamics under tolerable conditions , 27 and The evidence of this study 9–19) emphasized that AAD patients should receive monitoring and treatment in the emergency department. Emergency physicians closely observe to avoid potential factors that affect blood pressure changes and effectively reduce related complications and mortality . Studies emphasizβ receptor blockers are the first choice for the treatment of AAD [β receptor blockers still cannot achieve the expected antihypertensive goals, it is recommended to [The evidence in this study 20–31) elucidated the selection and considerations of drugs. In drug selection, t of AAD , except ended to , 25 use –31 eluciended to . Some stended to .The evidence from this study 32–34) clearly describes that emergency physicians should select the best diagnostic method based on the patient's hemodynamic status through careful and rapid comprehensive evaluation. This can not only quickly determine whether the target organs such as the kidney and intestine are damaged but also determine the location and extent of aortic dissection. In addition, there is evidence (35-36) that emergency physicians should provide patients with a comfortable diagnosis and treatment environment, necessary disease-related knowledge education, and psychological intervention, fully utilize a good social support system, alleviate negative emotions such as fear and anxiety, and avoid excessive blood pressure fluctuations. Meanwhile, smoking is the second largest risk factor for AAD, and strict smoking cessation interventions should be carried out for patients , 32. Gui–34 clearDue to limitations or potential bias in individual studies, the assessment tools we used did not allow for such individual studies and could only target most of the literature. In addition, due to limitations of the review process, it could not address potential publication bias or the possibility of missing relevant studies.This study summarizes the best evidence for target blood pressure management in an AAD emergency. This study provides the best strategy for blood pressure management. At the same time, the doctors and nurses in the emergency department should also consider the patient's situation and the family's expectations in an all-round way, formulate an individualized target blood pressure management plan, fully analyze the factors that promote and hinder the application of the evidence, and prudently apply the evidence to the clinic. In addition, emergency management personnel should actively improve and standardize blood pressure management rules and regulations, carry out training, and promote the transformation of knowledge and skills into practice.