Over the years, there have been significant advances in oncology. However, the rate that therapeutics come to market has increased, while the strength of evidence has decreased. Currently, there is limited understanding about how these uncertainties are managed in provincial funding decisions for cancer therapeutics. We conducted qualitative interviews with six senior officials from four different Canadian provinces  and a document review of the uncertainties found in submissions to the pan-Canadian Oncology Drug Review (pCODR). Participants reported considerable uncertainty related to a lack of solid clinical evidence . Proposed strategies to deal with the uncertainty included risk-sharing agreements, collection of real-world evidence (RWE), and ongoing collaboration between federal groups and provinces. The document review added to the reported uncertainties by classifying them into five main categories: trial validity, population, comparators, outcomes, and intervention. This study highlights how decision makers must deal with significant amounts of uncertainty in funding decisions for cancer drugs, most of which stems from methodological limitations in clinical trials. There is a critical need for transparent priority-setting processes and mechanisms to reevaluate drugs to ensure benefit given the high level of uncertainty of novel therapeutics. Decision making for funding cancer drugs has become increasingly complex in recent years. This is partly due to a rise in cancer incidence, survivorship, drug costs, and subsequent health system expenditure. More recently, these factors have been coupled with the concern that many novel therapies are associated with considerable uncertainty due to methodological limitations from clinical trials. Uncertainty from clinical studies flows into economic evaluations and introduces additional challenges in formulary decision making. While economic evaluations can incorporate uncertainty into models using various methodological techniques, the rapidly increasing numbers of experimental and costly drugs in oncology adds new complexities that challenge traditional methods . Then, tAny uncertainty about the magnitude of benefit of new therapeutics from clinical trial evidence and subsequent economic evaluations can be exacerbated by “external factors” such as political priorities and pressure from media, industry, patients, and clinicians . For exaFor a drug to come to market in Canada, it must be approved by Health Canada, evaluated by the pCODR  in Quebec), and funded for reimbursement at the provincial level. While Health Canada, the Canadian Agency for Drugs and Technology in Health (CADTH), and INESSS review similar evidence, their goals vary slightly. Health Canada focuses primarily on safety and efficacy, whereas CADTH and INESSS evaluate therapeutics for value based on specified criteria. Health care financing and delivery is primarily the responsibility of provincial governments. For cancer care, provinces generally rely on the recommendations from the pCODR program at CADTH. pCODR assesses the value of a new therapeutics through a deliberative framework that includes clinical and economic evidence, patient input, and adoption feasibility. The submissions are evaluated by pCODR and then reviewed by the pCODR Expert Review Committee (pERC). pERC is comprised mainly of medical oncologists; however, it does include other membership such as pharmacists, patient representatives, health economists, an ethicist, and non-oncologist physicians. Once a submission is reviewed, pERC provides provincial and territorial decision makers with recommendations regarding whether a drug should be reimbursed. Some provinces have also established their own review boards such as the Priorities Evaluation Committee in BC and the Ontario Steering Committee on Cancer Drugs in ON .Despite pCODR support in reimbursement recommendations, it is known that resource allocation occurs differently across provinces. Public coverage for the same drug can differ province to province, which has led to concern about possible “fragmentation” of the cancer system across Canadian provinces . DependeAs oncology enters into an era of precision medicine—where evidence becomes more complex—decision makers are increasingly forced to make reimbursement decisions on the basis of uncertain evidence that can have significant opportunity costs . DespiteA semi-structured interview guide was developed to assess funding processes, the nature and weight of various sources of evidence , and the role of federal bodies such as pCODR and the pCPA with key informants. Respondents shared characteristics of being either a ‘decision-maker’ or someone “involved in decisions for funding cancer drugs” and were purposively sampled from their jurisdiction. All interviews were audio-recorded with permission and transcribed verbatim.To supplement the key informant interviews, submissions to pCODR between 1 January 2015 and 31 December 2019 were reviewed for uncertainties. Uncertainty meant “an unresolved issue, limitation or methodological deficiency”. This definition has been used in prior studies . The seaQualitative content analysis was used to analyze the interviews and pCODR documents. Based on prior knowledge from the literature review and key informant interviews, a data extraction table was constructed a priori. Following qualitative descriptive methodology, codes were reviewed and compiled in broad categories . NVivo qOverall, a total of six key informant interviews were included from provincial cancer agencies (2), ministries of health (1), and national or provincial HTA organizations (3). Participants were from four provinces: BC (1), AB (1), ON (1), and QC (2) and held a variety of roles including senior management, directors of oncology programs, health technology assessment (HTA) methodologists, and members of drug review or advisory committees.The key informant interviews identified four main sources of uncertainty in funding decisions for cancer therapeutics: (1) a lack of a solid evidence base due to methodological limitations from clinical trials, (2) increasing costs, (3) external influences such as pressure from the FDA, patients and clinicians, and political will, and (4) strategies to manage uncertainty. These themes, along with illustrative quotations, are summarized in The most common source of uncertainty identified was uncertainty about the clinical evidence. Participants discussed challenges in the context of clinical trials, which has historically been used as the foundation for the risk benefit threshold. Subthemes included concerns about selective recruitment based on favorable performance status that make it difficult to generalize the effectiveness of a therapeutic to the provincial population. Trial participants are often heavily treated or selectively enrolled. Furthermore, once a drug is approved for a certain demographic, there is considerable pressure to expand its use to patients who have shown poor responses to other drugs, in which the evidence is more uncertain. Participants noted increased uncertainty when new therapeutics do not demonstrate improvements in patient-centered outcomes such as overall survival and quality of life. Furthermore, it is hard to fund a drug that has not been compared to the current standard of care. The concerns related to clinical evidence were exacerbated by the increasing pace of drug approvals at the federal level, which translates into a faster flow from federal bodies to provincial decision makers.Every participant acknowledged the rising cost of oncology drugs as a major source of uncertainty; however, decision makers were hesitant to acknowledge that this factor alone would affect the outcome of the funding decision. Two participants from QC explicitly stated that efficacy is the first criteria for a drug funding recommendation, even if it means funding a drug based on small incremental benefits and significantly higher costs. Furthermore, all participants noted that the budget impact is often underestimated, especially with new targeted therapies, which add significant burdens in their adoption in health care systems.Participants noted several challenges from outside of the regulatory processes. These included patient and clinician pressure, US Food and Drug Administration (FDA), industry, media, and political influences. Participants noted additional uncertainty from clinician and patient advocacy groups. Understandably, these groups have different goals from decision makers. Patients and clinicians focus on individual need rather than the population and therefore might have higher tolerance for uncertainty. Furthermore, a clinician participant noted that the proximity of the United States to Canada creates pressure for payers to make similar funding decisions and adds challenges to implement standards for value. Other sources of uncertainty included media and industry, which can influence the public and political members to adopt certain therapeutics contrary to the evidence. Participants often expressed ambiguity about the power of political agendas.Participants suggested various approaches to managing uncertainty in provincial drug funding decisions. These strategies fell into four categories: financial risk management, real world evidence, reassessment of drugs with uncertain benefit, and the opportunity to participate in pan-Canadian collaborations. Participants discussed risk-sharing agreements between public payers and industry to manage uncertainty. Payers seemed to favor sharing the risks and cost burden with the pharmaceutical companies, especially in the initial stages of adoption where uncertainty is at its highest. All participants seemed to agree on the importance of collecting RWE and, at times, even negotiating these conditions into the initial contracts with pharmaceutical companies. However, challenges noted for collecting RWE stem from a historical reliance on clinical trials in oncology and subsequent reluctance to use other methods such as observational designs. All participants noted that reassessment of the treatment space generally does not occur and that this is a current gap. There were numerous reasons for this, including the regulatory approval pace, limited human and financial resources to reassess drugs, political will, and a lack of systematic ways for disinvestment.Pan-Canadian collaborations such as pCODR, pCPA, CDIAC, and others have increased opportunities for collaboration, partnership, and transparency and had positive impacts on managing uncertainty in funding decisions. Positive aspects included streamlined processes based on one federal HTA process that generates comprehensive reports that identify areas of uncertainty. Furthermore, another positive was “less neighbor checking” between provinces. One decision maker noted that prior to the formation of pCODR, some provincial payers would monitor what drugs other provinces were funding and make decisions based on this. However, with one recommendation from pCODR, provinces can rely on one source of reliable evidence to make their own decisions. However, one participant noted that pCODR might also contribute to uncertainty in formulary decisions as there is no obvious bar for what constitutes as “good evidence.” This can incentivize manufacturers to submit earlier evidence, as there seems to be little consistency for what receives a positive or negative recommendation in terms of immature evidence. However, other decision makers noted that it was not clear who ought to be setting a bar for the standard of evidence—whether that be Health Canada or CADTH. Payers are struggling to understand what is acceptable.Overall, there were a total of 73 distinct submissions to pCODR between 2015 and 2019. One report per tumor type was included in this analysis, for a total of 47 distinct submissions included in the qualitative analysis. The pCODR document review identified five sources of uncertainty in the clinical evidence. These included issues with trial validity, non-generalizable population, lack of or unreliable comparators, unvalidated or missing outcome measurements, and resource intensive implementation. An overview of categories along with representative quotations can be found in In approximately 50% of the submissions, reviewers noted uncertainties related to methodological limitations in the study design, which raised questions about meaningful long-term benefit. The most common were selection bias, reporting bias, performance bias, and attrition bias. Selection bias can occur when patients are selectively recruited into trials based on characteristics that differ from the wider population. For example, some participants were chosen on performance status, which might ensure resilience to withstand treatment and can lead to better outcomes. Furthermore, reporting and performance bias can be introduced when patients and clinicians are aware of the treatment assignments. Uncertainty related to attrition bias is introduced when participants exit studies for unknown reasons. One common example was data related to health-related quality of life where data are collected from individuals who remain in the study rather than all initial study participants.In 47% of the submissions, there was uncertainty about whether the sample of participants in clinical trials is generalizable to clinical practice. Due to the investigation of often rare molecular alterations, it can be difficult for clinical trials to recruit enough participants to adequately power a trial. To remedy this, trials can have an international scope where patients are enrolled from centers around the world. The varying demographics from those enrolled can create uncertainty about its effectiveness in a specific population, such as Canada. Indeed, assessing the generalizability of the trial results can be a challenge for all countries in all international trials In 40% of the submissions, reviewers noted how the lack or inappropriate use of a comparator added uncertainty. It is common that trials do not compare to clinically relevant standards of care. At times, trials will only have an experiment arm or compare against placebo. This can make a drug benefit appear substantial. However, this might not be the case. It can be hard to make a reimbursement recommendation when there is uncertainty to its performance compared to the drug used in current clinical practice.Uncertainties related to outcomes were indicated in 72% of the submissions and fell into two categories: the use of unvalidated endpoints and missing data related to important patient-centered outcomes such as overall survival and health-related quality of life. There were numerous issues with the use of unvalidated endpoints for certain tumor types, which raised questions about whether the efficacy translated into effectiveness in real world conditions. Furthermore, there were additional uncertainties when trials did not collect important patient-centered information such as health-related quality of life.Although this analysis focused on clinical uncertainties, there were substantial references to the resources required for implementation of a therapeutic. These uncertainties were indicated in almost all of the submissions (83%) and were related to the duration of treatment, adoption feasibilities, and administration of the drug. The duration of a treatment has important effects of the quality of life of a patient. There were additional uncertainties related to the administration of certain therapeutics. Some therapeutics require additional resources such as staff with special training or new facilities for administration. The uncertainties generated from the duration of treatment and resource-intensive administration flow into considerations for their adoption in a health care system. It is often the case that the therapeutic itself is also costly. Therefore, high costs and additional resources creates uncertainty for the feasibility of its adoption.The key informant interviews confirm that there are many areas of uncertainty that challenge decision makers in oncology, most of which relate to evidence from clinical trials. The results from the pCODR document review add to this finding by systematically categorizing these uncertainties into five main themes. Both sets of findings demonstrate how uncertainty is prevalent in oncology. Overall, pCODR and payers raised similar concerns, especially about the generalizability of the trial results into a broader patient population. However, payers were more concerned about how a therapeutic will translate into existing lines of treatment, whereas pCODR focused on recommendations for one submission at a time.Provinces generally rely on the reimbursement recommendations from pCODR. However, the document review revealed many sources of uncertainty that are embedded within these evaluations. These findings are not surprising, given the quality of evidence submitted to pCODR by manufacturers. For example, Meyers et al. (2021) found that over half (53.9%) of positive recommendations by pCODR between 2011 and 2020 were based on a surrogate endpoint, such as PFS, while only a minority offered OS gains (32.1%). Of the drugs that demonstrated OS benefit, the median survival gain was only 3.7 months . An analDrugs submitted with suboptimal evidence from clinical trials exacerbate regulatory weaknesses. For example, uncertain therapeutics often receive conditional recommendations from pCODR. However, it has been shown that provinces often interpret conditional recommendations as positive endorsements . This caIf trials with immature data continue to be used for reimbursement decisions, analytical methods and mechanisms for reassessment require strengthening .Participants offered suggestions for ways uncertainty can be managed in oncology. These strategies included the collection of RWE, outcome-based agreements, and mechanisms for reassessment. Many participants discussed risk-sharing agreements between public payers and industry to manage uncertainty. There are some innovative strategies internationally. For example, one participant cited a Cancer Drugs Fund from NICE  . The key informants all noted that they could name the pieces of the evidence in the provincial decision-making process but did not know exactly how each one was weighed in the final decision. pCODR publishes a deliberative framework that includes addressing four criteria: clinical, economic, patient values, and adoption feasibility. However, the weighting scheme of each of these components is unknown. It might be assumed that each review team apply their own implicit weights to these criteria, which create questions about the consistency of the process . A recenThe lack of formal priority-setting processes for implementing and reassessing therapeutics has created a challenging environment for Canadian decision makers in cancer control. This challenge, combined with the high levels of uncertainty from pivotal clinical trials identified during the document review, means that making decisions with limited evidence is a reality for those involved in provincial cancer drug funding. However, it is also evident from this study that there is an appetite for mechanisms to manage uncertainty, namely ways for ongoing reassessment of uncertain therapeutics. With the rise of complex study designs  and methodological limitations in clinical trials , there is a question as to which agency  ought to set the bar for quality as payers are struggling to understand what is acceptable evidence for reimbursement. Without some evidentiary standard, manufacturers will continue to submit suboptimal evidence. Future policy initiatives and research ought to investigate how health technology management might occur in the Canadian institutional setting. Furthermore, mechanisms to strengthen follow-up for conditional recommendations and RWE collection are needed.The current study provides a qualitative analysis of the uncertainties for oncology drugs at the time of the provincial reimbursement decision in Canada. However, the results should be interpreted in light of certain methodologic limitations. First, the key informant interviews were from a small group of participants; therefore, it might be hard to generalize the findings to all settings. However, concerns related to a small sample size are not as limiting in qualitative analyses. In qualitative designs, a small number of interviews can be analyzed with more depth, increasing the internal validity of the study . FurtherThe pCODR document review also should be interpreted in light of other limitations. First, the study relied on publicly available documents. Since pCODR considers all available evidence in its evaluation process, some of which may not be clear in public documents, it might be difficult to draw conclusions solely examining one portion of the process. Furthermore, the document review was limited to comments of the pCODR reviewer in lieu of an independent critical appraisal. This is important to consider, as a critical appraisal would likely generate a more realistic and perhaps more substantial list of uncertainties. This is especially relevant in the quantitative content analysis to indicate the frequency at which these uncertainties occurred. However, similar studies have found comparable results. For example, Naci et al. (2019) used the Cochrane risk of bias tool to critically appraise the trials of the drugs approved by the European Medicines Agency . The stuThe key informant interviews identified numerous sources of uncertainty, many of which were associated with a lack of solid clinical evidence, which stemmed from methodological limitations in clinical trials. The pCODR document review adds to these findings by systematically categorizing uncertainties into five main categories. These categories highlight the substantial challenges decision makers face when funding therapeutics at a provincial level. Many of the uncertainties in the document review were raised by provincial decision makers. However, one major difference was the focus on the management of a therapeutic space in contrast to pCODR, which generally focuses on individual drug submissions. Although there has been federal movement to focus on implementation with the incorporation of agencies such as CDIAC into the pCODR process, the impact has yet to be evaluated. This study raises important questions about the evidential standard in oncology and how might this adapt in the era of precision medicine.


In this review, we discuss how both host and pathogens use lipid rafts and associated proteins in an arms race to survive. Special attention is given to the involvement of the major vault protein, the main constituent of a ribonucleoprotein complex, which is enriched in lipid rafts upon infection with vaccinia virus.Lipid rafts, also known as microdomains, are important components of cell membranes and are enriched in cholesterol, glycophospholipids and receptors. They are involved in various essential cellular processes, including endocytosis, exocytosis and cellular signaling. Receptors are concentrated at lipid rafts, through which cellular signaling can be transmitted. Pathogens exploit these signaling mechanisms to enter cells, proliferate and egress. However, lipid rafts also play an important role in initiating antimicrobial responses by sensing pathogens  FurIt is interesting that, although cytokine release is dependent on lipid rafts, the integrity of lipid rafts is also reciprocally affected by cytokine signaling. For example, interferon-induced viperin interacts with farnesyl diphosphate synthase (FPPS) to inhibit cholesterol synthesis and lipid raft formation , in addiphox, P67phox, P40phox and RAC) to the plasma membrane, which already harbors the gp91phox and P22phox components upon priming with interleukin 8 (Il-8) -induced necroptosis pathway, activation of mixed lineage kinase domain-like protein (MLKL) lead to oligomerization of receptor-interacting protein3 (RIPK3) which is translocated to lipid rafts in the plasma membrane where it enhances sodium influx to induce cell rupture (Reactive oxygen species (ROS) produced in phagosomes eliminate pathogens through oxidative damage by innate immune cells such as neutrophils , represe8 (Il-8) –52.Other rupture . Lipid r rupture –56.+ T-cells through the lipid raft-associated receptors CD4, CCR5 and CXCR4  and cell rupture, by forming actin-mediated protrusions, or by inducing bud formation, with this latter potentially involving lipid rafts. Endosomal sorting complexes required for transport (ESCRT) are essential for membrane scission, as well as being involved in viral budding. Many enveloped viruses such as HIV, Murine Leukemia Virus (MLV) and vaccinia virus employ ESCRT-dependent budding or egress mechanisms –136. Knos) from lipid rafts, and drugs such as fluvoxamine, and fluoxetine are known to block the entry of viruses  recruited MVP to lipid rafts and activate NF-κB signaling, IL-8 secretion and apoptosis induction. In MVP knockout (MVP-/-) mice bacteria uptake in lungs was reduced to 45% when compared with the wild-type mice. Further analyses concluded that MVP is critical for formation of stable membrane microdomains after P. aeruginosa infection. MVP translocation to lipid rafts was also induced by microbial metabolites such as N-(3-oxo-dodecanoyl) homoserine lactones (C12) released by proteobacteria and Pseudomonas aeruginosa  of MVP, as well as the other components of the vault complex, will reveal interesting biology and possibly therapeutic opportunities.RK, WC, and EW wrote and revised the manuscript. All authors contributed to the article and approved the submitted version.WC was supported by a grant from the Academia Sinica and Ministry of Science and Technology (110-2320-B-001-015-MY3).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Inflammatory bowel diseases (IBDs) have emerged as a public health problem worldwide with a limited number of efficient therapeutic options despite advances in medical therapy. Although changes in the gut microbiota composition are recognized as key drivers of dysregulated intestinal immunity, alterations in bile acids (BAs) have been shown to influence gut homeostasis and contribute to the pathogenesis of the disease. In this review, we explore the interactions involving BAs and gut microbiota in IBDs, and discuss how the gut microbiota–BA–host axis may influence digestive inflammation. Inflammatory bowel diseases (IBDs), including both Crohn’s disease (CD) and ulcerative colitis (UC), are disabling chronic immune-mediated disorders that have been increasing worldwide . The etiStudies that aimed to understand the relevance of bile acids in digestive inflammation are portrayed in this review. Specifically, to obtain an overview of the research in this area and results achieved so far, we carefully reviewed the literature available on PubMed. The main keywords used for this analysis included microbiome, bile acids, IBD and signaling. After a detailed analysis by at least two co-authors, 74 papers were found to focus on gut microbiome–bile acid interactions in IBDs, which is the main emphasis of this review. Bacteroides, Clostridium, Bifidobacterium and Lactobacillus for the deconjugation of taurine- and glycine-conjugated BAs into their respective unconjugated forms by bile salt hydrolase (BSH) enzymes [Bacteroides, Clostridium, Escherichia and Eubacerium perform the C7β epimerization of CDCA to generate the 7β epimer, i.e., the 3α-, 7β-dihydroxy-5β-cholanoic acid, also known as ursodeoxycholic acid (UDCA). Bile acids are exclusively synthesized by hepatocytes through cytochrome P450-mediated cholesterol oxidation, a process that follows two pathways—the classic and the alternative pathways ,14. The Clostridium groups XIVa, Eubacterium, Bacteroides and Ruminococcus [Bacteroides, Eubacterium and Lactobacillus are known to carry out esterification whereas Clostridium, Fusobacterium, Peptococcus and Pseudomonas execute desulfation [In addition to secondary BAs, the gut microbiota produces oxo or keto BAs by the oxidation of the hydroxyl groups at ring positions 3, 7 or 12 that are catalyzed by bacteria with hydroxysteroid dehydrogenases (HSDHs). Known bacterial genera involved in such reactions include nococcus . Other gulfation .Clostridium bolteae. The precise mechanism of this microbial reconjugation has not yet been resolved. It may rely on a similar mechanism involving a Cys–Asp–His triad with the cysteine acting as the catalytic residue for the nucleophilic attack [A new group of recently uncovered BAs were conjugated to the C24 acyl site, similar to the host conjugation mechanism . As oppoc attack . RegardlIn addition to their role as emulsifiers that promote fat absorption, BAs may directly target bacterial membranes and cause bacterial damage ranging from envelope and membrane disruption to the complete leakage of intracellular material ,28,29,30Clostridium spp., whose relative abundance increased from 39% in the controls to 70% in the treated groups [Bifidobacterium breve and Lactobacillus salivarius [Clostridium difficile growth in vitro and promote resistance to infection in vivo [Significant changes in the gut microbiota composition were reported in rats fed with a primary BA . A CA-sud groups . CA and livarius . Such BAlivarius ,37. On t in vivo . BAs are likely to influence the gut microbial communities and vice versa, thus highlighting the inter-relationship of the gut microbiota–BA–host axis. Note that the effects of such BAs on the gut microbiota and intestinal epithelium may be inflected by several factors, including: (i) the concentration of BAs  and the exposure time; (ii) the receptors involved; (iii) the site of inflammation (ileum or colon) and BA transport/absorption processes; and (iv) the host species (whether it is mouse or human). Accordingly, BAs can act in different ways and show either pro-inflammatory effects or anti-inflammatory properties instead.Earlier studies noted increased levels of unconjugated BAs in both CD and UC patients compared with healthy subjects . SimilarBile acid malabsorption was reported in both CD and UC patients, which may represent a common feature that can be correlated with the severity of the disease . These fIn addition to FXR, BAs are ligands of TGR5, which is known to mediate ileal and colonic motility . A dysreDifferent BAs are known to have a different potency towards FXR and TGR5 . Accordibsh genes and IBDs was established [bsh genes belonging to Proteobacteria increased in IBDs whereas Firmicutes decreased in CD. These data are consistent with previous studies that reported a dysbiosis in IBDs characterized by increased levels of Proteobacteria and decreased levels of Firmicutes [Bile salt hydrolase enzymes catalyze the hydrolysis of the amide bond from taurine/glycine residues in conjugated BAs, allowing a further microbial modification of unconjugated BAs . Due to ablished . The aburmicutes ,64,65. Trmicutes  (Figure rmicutes ,67. By crmicutes . Increasrmicutes ,12,68,69rmicutes .Clostridium Cluster XIVa, are known to perform the relatively rare 7α-dehydroxylation necessary to convert primary BAs to secondary BAs [bai genes were expressed in significantly lower levels in UC pouches than in the controls [Clostridium leptum that was significantly reduced in the IBD fecal samples compared with the healthy subjects [Only a few known bacteria, including all in the dary BAs ,72. Of tdary BAs . A new mcontrols . A deficsubjects . Of partsubjects . Converssubjects . Likewissubjects .As the prevalence of IBDs has been increasing worldwide, the social and economic burdens related to the disease have been alarming. As such, a better understanding of the underpinning drivers seems of prime importance, particularly because the etiology of IBDs is still largely unexplored. Emerging evidence suggests a potential role of BAs in IBDs. Although BAs have been studied for centuries, recent findings show that we still have much to learn. Bile acids play key roles in intestinal metabolism and cell signaling and are believed to influence the gut microbial composition. In turn, the microbial metabolism of these BAs is known to shape the host physiology. Alterations in BA metabolism and signaling have been shown to influence intestinal homeostasis and drive gut dysbiosis in IBDs, thereby making these molecules an attractive therapeutic target in these diseases. The mechanisms of microbial modifications of BAs continue to be elucidated as do the roles that BA metabolism plays in host health and disease. Bile acids are at the interface of complex molecular interactions between the host and their gut microbiota. The precise impacts of increased levels of BA subtypes associated with IBDs are not yet well-understood. Microbially transformed BAs may be closely intertwined with those of the host and seem to exhibit significant consequences for human physiology. The relevance of these microbial reactions is still largely untapped. The emergence of functional metagenomic tools constitutes a hope to better analyze the role of gut microbiota on BAs in health and disease.


Evidence from previous studies is often used relatively informally in the design of clinical trials: for example, a systematic review to indicate whether a gap in the current evidence base justifies a new trial. External evidence can be used more formally in both trial design and analysis, by explicitly incorporating a synthesis of it in a Bayesian framework. However, it is unclear how common this is in practice or the extent to which it is considered controversial. In this qualitative study, we explored attitudes towards, and experiences of, trialists in incorporating synthesised external evidence through the Bayesian design or analysis of a trial.Semi-structured interviews were conducted with 16 trialists: 13 statisticians and three clinicians. Participants were recruited across several universities and trials units in the United Kingdom using snowball and purposeful sampling. Data were analysed using thematic analysis and techniques of constant comparison.Trialists used existing evidence in many ways in trial design, for example, to justify a gap in the evidence base and inform parameters in sample size calculations. However, no one in our sample reported using such evidence in a Bayesian framework. Participants tended to equate Bayesian analysis with the incorporation of prior information on the intervention effect and were less aware of the potential to incorporate data on other parameters. When introduced to the concepts, many trialists felt they could be making more use of existing data to inform the design and analysis of a trial in particular scenarios. For example, some felt existing data could be used more formally to inform background adverse event rates, rather than relying on clinical opinion as to whether there are potential safety concerns. However, several barriers to implementing these methods in practice were identified, including concerns about the relevance of external data, acceptability of Bayesian methods, lack of confidence in Bayesian methods and software, and practical issues, such as difficulties accessing relevant data.Despite trialists recognising that more formal use of external evidence could be advantageous over current approaches in some areas and useful as sensitivity analyses, there are still barriers to such use in practice.The online version contains supplementary material available at 10.1186/s13063-021-05759-8. The importance of using existing evidence to inform the design and analysis of a randomised controlled trial (RCT) is increasingly recognised by trialists and funders alike . IntuitiA more formal approach to using existing evidence is to use a Bayesian statistical framework in which previous evidence about a parameter is used to derive a prior distribution . ParametWe undertook a qualitative study to explore trialists’ views on, and any experiences with, incorporation of external evidence through a Bayesian statistical approach. We focused on the use of a synthesis of relevant evidence on particular parameters, with reference to examples which we described, and identification of any barriers to the use of these approaches. We explored which types of external evidence were considered most potentially relevant and useful, and the likely acceptability of such use in practice.Ethical approval was obtained by the University of Bristol on 27 April 2017 (Reference number 48101). We report our study according to the Consolidated Criteria for Reporting Qualitative Research (COREQ)   the intervention effect,  (2) potential bias associated with unavoidable trial limitations and (3) ‘nuisance’ parameters such as baseline rates of adverse events. We also explored the potential barriers to implementing these methods in practice. Interviews were recorded using an encrypted audio recorder.Interview recordings were transcribed verbatim whole to conduct a comprehensive analysis. Transcripts were analysed thematically and inductively by GLC , under the guidance of DE , using techniques of constant comparison whereby similarities and differences between interviewees were explored . Coding The first three transcripts were double coded by DE, and a further three transcripts were double coded by a member of the study team with expertise in statistics and evidence synthesis (HEJ). The overall meaning and interpretation of codes were found to be similar, and minor disparities were discussed until there was a consensus. After analysing the first 13 interviews, we felt that maximum variation had been reached . We condOf those individuals approached, only one declined. Amongst the 16 interviewees, three had a clinical background (two of whom were Chief Investigators), while 13 had a statistics background. 25% (4/16) had greater than 10 years of experience working in trials. Interviews lasted a mean of 54 minutes (range 37–79). Table We report our findings in four themes, supported by quotations.I suppose it’s something that people do informally but not in a structured Bayesian [way]."Senior stat, P12: "When I was determining a minimal clinically important difference I had, you have various methods to determine a minimal and clinically important difference. I basically did a meta-analysis of all of those results and came up with a value and that’s the value I reported."Senior stat, P1: "Participants across all trials units were using evidence syntheses informally in a number of ways to inform trial design. Uses of evidence were included to justify the trial and inform the choice of outcomes or parameter values for sample size calculations.Obviously, there’s the evidence of equipoise. There’s the evidence of the knowledge gap."Ch inv, P5: "And unless you can convince a funder or ethics committee of equipoise to two treatment arms then you won’t get, you can’t do the study. There’s got to be some sort of uncertainty."Ch inv, P3: "Participants reported that the sourcing of previous evidence was often instigated by the clinician, who would share a published paper, usually a systematic review, with the study team. This was typically used to support the need for the trial and to demonstrate equipoise in funding applications.It’s generally in a way just the simplest technique that will get the job done and not overcomplicating it. Calculations get confused enough as it is!"Methods lead, P10: "All sixteen trialists reported that they consistently used ‘standard’ and ‘simpler’ statistical models such as logistic, linear and Cox regression, or mixed effect models for repeated measure data, that did not incorporate external evidence through a Bayesian analysis.I don’t think I’ve ever used previous evidence in the analysis stage other than if I was looking it up before I did the analysis to inform what analysis I might do, but not actually [using previous evidence]."Methods lead, P4: "Some participants indicated that they had used previous studies informally to inform the choice of statistical methods for their analysis.I rely on the DMC [Data monitoring commitee] quite a lot basically. I don’t think we’ve got good methods for looking at adverse event rates really. It’s often just listings or tabulations."Methods lead, P10: "I think a lot of the adverse events that I’ve reported, we then compare them to cohort data or kind of a population level data rather than trial specific."Senior stat, P1: "Participants indicated that any external information on adverse event rates is summarised descriptively.Yes, I suppose it can do [bias the results] but I’ve never been particularly worried about it.…I haven’t done it [bias adjustment]; not thought about it or even something we discuss as being potentially biased; just see it as a limitation."Senior stat, P1: "None of our participants had used external evidence to adjust for potential biases in their numerical results. Trialists indicated they would simply describe limitations in their trial design, e.g. inability to blind outcome assessors, in their discussion.Whether it would be accepted by decision makers. I guess if you’re doing anything that’s not the norm, you’d just be a bit scared, even getting it published. Reviewers could be like ‘what on earth have you done? I’ve worked in trials all my life and I’ve never done this."Methods lead, P4: "Some senior statisticians, particularly methods leads, voiced concerns that trials using Bayesian methods might be less likely to be published or funded.I think actually clinicians and things are more familiar with the frequentist approach rather than Bayesian, and actually it can be more difficult when you say, ‘I’ve used Bayesian methods,’ and they think, ‘Oh, what have you done?’"Senior stat, P11: "Some also felt that Chief Investigators, who ultimately sign off the analysis plan, would not understand Bayesian methods and, moreover, would not encourage their use.ut I think you’d have to do a lot, change a lot of peoples mind set to be able to make them do this type of analysis compared with the analysis we already do."Senior stat, P1: "BThere was also a reluctance to change current methods.I am always a bit uncertain with meta-analysis about how you can group together different trials, because they are different trials. They don’t use the same patient groups and there are different intricacies in there. I suppose it depends on the call to the evidence and if there were reasons why that cohort were different, or the outcomes were different, or the intervention was different."Senior stat, P11: "All 16 participants also indicated that they felt it was difficult to trust external evidence and expressed concerns that incorporating it in their analysis could bias their own trial results. For example, participants were concerned about likely differences in the population between the external evidence and their own trial.I suppose if there was, if there was consistency in the way the studies were reported and there was a way, a simple way of collecting all of the high-quality evidence together very quickly, then that would obviously be a big help but yes, I suppose that’s a bit of a pipe dream really."Trial stat, P8: "If it’s publicly funded you need to make the data available and that seems reasonable. But there’s still always an administrative exercise in getting through approvals and getting that, and for somebody to create a dataset that can be shared without risking identifiable data."Methods lead, P10: "Throughout the interviews it was clear there were practical challenges participants felt they  would face if they wanted to use external evidence formally in practice. One of the most common issues surrounded logistics and the administrative burden associated with accessing external data, and the corresponding consideration of anonymisation of research participants.One of the problems is there’s probably a shortage of systematic review capacity. So, finding systematic reviewers is really tough actually."Ch Inv, P5: "Most participants thought a systematic review was the most obvious source of external data. However, most indicated that their trial units did not have direct access to a systematic review team, and they viewed systematic reviewers as having a different skill set from their own.I’m trying to get funding for a study now to do this comparison, I can’t easily spend loads of money having a statistician spending ages trying to make a brilliantly efficient trial design..."Ch Inv, P3: "More senior trial members identified concerns regarding how much extra time would be needed to implement Bayesian methods and the implicit costs associated with this.So, I think that would be a helpful if there was, I mean certainly if there was some sort of guidance that had been produced elsewhere."Trial stat, P8: "I think that’s partly about real world examples that you can look at and see how somebody did it and then it’s also about software and knowing how to implement it even if you wanted to."Methods lead, P10: "It was frequently brought up that, in order for these methods to be used in practice, there would need to be guidelines and requirements by funders.I personally don’t go anywhere near them [Bayesian methods]. I think I did do a course in Bayesian stuff, but I just don’t think I work that way and I don’t feel comfortable using Bayesian methodology, so I personally would shy away from it."Senior stat, P11: "It [Bayesian analysis] was a black-box moment of it went into the system and came out and I didn’t really know what had gone on in between [laughs]. Very bad statistician!"Trial stat, P9: "I think a lot of it is accessibility of the software because Stata it’s just very straightforward, WinBUGS it’s not. So, I think that’s a massive hurdle. If you could do it in Stata people would probably do it."Methods lead, P4: "Many statisticians also did not feel confident in using Bayesian methods or Bayesian statistical software. They expressed concerns about the time and financial pressures associated with having to learn these techniques.OK, as a statistician, you’re always taught the more data you have, the better. The more information you have the better. So why – if you’ve got the information there – would you not use it?"Senior stat, P16: "… I think it would take a lot, as a said before, a lot for people to change the specific analysis they were going to do. So I think this would be a subsequent or secondary analysis that people would do but it would be interesting."Senior stat, P1: "Despite the barriers described in themes 2 and 3, many of the trialists expressed enthusiasm for the concept of making more use of existing data in particular as secondary or sensitivity analyses.We don’t want to do a trial that wastes a) time and b) money, so if we had existing evidence which would cut down time and money then I think we should do it to start with."Senior stat, P1: "I guess, because you do collect a heck of a lot of data for each trial and obviously not everyone has registry databases like ourselves, I don’t know if there is some way that there will always be like an evolving cycle of data. …. I think I’ve heard it talked about the trial in a certain area you always collect certain variables and then those variables could be uploaded to a dataset and then it actually creates a big one. Everyone’s trial data gets compiled together and then you do have a big database that you could then use to inform sample size calculations and other things like that."Senior stat, P11: "Many thought that making more use of existing data would be advantageous, as a lot of time and money is invested in trials, which it is important not to waste.So, we do make use of it [external evidence on adverse event rates] but obviously in a suboptimal way and I can imagine that doing this kind of approach for adverse events for example. would offer greater safety would allow safety signal to become obvious in my study earlier maybe so therefore better."Ch Inv, P3: "We observed that when trialists think of Bayesian methods, they were generally only thinking about prior information on the treatment effect—and may be unaware of available methods to make use of data on other parameters. In discussing the potential to use external evidence to inform other types of parameters see the ‘’ sectionIf you’re wanting to change practice, your one trial is not going to change practice. The body of evidence [meta-analysis] is going to change practice."Methods lead, P4: "You’re not gonna sort of waste time and money showing an effect size in a single trial when you might be able to do it in a combination with existing studies. I think that’s quite sensible, but I guess it’s a case-by-case basis."Senior stat, P1: "I think it’s quite sensible probably to power it based on, you know, making a change to that if it means that you, you know, you’re gonna recruit less participants."Trial stat, P8: "The concept of using an existing meta-analysis to power a new trial, based on its ability to impact an existing meta-analysis , 11, 33,We found that trialists were using existing evidence in many ways, including to justify there is a gap in the evidence base and to inform parameters in sample size calculations. However, none of the trialists in our sample had an experience of explicitly incorporating prior information in either trial design or analysis through the use of Bayesian statistical methods. Our study showed that trialists felt they could be making more use of existing data to inform the design and analysis of a clinical trial in particular scenarios, such as in secondary or sensitivity analyses. We observed that when trialists thought of Bayesian methods, they appeared to be thinking about the use of prior information on the treatment effect only and may be unaware of available methods to make use of data on other parameters. Several participants in our study found the idea of formal use of evidence on other parameters appealing and thought improvements could be made to current methods. The use of informative priors based on external evidence in sample size calculations and to assess whether adverse event rates were higher than baseline was perceived as attractive. Similarly, although trialists do not think about how their trial results will influence a future meta-analysis, many thought it would be useful to investigate when conducting the sample size calculation. In contrast, no participant expressed enthusiasm for the concept of ‘bias adjustment’ based on external evidence. Participants also identified barriers to implementing these methods in practice. Trialists expressed concerns about the relevance or quality of external data and how incorporation of this could potentially affect their own trial. We also found that trialists did not feel confident in the use or interpretation of Bayesian methods and identified practical issues including difficulty accessing relevant data, anonymisation issues and the extra time associated with this.Our finding regarding the relevance of prior information being a key concern to trialists is consistent with the results from a recent survey of trial methodologists  and has Having found that the statisticians in our sample did not feel confident in the use of, and/or had concerns about the acceptability of, Bayesian methods, more training and specific methodological guidelines on the use of Bayesian approaches in trials may be beneficial. In particular, guidance could raise awareness of Bayesian approaches to incorporate external evidence on parameters other than the treatment effect, given that our participants knew little about options in this area. Tutorial papers, user-written packages in generic rather than specialist software and provision of example code may increase accessibility. We note that Bayesian approaches are becoming easier to implement in practice via, for example, the development of core R packages . DevelopOne limitation of this study is that snowball sampling was used to identify participants after initial key contacts in each group were sampled from colleagues known to the study team. This potentially limits the generalisability of the findings to all trialists. However, as data collection continued, sampling became increasingly purposive, with a view to achieving a sample of maximum variation, to ensure insights were captured from a range of informants operating in different contexts . We succIn conclusion, trialists recognise that more formal use of external evidence could be advantageous over current approaches in some areas, particularly to inform parameters other than the treatment effect, for which very limited information may be available from the trial, and useful as sensitivity analyses. Trialists do however note that there are still many barriers to such use in practice. Clear guidance, user-friendly software and accessibility to a repository of data might increase uptake of Bayesian approaches in practice.Additional file 1: Table S1. COREQ checklist. Figure S1. Example of topic guide.


Skills, knowledge, and awareness of digital and technological tools are essential to improve the state of well-being and health of older adults and also to mitigate the condition of social isolation in the aging process. For this reason, it is necessary to implement a social learning of electronic/digital tools for health of older people to support the achievement of eHealth and digital competences. The paper reports the results of an Italian innovative eHealth training for the European project ACCESS. The training has been based on blended didactical and interactive educational techniques, aimed at collecting as many points of view as possible from older adults. A total of 58 older adults were recruited to attend a four-week training program, which included five modules. The results showed a statistical significant difference between the eHealth Literacy Scale (eHEALS) mean value before and after the course. A significant negative correlation was found between eHEALS and positive/total Survey of Technology Use (SOTU), suggesting an inverse relationship between positive/total SOTU and eHEALS. There is a strong positive and statistically significant relationship between satisfaction with the training and eHEALS. The results indicate that the intervention increased the digital competences of participants connected to health. Skills, knowledge, and awareness of digital and technological tools are essential to improve the state of well-being and health of older adults ,2 and alIn fact, social distancing measures forces individuals to minimize physical interactions that result in increasingly widespread and grave social isolation and loneliness. Health technologies can support older adults to mitigate the overwhelming impact of the pandemic situation and enhance well-being, while COVID-19 is an “alarm bell”, reminding that an immediate attention should be paid to improve eHealth literacy among older people to use technological/digital innovations as a “complementary tool” to provide care services . During Nevertheless, there are a plethora of ageing-specific barriers that may represent obstacles to the positive use of technological tools and the enhancement of eHealth literacy, such as multimorbidity and the presence of physical impairments or cognitive deterioration. Other major impediments concern financial resources ; others are technical, as the compatibility between different eHealth tools or insufficient ICT support and infrastructures; or legal, as the absence of a legislative framework more clearly defined to support eHealth literacy achievement . SimilarSimilar argumentations suggest that it is mandatory to implement a social learning of electronic/digital tools for health of older people to support the achievement of eHealth and digital competences. eHealth literacy has been conceptualized as “the ability to seek, find, understand, and appraise health information from electronic sources and apply the knowledge gained to addressing or solving a health problem”, representing a factor of critical importance to counteract multiple access barriers to technology for older adults, related to motivation, material, skills, and usage spheres ,12. Training focused on eHealth literacy is becoming increasingly essential in the context of an ageing Europe: with the potential offered by digital tools, eHealth literacy can strengthen health literacy itself and enable a deeper knowledge and better self-management for patients, particularly for older adults ,14. In fact, eHealth training can directly improve motivation, reducing negative emotional factors such as stress, fear, and anxiety that block the use of eHealth technologies ,16, as wIn the current state of the art, there is still a scarcity of theory-based learning interventions focused on eHealth literacy that assess the direct impact on health outcomes, and there is a need to develop and implement a high-quality research study design for this purpose . Taking into account the framework of barriers and benefits, the paper reports the results of an innovative eHealth training, piloted in Italy during November 2020, involving 58 older people, for the European project ACCESS , aimed at (a) exploring, implementing, and evaluating new modes of socially embedded learning opportunities for older adults with low technical skills; (b) identifying ways to improve digital literacy in regard of internet skills and the everyday usage of assistive technologies in older individuals; (c) fostering a new learning culture for later-life learning.The ACCESS eHealth training has the ambitious purpose of advancing toward a clearer definition and measurement of eHealth literacy in practical scenarios, improving the overall eHealth literacy and thus supporting the positive use of technology .The training was based on blended didactical and interactive educational techniques, aimed at collecting as many points of view as possible from older adults. The training’s program included 5 modules and was conducted over 4 weeks. On average, the duration of each session was 90 min. The sessions were conducted using the GoToMeeting platform. The overall training objectives refer to the three learning competencies of the European Qualifications Framework (EQF) reported in Module I: Raising awareness of eHealth and health literacy: introduction to the aims and context of the ACCESS project; Achieving new knowledge: introduction to Health and eHealth literacy;Module II: Practicing new skills: digital health apps and skills with practice session;Module III: Practicing new skills: usability with practice session;Module IV: Social communication: inter-generational mode;Module V: Self-evaluation and sustainability of the improvement .The training is divided on the following modules:Module 1 introduced the objectives of the ACCESS project and analyses the definition and meaning of eHealth literacy. An overview of the initiatives and projects for the digitization of the older people in Italy is provided, with a focus on the barriers to the use of technological and digital health  solutions . The first part of the module is managed as a frontal lesson. In the second part, a discussion is conducted, in focus group mode, to reflect and share the point of view on approach and perceived images of technology. The aim is also to lead older participants to reflect on the concept acceptance/rejection of technological tools, trying to distinguish the barriers to access  that are experienced more in everyday life. Module 2 combines theoretical and practical aspects, guiding participants to know what health literacy and eHealth literacy is and providing information to improve health/eHealth literacy, in order to enhance knowledge and awareness of digital tools and applications more functional to psychophysical well-being. The second part of the lesson is managed as a practical exercise, starting from the selection of freeware digital health apps, to promote in older people a more autonomous and conscious management of health and increase the degree of health and digital literacy . The objective is to provide participants with a selection of apps with health information from secure and verified official health systems’ sources, easy to use and usable even after the end of the training, so that they will be more familiar with, and gain greater utility from, the use of such tools in their daily lives.Module 3 is focused on the concept of usability of digital and technological services and devices, presented in frontal lesson mode. One of the theoretical assumptions to be learned by older adults is based on the idea that no technology is positive or negative in itself, but often the poor usability of tools causes frustration in use and consequent refusal. The scope is to acquire greater awareness of the problems or errors in use, trying to distinguish situations in which the ineffective use, or non-use, is due to poor user skills or, conversely, to an inadequate degree of usability of the service/technological tool. The second part of the module is conceived as a practical exercise, based on an example test of usability of online portals that offer a service of wide use, especially for the health of older people. This test, for instance, concerns the online booking center of medical examinations. In particular, the main usability problems of an online site, which can cause difficulties of use for the older population, are shown. Module 4 is designed considering an intergenerational learning context: in agreement with a high school, students, coordinated by their teacher, conduct a lesson on the use of social networks  to promote the use and social inclusion of the older adults. The direct involvement of so-called “digital natives” represents a great added value for older people, recalling the experiential/emotional interaction between grandparents and grandchildren. By describing the characteristics and functioning of some of the main web tools, apps, and socials in common use, the young students stimulate the older adults to think about current issues concerning the relationship with technology and the potential inherent in new forms of communication and sociality. This results in a reflection from the different point of view between a technological generation and a non-technological one.Module 5 aimed to assess the self-evaluation of enhanced awareness, knowledge, and skill levels of technological use and digital health literacy, with a concluding section regarding the evaluation of the training activity and teaching carried out. In the final session, the trainer describes to the participants the characteristics of the final questionnaire to support them in filling it out.Moreover, the willingness to pay will be analyzed at the end of the training. In addition, an attempt will be made to analyze the relationship between familiarity with technology and appreciation of the intervention with the health literacy.The training is designed for older adults, sorted into groups of approximately 20 participants for online mode, led by a trained facilitator. For the pilot, it was possible to recruit 58 older adults from all provinces of the territory, with a mean age of 68.2 (±5.0) years, in agreement with a regional union of retirees (FNP CISL Marche). For a better management and a more effective learning, the participants were subdivided into three distinct groups, independently from education level and digital skills. The recruitment of the participants was conducted during the COVID-19 lockdown, through the NGO’s contacts. An email was sent to the newsletter and the interested persons contacted the researcher directly. As a prerequisite to take part in the study, the availability of an internet connection and a pc or tablet were required, in order to be able to follow the group lessons. The materials were sent to the participant after each lesson by email.Before starting the training, informed consent was provided to the participants and a copy of the signed informed consent was collected by post. During the first session, a questionnaire was presented to the participants containing information on experience with technology, eHealth literacy, socio-demographic information.-an ad hoc checklist to collect socio-demographic information;-the Survey of Technology Use (SOTU) from the Matching Person and Technology Model. SOTU is composed by a 29-item checklist which inquires into current experiences and feelings toward technologies. All items are presented in a three-point semantic differential format to elicit the consumer’s feelings towards these influences ; in this way, three subscales are scored, highlighting positive, negative, or neutral past experiences with technology as well as a total score .-The Italian version of the eHealth Literacy Scale (eHEALS), an 8-item measure of eHealth literacy developed to assess consumers’ combined knowledge, comfort, and perceived skills at finding, evaluating, and applying electronic health information to health problems .The preliminary questionnaire was composed by:-the eHealth Literacy Scale (eHEALS) ;-an ad hoc checklist, consisting of 8 questions to be rated on a 5-point Likert scale, to assess the satisfaction with the training, from 1 “Do not agree at all” to 5 “Completely agree”;-one ad hoc question to assess the availability of pay for the course.During the last session, a final questionnaire was administrated including:t-test or Mann–Whitney U test, as appropriate. Categorical variables were expressed as the absolute number and percentage and statistical significance was assessed by Pearson’s Chi-square test. In a second step, the analysis of follow-up data was carried out to evaluate the effectiveness of the intervention. Frequencies of eHEALS items were compared between baseline and follow-up via Pearson’s Chi-square test. The overall mean values of the eHEALS scale were compared between the two time points and statistical significance was assessed with a paired t-test. Willingness to pay was analyzed reporting the mean and SD of the program satisfaction for each cost item: statistical significance was assessed by one-way analysis of variance (ANOVA). The relationship between SOTU subscales, overall SOTU, satisfaction with the training program, and eHEALS was estimated by calculating the pairwise correlation coefficients. The statistical significance was set at p < 0.05. Statistical analysis was conducted using the Stata 15.1 Software Package for Windows .Continuous variables were reported as either mean and standard deviation (SD) or median and interquartile range (IQR) on the basis of their distribution (assessed using the Shapiro–Wilk test). Comparison of variables between groups were performed by an unpaired Student The demographic, social, and eHealth literacy characteristics of the sample are reported in p = 0.001).Another interesting aspect is the response of the sample to the question of how much they would pay for the course. In fact, 18 people would pay more than 70 € . There ip = 0.048 and p = 0.032), suggesting an inverse relationship between positive/total SOTU and eHEALS. There is a strong  positive and statistically significant relationship between satisfaction with the training and eHEALS.The eHealth concept can be a starting point to better understand how to support older people in using devices to take care of their own health. The absence of standardized eHealth and technological training for older people is a matter of particular relevance for the support of health and well-being during the ageing process. In the current state of the art, in fact, the weak link is represented by the lack of a training that is not limited to teaching how to use PCs, tablets, or smartphones as a more or less advanced practical skill, but that includes broader concepts of paramount importance for the construction of realistic expectations towards technology, such as usability, i.e., how to avoid frustration in use when a usability problem is recognized; a user-centered design and participatory approach, i.e., feeling be part of the process of designing technology and not feeling excluded; and the awareness of access barriers to technology. The most important outcome of the ACCESS training is the decisive improvement of the eHealth literacy itself: the intervention has demonstrated to significantly improve the digital health competences of the older participants, especially the ability to retrieve useful and reliable health information on the Internet to increase the ability of older adults to use Internet links and find desired health-related information, as already demonstrated by a study in the field . This maFrom a very practical point of view, the participants report to like the format of the training, consistent with the literature on e-learning programs on eHealth literacy . In factMoreover, the results reported in A recent analysis of the literature  has examIn this way, it seems essential to develop a specific theoretical framework to guide eHealth intervention research with older adults as well as to improve eHealth interventions in real settings. In our case, in addition to the well-known definition of health and eHealth literacy, we have started our assumption from the overall concept of technology literacy, in its definition from ITEA (2000/2002) that refers to “one’s ability to use, manage, evaluate, and understand technology. In order to be a technologically literate citizen, a person should understand what technology is, how it works, how it shapes society and in turn how society shapes it”. If we try to redefine the concept of eHealth literacy by introducing the wider perspective adopted by technology literacy, it is possible to define an “e-health technologically literate person as is comfortable with and objective about the use of technology for health, by involving a vision where every person has a degree of knowledge about the nature, behavior, power and consequences of many aspects of technology—especially for health—from a real world perspective” (adapted by ITEA). The empowerment of older people’s eHealth literacy is of crucial importance, especially to navigate in the COVID-19 infodemic; for this purpose, researchers, academics, and health authorities have to consider eHealth literacy as a crucial factor to facilitate infection prevention, for example, . Recent Moreover, together with family, health professionals are important mediators of technology use for health. For this reason, a dedicated and complementary training on how to support older people with low eHealth competences should be developed also for health professionals, in order to provide them practical strategies for saving time in habitual activities, for example, and reducing the burden of care. During the ACCESS study, the online modality was appreciated by the participants and allowed the management of the course during the lockdown due to COVID-19, but the provision of digital health courses for older adults could be part of a long-term inclusive local digitalization strategy ,32 to coTo summarize, it is possible to recognize the positive effect of the ACCESS training on eHealth literacy, highlighting the potential of educational intervention in providing useful knowledge and skills to overcome erroneous representations of technology as well as misuse of the health technological devices. The expected benefit of training as ACCESS is the inclusion of older people in the technological world, on a global perspective, as well as the improvement of perceived self-efficacy in dealing with technology and health, with positive pitfalls on the health status. Despite its undeniable wealth, there are some limitations that need to be taken into account to improve the study design of the training. First of all, future pilots should take into consideration the opportunity of including a control group as well as a larger sample to assess the efficacy of the training from a more evidence-based perspective. Moreover, follow-up evaluations should be performed in order to assess the maintenance of the improvement after the training. Future plans should also include sustainability strategies, as the educational training should be integrated not only in the social and community services but should also be delivered by public and private health providers.To conclude, fostering eHealth literacy in older adults hosts the potential to improve the wellbeing of older adults in today’s rapidly developing society. Currently, suitable training programs targeting older adults combining health and digital literacy are missing. In our paper, we introduce an eHealth training program, which was delivered to older adults across four weeks through online activities. Our results indicate that the intervention increased the digital competences of participants connected to health. In order to effectively address eHealth literacy, a comprehensive approach is required as future work, building on innovative evidence-based tools and best practices, such as the proposed training course, to simultaneously reach out and target citizens, communities, professionals, the industry, and health and social care systems, with specific attention paid to the inclusion of ‘hard-to-reach’ people so as to ensure that no one is left behind.


Duchenne muscular dystrophy is a rare, progressive, life-limiting genetic neuromuscular condition that significantly impacts the quality of life of informal caregivers. Carer quality of life is measured using heterogeneous self-report scales, yet their suitability for Duchenne remains unclear. This review aimed to identify and evaluate the reliability and validity of quality of life instruments in Duchenne carers.Systematic searches were conducted in Embase, MEDLINE, CINAHL, PsycINFO, Cochrane Library and Google Scholar. Full research articles reporting data on multiple-item self-report quality of life instruments in informal Duchenne carers were included. Extracted evidence was qualitatively synthesised and evaluated, including risk of bias, against the Consensus-based Standards for the selection of health Measurement Instruments. Duchenne carer collaborators (N = 17) helped rate the instruments’ content validity.Thirty-one articles featuring thirty-two quality of life instruments were included. Content validity was rated as “inconsistent” based on very low quality evidence. For Duchenne carer collaborators, the best instrument was PedsQL Family Impact Module. Only one instrument had evidence for structural validity (rated “unsatisfactory”) and measurement invariance (rated “satisfactory”). Instruments received “satisfactory” ratings for internal consistency and mixed ratings for construct validity and responsiveness. There was no evidence for reliability, measurement error, or criterion validity.Instruments used to measure Duchenne carer quality of life have limited and often inconsistent supportive psychometric evidence. Further work must investigate instruments’ measurement properties in Duchenne carers and/or the development of new tools. In the interim, we recommend considering the PedsQL Family Impact Module based on Duchenne carer ratings.The online version contains supplementary material available at 10.1186/s12955-022-01964-4. Duchenne muscular dystrophy (DMD) is a rare x-linked genetic neuromuscular condition with an estimated prevalence of 19.8 per 100,000 live male births . ImproveAs a pervasive and life-limiting condition, DMD has been observed to impact the health-related quality of life (QoL) of people with the condition in multiple ways. Key areas of impact include independence, relationships and social participation, and psychological wellbeing . As wellDocumented effects on QoL of caring for someone with DMD include problems with sleep, psychological wellbeing, relationships, family resources, physical burden, and impact on the wider family . HoweverAs competing instruments exist to assess carer QoL in DMD, without further data and an evaluation of the evidence on the psychometric properties of these measures, it is difficult to ascertain which instruments are most suitable for use in this context. Given the degree and breadth of the impacts of DMD on daily life for people living with the condition and their informal caregivers, it is not known whether available instruments are sufficiently reliable and valid for assessing carer QoL in DMD. In other progressive conditions, such as neurodegenerative diseases, condition-specific carer questionnaires have been advocated for . GettingHealth technology assessment (HTA) agencies, such as the National Institute for Health and Care Excellence (NICE), promote the inclusion of “all direct health effects for patients or, when relevant carers” in their Guide to the Methods of Technology Appraisal . This inThe COSMIN approach represents a structured way of assessing the psychometric evidence of available questionnaires across a number of agreed-upon criteria. Content validity is argued to be the most fundamental psychometric property and refers to the extent that the content of a measure adequately reflects the target construct that is being assessed . It can According to COSMIN, the second most important psychometric property is structural validity . StructuCOSMIN has provided internationally-consensual definitions of other important measurement properties, which, when good content and structural validity are documented, all contribute to a measure’s psychometric performance . These iThis systematic review has been designed to evaluate the content and psychometric properties of instruments used to measure QoL in informal carers of people with DMD using the COSMIN approach , 15. COSIdentify which questionnaires have been used to assess QoL in informal carers of people with DMD.Evaluate the measurement properties, including the strength and quality of evidence, of questionnaires that have been used to measure QoL in informal carers of people with DMD.Make a recommendation for which questionnaire(s) (if any) are best suited to assess QoL in DMD informal caregivers, based on the current evidence, and identify gaps for future work.For the purposes of this review, we define informal carers as someone providing care to a person with DMD with whom they have a non-professional caregiving relationship, including a parent or guardian, or other family member, friend, neighbour, or other relative or non-kin (where a caregiving relationship is defined) . We exclhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020200120. The manuscript has been written using the PRISMA 2020 reporting guideline and checklist )The focus of this review was to report on the measurement properties of instruments that have been used to quantify QoL of carers of individuals with DMD. However, it is clear when applying COSMIN methodology that the content validity of the instruments identified was questionable. It could be argued that the appropriateness of such questionnaires to assess carer QoL for other health conditions is not justified. Whilst there is still a requirement to assess the relevance, comprehensiveness and comprehensibility of the instruments for other health conditions, this does not overcome the limited evidence for the content validity (i.e. development) of the measures themselves. This review has highlighted the need for future studies to support the content validity of instruments for the target population. It can be postulated that other neuromuscular disorders could imply similar impacts upon carer QoL, however this has not been explored within the context of this review. Furthermore, there are other instruments available which can be used to measure carer QoL which were not included in this review (as they had not been used in studies relating to DMD).doubtful or inadequate. Secondly, many of the questionnaires identified in the review could be considered as legacy measures. They were developed at a time when detailed descriptions of instrument development were not necessarily reported and/or different methods for instrument design were accepted. The COSMIN approach is such that these instruments score poorly. It is important to recognise that this does not necessarily mean that the development of these instruments was fundamentally flawed or inappropriate such that have no utility whatsoever, but that an assessment of the available evidence by modern standards has found them lacking. Thirdly, whilst the inclusion of the lived experience (i.e. carer perspective) was incorporated into this review, it must be acknowledged that there may be a degree of bias associated with the responses. Whilst efforts were made to mitigate this , it must be noted that all respondents were from the UK. It is possible that their experiences  may have influenced their ratings. It is not clear whether the findings are replicable in other countries. In addition, the vast majority of informal carer ratings were provided from mothers. Indeed, a number of the studies included in the review also assessed the impact of mother’s QoL . However, it can be argued that modern-day parenting situations and roles have altered over recent years, and it cannot be assumed that paternal ratings of the instruments included in the review would align with maternal views.This review is not without its limitations. Whilst the methodological approach adopted is recognised and robust, it does have some limitations, as previously noted , 20. FirDue to the large number of instruments included within our review, and the focus on quality of life as a multidimensional construct, we made a pragmatic decision to present the results of instruments, rather than individual subscales (where appropriate). Furthermore, in the assessment of comprehensiveness of the instrument, we applied this to the construct of overall quality of life (rather than the construct the instrument may have been designed to measure).Finally, the assessment of measurement properties of the instruments undertaken here does not incorporate consideration of the acceptability or feasibility of the identified measures. These are also important factors when assessing their suitability. For example, this may include the length of the instrument and how cognitively demanding it is. Practical issues of PROM availability, such as costs and licensing requirements, availability in all required languages, and mode of administration (i.e. electronic versus paper) also play a key role. This review was limited to those instruments where a free or review copy was available for research purposes.The instruments used to measure impact on Duchenne carer quality of life have limited psychometric evidence to support their use. To that end, the published evidence reporting QoL in carers of people with DMD may not accurately reflect the true impact of caregiving on QoL. Further work is thus required to investigate the measurement properties of common QoL measures in DMD carers, including content validity studies. Research should also examine whether a) the constructs of the instruments identified as part of this review map onto a conceptual framework of carer quality of life in DMD; and b) whether this differs for other paediatric life-limiting conditions. Given the results of this review, work may also be justified in the development of condition-specific carer QoL measures (or within paediatric life-limiting conditions) for use in DMD to better capture the true impacts of the condition on carers. In the interim, we recommend the consideration of the PedsQL FIM as a QoL measure in Duchenne carers, as it showed most promise from evaluation by carers themselves.Additional file 1: Database search strategiesAdditional file 2: Data extracted from included studiesAdditional file 3: Instructions for carer ratings of instruments’ content validityAdditional file 4: Full list of questionnaires identified in the searchesAdditional file 5: COSMIN rating sheets