Many treatments developed for rare diseases will have an Orphan Medicinal Product (OMP) designation, indicating that they are likely to deliver benefit in an area of high unmet need. Their approval may be based on a small or uncontrolled trial, as randomised controlled trials (RCTs) of sufficient size are often difficult to conduct, or repeat, as a result of the rarity of the condition, sparsity of patients, or for ethical reasons. Furthermore, many products are given a conditional marketing authorisation, requiring additional evidence to be collected after product launch. This is even more challenging with the advent of advanced therapeutic medicinal products, which use novel scientific approaches like gene or somatic cell therapy.Given the high unmet need associated with these products, there is pressure for Health Technology Assessment (HTA)/reimbursement bodies to enable rapid access to effective treatments. However, there is often only limited evidence available for assessment.TRUST4RD proposes an approach to identify uncertainties of most concern for decision-makers by developing an iterative and informed dialogue amongst stakeholders , so that potential approaches to resolution can be discussed. As evidence is generated, uncertainties are reviewed and prioritised, and evidence-generation plans revised or clarified accordingly. The aim is to develop – both pre- and post HTA submission – a better understanding of evidence requirements versus evidence-generation trade-offs as an evidence base grows and the potential value of a product becomes clearer.TRUST4RD presents guidance on defining uncertainties and evidence gaps in the assessment of value and value for money of specialised treatments for rare diseases. It also provides guidance on the potential of Real World Evidence (RWE) to help address such uncertainties, including the typology of evidence uncertainties, the importance of different uncertainties and the data sources available to address them before and after HTA submission. In making use of the guidance, authorisation and reimbursement discussions on such treatments can be embedded in an evidence-rich context, thereby ensuring value to all parties, particularly to patients. Many of the treatments developed for rare diseases will have an Orphan Medicinal Product (OMP) designation indicating that they are likely to deliver benefit in an area of high unmet need. Their approval may be based on a small or uncontrolled trial, as randomised controlled trials (RCTs) of sufficient size are often difficult to conduct, or to repeat, as a result of the rarity of the condition, sparsity of patients, or because of ethical reasons. Furthermore, many products are given a conditional marketing authorisation, requiring additional evidence to be collected after product launch. This situation has become even more challenging with the advent of advanced therapeutic medicinal products, which use novel scientific approaches like gene therapy, somatic cell therapy or tissue engineered products administered to human beings with a view to regenerating, repairing or replacing a human tissue .Given the high unmet need associated with these products, there is pressure for Health Technology Assessment (HTA)/reimbursement bodies to enable rapid access to effective treatments, which requires spending public money. However, related to the rare and complex nature of the conditions they treat, there is often only limited evidence on these products available for assessment. Uncertainties may occur about the care pathway, natural history, treatments’ clinical outcomes in the longer term, added value to patients and value for money to society .For industry the investment to develop these specialised treatments is important with limited possibilities for economies of scale, and for society there is a high treatment cost per patient, albeit mostly with a rather limited overall budget impact.As a result of the combination of high prices  and uncertainty in evidence, decision-makers in healthcare, particularly HTA agencies and healthcare payers find themselves forced to make decisions about reimbursement under difficult conditions.Guidance is therefore needed that supports discussion amongst all stakeholders to develop an understanding of the potential evidence that could be generated both pre- and post-HTA submission and to allow trade-offs in different approaches to evidence generation versus the societal issues of access to these medicines and wise use of limited healthcare resources.This paper aims to develop a technical but pragmatic tool and methodology that allows the uncertainties in evidence for a specialised treatment for a rare disease to be made explicit, to be prioritised and to be addressed in an adequate and timely way. Additionally, the paper provides guidance on the potential of Real World Evidence (RWE) – i.e. data collected outside the context of RCTs – to help address such uncertainties.It builds on existing initiatives from the European Commission and the European Medicines Agency (EMA) –5, the ICommissioned by the Belgian Institut National d’Assurance Maladie-lnvalidité/ Rijksinstituut voor ziekte- en invaliditeitsverzekering (INAMI/RIZIV), the paper was developed through a multi-stakeholder dialogue. Starting from a two page document explaining the issues related to evidence uncertainties for orphan medicines, and stating the objectives of the the multi-stakeholder dialogue – namely to develop the methodological tool – stakeholder representatives from patient groups, healthcare professional organisations, government bodies (including payers and HTA authorities) and the pharmaceutical industry were invited to participate in a series of 3 roundtable discussions. During the roundtable sessions, discussions took place under the ‘Chatham House’ rules. After each Roundtable, a summary was written, on which all participants were invited to comment. Initially, existing insights and recommendations from other papers were presented and discussed. During a second roundtable, the components of the tool were established (see below), based on presentations and proposals of the different stakeholders. During a 1 day workshop, template aimed at supporting the development of the tool was pilot tested based on real cases of orphan products for which evidence gaps were observed and whereby the draft tool was applied to systematically address these gaps. During the third workshop, consensus was achieved on the content of the tool. The draft tool was presented at the ISPOR European meeting in Barcelona, novermber 2018 and comments from the audience were taken into account to finalize the tool. A drafting committee comprised of a smaller group of similar stakeholder representatives supported the writing of this paper.As stated above, uncertainties exist in the evidence base submitted to HTA for specialised treatments for a rare disease. Uncertainties will, of course, always exist and may also evolve over time. Typically, some uncertainties may be unavoidable at an early stage but may be addressed later on. This paper proposes an approach to identify the uncertainties that are of most concern for decision-makers. It sets out a way to reduce these uncertainties that centres on developing an iterative and informed dialogue amongst stakeholders so that potential approaches to resolve them can be discussed. As evidence is generated, the uncertainties are reviewed and prioritised, so that evidence-generation plans can be revised or clarified. The aim is to develop – both pre- and post HTA submission – a better understanding of evidence requirements versus evidence-generation trade-offs as the evidence base grows and the potential value of a product becomes clearer. Like the advice given in current regulatory and HTA settings, such as Scientific Advice and Early Dialogues, , 7 the aThe methodological tool was conceived to consist of three building blocks: evidence gaps, data sources and design, and the presence of an iterative dialogue. Each of these building blocks is subject to an evolution over time, as shown in Fig. We propose a new taxonomy of evidence gaps whereby we distinguish four main types of uncertainties that are common at the time of access decisions for treatments developed for complex or rare diseases: uncertainties related to the size and characteristics of the population; uncertainties related to the natural history of the disease and its current management; uncertainties related to the new treatment; and uncertainties related to the health ecosystem. We describe these here in more detail, using examples, however, without the ambition to provide an exhaustive list. Obviously, for a given orphan medicine multiple uncertainties may exist at the same time.size and characteristics of the population. We refer here to uncertainties about the incidence and prevalence of the disease; the exact size of the target population; the characteristics of subpopulations and target populations, such as age and time since diagnosis; the spectrum and variations of disease manifestations, such as symptom severity; and different genotypes or phenoyypes.The first set of uncertainties relates to the natural history of the disease and its current management. Disease are often characterized by a typical natural course or history of the disease over time, with different prognoses for patients with varying characteristics. In the case of rare diseases evidence with this regard is often lacking. Typically for rare diseases is also the absence of current standards of care, uncertainty about the relevant comparator  [The second set of uncertainties is about the er time)  as well new treatment. We refer here to uncertainties about the size of the treatment effect ; the optimum posology; the treatment effect with different subgroups; the effect size in the real target population when the trial population is different; the characteristics of patients benefiting more from treatment (and the ablity of a biomarker to identify those patients); the durability of the effect and the possibility to retreat after recurrence; the way in which the new treatment will modify further treatments in the treatment sequence; and finally uncertainty about adverse events and safety not yet observed in the trials.The third set of uncertainties is related to the healthcare ecosystem and its actors, such as patients, clinicians, and hospitals. We distinguish here uncertainties about patient acceptability and compliance  and treatment effect); about prescription patterns (will the medicine be prescribed in the intended patients?); about the available diagnostic and treatment capacity in the healthcare system ; about consequences to the healthcare system ; and about consequences to society such as reduced absenteeism.Finally, a set of uncertainties is related to the The tool involves as a first step that the known (current and expected) evidence gaps for a given “dossier” are explicitly listed early in the development of the treatment, according to the here described taxonomy .Obviously, uncertainties and data gaps evolve over time. They might be explained by a combination of factors related to the nature of the disease, its treatment or the system as well as to the quality of the (planned) evidence generation. At the time of submission for HTA some data gaps will be unavoidable . Others might however be avoidable if adequate data are obtained during the development process.The impact of these uncertainties for a given dossier needs to be addressed early to identify the highest priorities for evidence generation. Indeed, some of the uncertainties may have a much larger impact on the eventual value of the treatment than others. The collection of data that are unlikely to help demonstrate the value of a technology should be avoided and therefore a process of prioritisation is needed.Multi-stakeholder input at this point is essential as stakeholders’ views may differ and coming to a common understanding of issues will help identify priorities. See the first milestone in the iterative dialogue process further on in the text.An impact score may be envisaged to distinguish between uncertainties that matter most versus those that are much less relevant in the ultimate assessment of value and value for money of the orphan medicine. This score could be informed by both quantitative and qualitative inputs. The quantitative inputs refer to ‘what-if’ scenarios  on key final endpoints such as survival and quality-adjusted survival, cost-offsets etc. The qualitative inputs involve determining the perspectives of patients and clinicians regarding the importance of the uncertainty from their perspective.Different data sources/study designs may be needed and can be used (if available) to address the uncertainties in a given dossier and generate reliable evidence. Typically, for the new treatment, some kind of comparative evidence is required .This might not necessarily be a randomized controlled trial. Single arm studies whereby the results are compared to the results in matched historical controls can be a practical and ethically more justified alternative. Prior to or while the evidence generation about the new treatment is undertaken or conducted, several data sources and designs can be applied to reduce the evidence gaps regarding the population, the disease and its current management and the health ecosystem.Such data can also be collected in an experimental interventional design , or rather based on observation of routine practice in a non-experimental setting, i.e. real- world data that – if well managed, analysed and reported – will lead to real world evidence (RWE).It is recommended that real-world data about the population, disease, current treatment(s), and health ecosystem can and should be collected as much as possible during the development phase of the new treatment.Real world evidence about the new treatment can obviously only be collected after market authorisation, with the exception of compassionate use or early access programmes.Each of these different data sources/designs have inherent pros and cons. We recommend that for each type of important evidence gap, the corresponding data source  and design to reduce that gap is proposed, and that the pros and cons of that data source/design for that specific evidence gap are discussed. Ideally, the most adequate data source/design must be selected to meet the evidence gap in a tailor-made fashion.Finally, uncertainty and increasing understanding between stakeholders requires an iterative communication between a company and the HTA body/payer and regulator for a particular dossier to regularly take stock of newly acquired knowledge and to revise evidence-generation commitments that might not be feasible.Although we want to emphasise the iterative character of this communication that evolves dependent on the needs of each product, three milestones are identified that we consider to be desirable pre-planned points for each treatment.A first milestone is an early dialogue between industry and regulatory authorities, such as EMA and HTA/payers, in the presence of clinicians and patient representatives. HTA/payer representatives from different countries should be involved. The rationale is that uncertainties can be avoided or solved by adjusting the design of pivotal interventional studies at an early stage, i.e. before undertaking the pivotal data collection. We refer here, for instance, to the work done by the International Rare Diseases Research Consortium (IRDIRC) on clinical trials with small sample size . It mustThis first dialogue should take place very early in clinical development with all stakeholers to share the scientific ethos behind the development of the treatment, discuss any potential disruptive aspects of the technology in the healthcare system, potential evidence uncertainties and the overall plan for evidence generation . More thIn each specific dossier, issues will occur with the available/planned data sources and designs. It is important that these issues are explicitly listed and discussed, leading to suggested solutions. The process for this should be as illustrated in Fig. Reliable: there should be no over-claiming;Reflective: critically robust positions should be aired and debated;Respectful: negotiations should take place in a democratic spirit.For Step 1, the list of possible evidence gaps can be consulted to identify the major gaps. For Step 2, the list of available data sources and designs can be consulted. For Step 3, the overview of pros and cons of the different data sources can serve as input. Step 4 requires the application of the principled compromise concept , 21. ThiThe following example shows how this may work during a first early dialogue:Example: ① Anticipated gap regarding long-term evidence of the new treatment. ② Plan follow-up of trial patients. ③ This will lead to more information about the sustainability of the effect, but it will still be based on a trial population ➔ ④ A solution might be a timely plan to include patients treated post launch in routine practice in a – preferably existing – registry and observe real-world long-term follow-up outcomes.Additional issues and solutions were raised during an interactive workshop with industry, representatives from HTA bodies, payers, patient associations and clinicians. We propose that an inventory of issues and solutions is created according to the above framework and regularly updated by HTA authorities so that future submissions and negotiations can learn from these and find inspiration in previous solutions. In the Appendix, examples of such issues and solutions are listed.Of course, not all uncertainties can be identified and discussed early on. Hence, the early involvement is needed but will not be sufficient to deal with all evidence gaps at that point.A second dialogue should ideally take place after the completion of the pivotal trial in order to address the still existing uncertainties, with the remaining data gaps explicitly on the agenda. Again, more than one dialogue is possible but at least one should be organised. This dialogue should take place before official submission for HTA and should again involve patients and clinicians. This dialogue may also be bilateral and on a country (or group of countries’) level. Importantly, the potential for post-launch data collection should be discussed here. Indeed, if there is post-launch data collection, this pre-HTA dialogue will already discuss what data should ideally be collected which will facilitate the eventual agreement on post-launch data collection . The same process as illustrated in Fig. The following example shows how this may work during this pre-HTA dialogue:Example: ① Uncertainty about the relationship between the effect on a surrogate outcome and the effect on a clinically relevant outcome . ② There has been a ‘historical’ correlation shown between the planned surrogate outcome and the clinically relevant outcome, but that was with current standard of care. ③ However, it is likely that this relationship may not be the same for the new treatment ➔ ④ A solution is to accept the historical correlation in the simulations for HTA submission and to explore the new relationship in a registry after launch.The first and second dialogues are both early dialogues, however, with different timings, namely before and after the major confirmatory evidence on the new therapy. There are existing models for scientific advice/early dialogues in EMA  and EUneA third milestone dialogue is then the post-HTA dialogue which will discuss the results of the additional evidence generation after launch and its further consequences. This third milestone is focused on assessing whether the predictions that were made upon the time of HTA submission are validated in the real-world setting. The consequences of ‘not making the promise’ may also be financial if it was decided upon launch to install a risk-sharing agreement. We refer to Makady et al. (2018) for several examples of therapeutic interventions whereby RWE has positively contributed to addressing uncertainties in the evidence base, leading to better informed decision-making .The above explained process, consisting of identifying, classifying and prioritizing evidence gaps, identifying the experimental or non experimental data sources that can be tailored to address the gaps, and the ongoing dialogue with at least 3 contact moments, can only work if certain conditions are put in place.The first requirement is investing in data generation. Consideration should be given to an EU fund  for realWith regard to data governance, strong rules are needed to define custodianship of, and access to, data, and to solve issues related to privacy and data integrity. This effort should not be underestimated as it requires investments beyond the building of an infrastructure and consensus on core data elements, endpoints and standardisation.Moreover, success of the methodological tool described in this paper requires an understanding that to generate evidence for HTA/payers the limitations of data sources and robust analyses are required, but that for some situations the optimal forms of analysis are not yet clear. There needs to be an agreement between the different stakeholders on a specific protocol for data collection but also on the methods used to interpret the results to assess their quality and acceptance by all partners.Dynamic outcomes based approaches to pricing and reimbursement of innovative medicines  [Finally, outcomes-based managed-entry agreements between industry and payers may be needed, given the level of uncertainty at the time of launch. These schemes can include individual-based or population-based performance linked reimbursement schemes with money payback guarantee or coverage upon evidence-development schemes, whereby the later reassessment leads to an adaptation of the reimbursement conditions. Despite the potential attractiveness of such schemes, several authors have pointed to the barriers for their implemention , 29. In ry 2017)  recognisThis tool should lead to more win-win solutions for all stakeholders involved, i.e. allowing payers and policymakers to control expenditure and improve the life of patients, industry to reduce the time lag between marketing authorisation and access to treatment while generating RWE, and patients to have earlier and appropriate access to new treatments.This paper presents guidance on defining uncertainties and evidence gaps in the assessment of value and value for money of specialised treatments for rare diseases. Additionally, the paper provides guidance on the potential of RWE to help address such uncertainties. In brief, the guidance addresses the following aspects: the typology of evidence uncertainties, the importance of different uncertainties and the  evidence sources available to address such uncertainties either before or after HTA submission. Importantly, this guidance is the result of multi-stakeholder, multi-round discussions and thus combines the different perspectives of stakeholders involved in discussions and decision-making on specialised treatments for rare diseases.A number of the recommendations made within this guidance correlate well to work within ongoing initiatives. For example, the authors recommend early dialogue between manufacturers, regulatory authorities and HTA agencies on the nature of  evidence to be collected. Presently, EUnetHTA’s work package 5a (WP5a) is specifically addressing this matter. Moreover, the authors advise to continue dialogue in the post-launch setting. Work package 5b (WP5b) of EUnetHTA is addressing the issue of joint post-launch evidence generation (e.g. through patient registries) for HTA purposes. In fact, two pilot projects are ongoing within WP5b, one of which is on a highly specialised treatment.In the previous section, we briefly refer to additional conditions necessary for advancing the generation of robust  evidence, including structural EU-wide collaboration on data collection, standardisation of databases and data governance. We have also previously mentioned the suitability of the ERNs as a vehicle for this. Another important initiative aiming to address similar issues is the Innovative Medicines Initiative (IMI)-European Health Data Network (EHDN). Over the next few years, the IMI-EHDN will strive to provide a harmonised data infrastructure model and pragmatic governance framework to accommodate cross-centre, cross-country analyses. The outputs of such initiatives are critical to successful implementation of the guidance presented in this article. The principles put forward in the EMA adaptive pathways project , the IMI-ADAPT SMART approach and the New Drug Paradigms (NEWDIGS) also show the important advances already made on this topic.Clearly, iterative discussions between stakeholders and continuous evidence generation support informed rational evidence generation.In conclusion we encourage all stakeholders including manufacturers, clinicians, patients, regulatory and HTA agencies, and payers to make use of the guidance provided in this article as they proceed in developing evidence-generation pathways on specialised treatments for complex or rare conditions. It is our hope that in doing so, authorisation and reimbursement discussions on such treatments can be embedded in an evidence-rich context, thereby ensuring value to all parties, particularly to patients.


The composition of follicular fluid (FF) has an impact on the developmental capacity of the oocyte and the resulting embryo. FF is composed of blood plasma constituents which cross the blood follicular barrier and the secretory components of granulosa and theca cells. Moreover, it has been shown recently that follicular cells have the ability to synthesize bile acids (BAs). BAs are present in several fluids of mammals especially in bile, blood and urine. FF is an essential impacting factor on the oocyte quality and therefore resulting embryos. To achieve a better understanding of this subject, the presence and concentration of BAs were measured in fluid collected from bovine follicles, categorized according to their size, throughout two entire oestrus cycles and compared to those in blood and urine. The body fluids were collected during the same examination procedure and in total samples from four heifers were obtained. A broad spectrum of 11 BA derivatives was measured applying liquid chromatography–tandem mass spectrometry (LC‐MS/MS). The simultaneous and direct quantification of BAs in different body fluids of cattle are reported. Within the follicular fluid, blood and urine, cholic acid and glycocholic acid are the dominant BA subspecies irrespective of the oestrus cycle stage. Moreover, BA concentrations in blood compared to those in the FF were similar. For the first time these results clearly highlight the presence of different BA subspecies in FF, blood and urine during the oestrus cycle in cattle. Bile acids have been identified recently in follicular fluid of humans and cattle. To achieve a better understanding of bile acids during reproduction, the presence and concentration of bile acids were measured in fluid collected from bovine follicles throughout the oestrus cycle and compared to those in blood and urine. Usually, bile is secreted by hepatocytes and is stored and concentrated in the gallbladder. During digestion, bile is secreted into the lumen of the small intestine, where its acids act as emulsifiers of nutritional components Russell, . From thBAs, particular primary BAs, are synthesized from cholesterol by the liver Russell, . Cholic BAs are present in several body fluids like bile, blood and urine. Recently, BAs were also detected in follicular fluid (FF) of humans . Undisturbed general physical conditions as well as sound gynaecological health were required. Before the individual OPU sessions, the animals received an epidural anaesthesia according to their respective body weight .All experiments with animals were conducted according the German ethical guidelines of animal welfare, which were approved by regional council (Regierungspräsidium) Giessen of the State of Hesse (Reference numbers V 54–19 c 20 15 hr 02 GI 18/14 Nr. A1/2016).The ultrasound guided aspiration of FF was implemented with a GE Logiq e ultrasound unit combined with a 7.5 MHz‐probe . The carrier for the ultrasound probe was individually developed, handmade by the precision mechanics of the Institute of Farm Animal Genetics of the Friedrich‐Loeffler‐Institute in Mariensee, Germany and equipped with a needle guide. The aspiration needle is a standard commercial cannula (20G x 2 ¾ " (0.9 x 70 mm) and a short bevel) of Terumo from Leuven, Belgium.All visible follicles were categorized according to their size . The aspiration was performed as described  without bovine serum albumin. Until arrival at the laboratory, the samples were stored on ice at least for 40 min.g to separate the fluid from components of any cells and the supernatant was stored at −20°C until further analyses.At the laboratory, the samples were centrifuged for 3 min at 300 2.2Blood samples were collected during two physiological oestrus cycles  and before the OPU sessions .The animals were examined via rectal palpation, sonography  and vaginoscopy to assess the oestrus stage. They were categorized according to the oestrus cycle stage based on morphological criteria , the serum was collected and stored at −20°C until further analyses.Blood was obtained from the vein at the tail . The samples were centrifuged  cholesterol as reported by Sanchez‐Guijo, Neunzig, et al. , LOQ: 602.5The serum obtained from the animals during two oestrus cycles and the OPU sessions was also analysed via RIA. The determination of estradiol‐17β (E2) and progesterone (P4) via RIA was applied to verify retrospectively the supposed cycle stage at the day of sampling.Concentrations of P4 and E2 were determined in duplicate using well‐established radio‐immunological methods after extraction of the samples with organic solvents. The measurement of P4 followed the procedure outlined by Hoffmann, Kyrein, & Ender  as previMeasurements of E2 were performed as previously described  concentration was measured in the urine samples obtained during the OPU sessions measuring a detectable colour reaction (Jaffé‐method) using a photometer .A standard commercial kit  was used as recommended by the manufacturer. The concentration of Cr was determined as the reference level for BAs in urine. The concentration of Cr is not influenced by nutrition and/ or protein metabolism  was performed. Data from all cattle used for OPU were pooled for each BA subspecies of serum. Also, FF data were pooled from all classes of follicles and cattle for each BA subspecies.Moreover, the linear correlation (Pearson correlation coefficient) was tested for the concentration of total and unesterified cholesterol in serum, collected within a physiological oestrus cycle. Data from all cattle used for serum collection were pooled for free and total cholesterol.p value less than 0.05 was considered to be significant. All statistical analyses were performed with SigmaStat .A 33.1CA and GCA are the dominate BAs in FF irrespective of the oestrus cycle stage. Moreover, CDCA was the BA in lowest concentration in FF during the whole oestrus cycle. Data are shown in Table 3.2The concentrations of BAs in blood collected during two physiological oestrus cycles are shown in Table The profile of the different BA subspecies in blood collected during the OPU sessions showed similar values compared to those in blood collected during the physiological oestrus cycles. The highest amounts were determined for CA and its amino acid conjugate GCA. The lowest concentrations were measured for CDCA. Results are shown in Tables 3.3Pairwise analysis for BA concentration in serum and FF yielded a strong correlation between CA in serum and CA in FF during the pro‐oestrus, oestrus and interoestrus. Also, a strong correlation was detected for GCA in serum versus GCA in FF during the oestrus and interoestrus. The correlation coefficients of the BA subspecies in serum versus FF during the different oestrus cycle stages are shown in Table Pairwise analysis of free versus total cholesterol concentrations in serum during the physiological oestrus cycle resulted in a significant correlation, irrespective of the cycle stage Table .3.4In urine, CA showed the highest concentration of all BAs, whereas GDCA was determined in the lowest concentrations. CDCA, TDCA, GCDCA and TCDCA were not detectable. The concentrations of BAs in urine were related to urine Cr concentration to eliminate variations in urine density. Also in relation to the Cr concentration, the BA derivatives show the same proportionality. Still CA is the BA with the highest concentration and GDCA with the lowest one. The results are shown in Table 4BAs are usually known to be involved in physiological processes like solubilization of dietary lipids. But recently published data suggested a relation between BAs and reproduction in humans  and ursodeoxycholic acid (UDCA) are the primary BAs (Bathena, Mukherjee, Olivera, & Alnouti, The precursor of BAs and steroids is cholesterol (Kraft & Dürr, BAs can also be cytotoxic and exhibit pathological effects if they accumulate in high concentrations. Therefore, in humans, the main pathway for detoxification and elimination of BAs is the sulfation. Bathena et al.  reported5This study reports the simultaneous and direct quantification of BAs in different body fluids such as serum, FF and urine during the oestrus cycle of cattle. Nevertheless, as data were obtained from four animals throughout two complete oestrus cycles, further studies will be needed to clarify the origin and the possibility of BAs synthesis via follicular cells. The knowledge about the impact of BAs on oocyte growth and maturation as well as on subsequent embryo development still needs to be determined in detail.6The authors confirm that the ethical policies of the journal, as noted on the journal's author guidelines page, have been adhered to and the appropriate ethical review committee approval has been received. The Directive 2010/63/EU for the protection of animals used for scientific purposes were followed.We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all authors. Click here for additional data file. Click here for additional data file.


Since the launch of the InvestSmart™ initiative in 2014, the government agencies in Malaysia have been actively engaging community and university students via their outreach programs to promote investment literacy. Given this background, the state of the investment literacy of Malaysian undergraduates and their readiness to invest is intriguing. Therefore, this article offers a dataset of Malaysian undergraduates’ readiness to invest and the role that investment literacy and social influence play in their readiness to invest. Using a non-probability sampling technique, 500 undergraduate students in Malaysia were engaged to participate voluntarily in this survey. Descriptive statistics are presented in this paper. The dataset provides insights into the current state of investment literacy among Malaysian undergraduates, the sources of information on stock investment, and the readiness of these undergraduates to participate in the stock market. Specifications Table•This dataset allows the analysis of the current state of investment literacy and readiness to participate in the stock market of a population of young adults in Malaysia .•The dataset will inform the implementation of the National Strategy for Financial Literacy 2019–2023.•Useful insights can be extracted from this dataset to assist finance or investment curriculum design at the university level.•Researchers may employ this dataset to empirically examine the association between investment literacy, social influence, demographic factors and undergraduates’ readiness to invest.1Since the official launch in 2014 of the nationwide investment-literacy campaign by Malaysia's capital market authority, the government agencies and professional bodies have been taking the initiative to engage the youth population, including university students, via their outreach programs. We provide a dataset describing investment literacy, sources of information and influence on stock investment, and readiness to participate in stock investment among Malaysian undergraduate students. Questionnaires were distributed online and through fieldwork. A total of 500 undergraduate students enrolled in private and public universities in Malaysia between December 2019 and April 2020 participated voluntarily in the survey.The dataset has three major groups. Part A contains the demographic data of gender, race, area of study, parents’ combined income and college/university zone. Part B contains investment-literacy scores (gathered through 17 quiz-type questions in the questionnaire) that measure participants’ financial knowledge about stocks, bonds, interest rates, and mutual funds. All responses to the questions in this section were rated with a score of one for a correct response and a score of zero for an incorrect response. Part C contains data on social influence, i.e. the sources of information and influence of stock investment. Part D contains data of the investment readiness index. The questionnaire is provided as a supplementary file. 2The primary data collection was performed through an online and field survey. Using a non-probability sampling technique , a total of 500 printed questionnaires was initially distributed to identified contacts of selected universities located in the central, east coast, and northern regions of Malaysian peninsular. The response rate was 49.4% or 247 completed questionnaires. For the online survey, we created the questionnaire using the Google form. We contacted student representatives from universities outside regions which were not covered during field work. Using social media platform, we provided these students with a link to the online questionnaire and requested them to share the link to their fellow students at respective universities.Our questionnaire design follows previous studies. Specifically, 17 quiz-type investment-literacy questions were adapted from Balloch et al. The questionnaire used for this research was approved by the Human Ethics Committee of Universiti Malaysia Terengganu. Informed consent was obtained from all respondents before they participated the survey. Participants were informed that the survey was anonymous.The authors declare that they have no known competing financial interests or personal relationships that could have appear to influence the work reported in this paper.


Once defined in rhetorical but ultimately meaningless terms as “the conscientious, judicious and explicit use of current best evidence in making decisions about the care of individual patients” , evidencThe trouble with pandemics is that these assumptions rarely hold. A pandemic-sized problem can be framed and contested in multiple ways. Some research questions around COVID-19, most notably relating to drugs and vaccines, are amenable to randomised controlled trials . ButAgainst these—and other—wider questions, the neat simplicity of a controlled, intervention-on versus intervention-off experiment designed to produce a definitive  answer to a focused question rings hollow. In particular, upstream preventive public health interventions aimed at supporting widespread and sustained behaviour change across an entire population (as opposed to testing the impact of a short-term behaviour change in a select sample) rarely lend themselves to such a design , 9. WhenPopulation-wide public health efforts are typically iterative, locally-grown and path-dependent, and they have an established methodology for rapid evaluation and adaptation . But eviWhilst evidence-based medicine recognises that study designs must reflect the nature of question , even sSuch criticisms appear to make two questionable assumptions: first, that the precise quantification of impact from this kind of intervention is both possible and desirable, and second, that unless we have randomized trial evidence, we should do nothing.th-century logic of evidence-based medicine, in which scientists pursued the goals of certainty, predictability and linear causality, remains useful in some circumstances . But at a population and system level, we need to embrace 21st-century epistemology and methods to study how best to cope with uncertainty, unpredictability and non-linear causality [It is surely time to turn to a more fit-for-purpose scientific paradigm. Complex adaptive systems theory proposes that precise quantification of particular cause-effect relationships is both impossible (because such relationships are not constant and cannot be meaningfully isolated) and unnecessary . This paradigm proposes that where multiple factors are interacting in dynamic and unpredictable ways, naturalistic methods and rapid-cycle evaluation are the preferred study design. The 20ausality .In a complex system, the question driving scientific inquiry is not “what is the effect size and is it statistically significant once other variables have been controlled for?” but “does this intervention contribute, along with other factors, to a desirable outcome?”. Multiple interventions might each contribute to an overall beneficial effect through heterogeneous effects on disparate causal pathways, even though none would have a statistically significant impact on any predefined variable . To illuIn the current fast-moving pandemic, where the cost of inaction is counted in the grim mortality figures announced daily, implementing new policy interventions in the absence of randomized trial evidence has become both a scientific and moral imperative. Whilst it is hard to predict anything in real time, history will one day tell us whether adherence to “evidence-based practice” helped or hindered the public health response to Covid-19—or whether an apparent slackening of standards to accommodate “practice-based evidence” was ultimately a more effective strategy.


This study investigated if the evidence on the success of the Pay for Performance (P4P) schemes in healthcare is changing as the schemes continue to evolve by updating a previous systematic review.A meta-regression analysis using 116 studies evaluating P4P schemes published between January 2010 to February 2018. The effects of the research design, incentive schemes, use of incentives, and the size of the payment to revenue ratio on the proportion of statically significant effects in each study were examined.There was evidence of an increase in the range of countries adopting P4P schemes and weak evidence that the proportion of studies with statistically significant effects have increased. Factors hypothesized to influence the success of schemes have not changed. Studies evaluating P4P schemes which made payments for improvement over time, were associated with a lower proportion of statistically significant effects. There was weak evidence of a positive association between the incentives’ size and the proportion of statistically significant effects.The evidence on the effectiveness of P4P schemes is evolving slowly, with little evidence that lessons are being learned concerning the design and evaluation of P4P schemes.The online version contains supplementary material available at 10.1186/s12913-021-06118-8. The use of Pay for Performance (P4P) schemes in healthcare has had its successes and failures. Using financial incentives targeted at healthcare providers to improve value-based healthcare provision is a key policy issue. Many governments and insurers use P4P schemes as a policy lever to change healthcare providers’ behavior to improve value for money in healthcare and make providers accountable. However, numerous literature reviews based on narrative syntheses of evidence have concluded that the evidence on P4P schemes’ impacts is both weak and heterogeneous . The In this paper, we examined whether more recent studies provided improved evidence on the effectiveness of P4P schemes. One may expect that those designing and evaluating P4P schemes are improving how these schemes work and are being assessed. We updated the first meta-regression analysis of the effectiveness of P4P schemes –43AdditiAdditional file 2. Appendix B. Metadata collected by the authors of [thors of  (44–75]–75Additi


Dirofilaria immitis and Wolbachia) and the results show that people who were in contact with heartworm showed total IgE and specific IgE against heartworm more frequently. Contact with heartworm may be a risk factor for the development of allergic diseases, although further studies to elucidate the relationship between heartworm and allergies should be carried out.Heartworm is a parasitic infection transmitted by mosquitoes to animals and humans. The risk of human infections is high in those areas with high canine prevalence, such as the Canary Islands. In these islands, there is also a high number of allergic inhabitants. Since some studies have shown a relationship between parasite infections and development of allergies, the aim of this study was to evaluate whether exposure to heartworm may contribute to the development of allergies. A survey carried out on dog owners in the Canary Islands showed that 51.3% of allergic owners had a heartworm-positive dog, and significant differences were found between allergic or not-allergic owners, according to whether the dog was negative or positive to heartworm. Furthermore, 66 serum samples from inhabitants of the Canary Islands were analyzed for the presence of unspecific allergy markers (Immunoglobulin E or IgE) and specific for heartworm (IgE against p < 0.01). Of the analyzed human samples, 43.9% were seropositive to heartworm and Wolbachia. Total IgE concentrations were increased in 34.5% seropositive samples and 8.1% seronegative samples. Specific IgE against heartworm was only found in human seropositive samples (17.2%). Contact with heartworm may be a risk factor for the development of allergic diseases, although further studies to elucidate the relationship between heartworm and allergies should be carried out.The Canary Islands are hyperendemic for canine heartworm and the risk of zoonotic infection is high. Additionally, there is evidence of development of allergies due to nematode infections in animals and humans. Since the population of the Canary Islands presents high prevalence of allergic comorbidities, and previous studies have shown a possible relationship between allergies and seropositivity to heartworm, the aim was to evaluate whether exposure to heartworm may contribute to the development of allergies in the human population. First, an epidemiological study was conducted on 248 owners of dogs with/without heartworm infection in the Canary Islands. Secondly, a serological analysis of the presence of total IgE and specific IgE against heartworm was conducted in 66 samples of inhabitants of the Canary Islands. The survey showed that allergic owners had heartworm-positive dogs more frequently ( Dirofilaria immitis, is a vector-borne disease that affects canids and felids. The domestic dog is the main reservoir of the parasite and the most studied host. Heartworm is a cosmopolitan disease, which is mainly established in areas with temperate and tropical areas throughout the world [Culex spp., Aedes spp. and Anopheles spp.) act as vectors for Dirofilaria. They feed indistinctly on animals and humans, and since heartworm is a zoonotic disease, inhabitants of endemic areas are at risk of infection. D. immitis is the causative agent of pulmonary dirofilariasis in humans, when preadult worms reach the branches of the pulmonary artery, they embolize and cause spherical granulomatous lung lesions. These lesions are benign and generally asymptomatic and, therefore, generally go unnoticed until detected by imaging techniques, in these cases, they are often mistaken for lung tumors [Heartworm disease, caused by he world . Differeg tumors .D. immitis, and reaching 9%–12.7% in the islands with higher canine prevalence [D. immitis antibodies; thus, they have been in contact with the parasite and are at risk of infection. On the other hand, the inhabitants of islands with low or non-existent canine heartworm, present very low or no seroprevalence [The Canary Islands are hyperendemic for canine heartworm, showing prevalence above 15% in most of the islands , and sevevalence ,5,6. ThiD. immitis, while the desertic islands present the lower seroprevalence [The climate influences the presence of the parasite, and those areas with vegetation, humidity and high temperatures are optimal for the presence of mosquito vectors and development of the parasite. Such is the case for the islands with higher canine and human seroprevalences of evalence ,4,5,6.Asthma, rhinitis, and eczema can be classified together as an allergic comorbidity cluster ; furtherThe prevalence of asthmatic adults in the Canary Islands is significantly higher when compared to the national average  ,10,11,12Although sensitization to house dust mites, pollen, animal epithelia or fungus are some of the main factors explaining the high prevalence of allergic diseases, other factors are involved, such as pollution of the air by dusty winds from Africa due to the geographical location of the islands, and increasing pollen presence due to global warming. On the other hand, the trade winds free the archipelago from excessive urban pollution together with the fact that industrialization is much lower than in other Spanish continental regions ,14. HoweAscaris lumbricoides, Toxocara canis, Trichuris trichiura, hookworm, and Schistosoma mansoni [D. immitis, may influence the development of hypersensitivity in people [Studies have shown the role of some helminth parasites in the development of allergic processes in humans, and have shown associations between allergic sensitization  and seropositivity to parasites, such as  mansoni ,17,18,19n people ,21.D. immitis may contribute to the development of allergic diseases in the population from the Canary Islands.Therefore, this study was designed with the aim of evaluating whether exposure to D. immitis antigens  following manufacturer’s instructions. Furthermore, owners were asked to fill in a questionnaire based on that from Asher et al., [For this study, two independent methodologies were developed. First, an epidemiological survey was conducted at the Veterinary Teaching Hospital of the University of Las Palmas de Gran Canaria (Canary Islands) in Gran Canaria, a hyperendemic island ,5. The s et al.,  (File S1D. immitis IgG and anti-Wolbachia surface proteins (WSP) IgG (Group A), and 37 were seronegative (Group B). Sera were randomly selected from the group of positive samples and from the group of negative samples. Levels of total IgE were determined in all samples in the reference laboratory by using chemoluminescence-ELISA techniques . Seropositivity was considered when total IgE were >150 IU/mL.Sixty-six human serum samples from inhabitants of the Canary Islands, obtained from a previous study , were seD. immitis IgE by non-commercial ELISA test, using adult D. immitis antigens. Then, 96-well microplates were coated with 0.8 μg of an extract of D. immitis adult worms. All serum samples were analyzed at a 1:100 dilution, respectively, and a goat anti-human IgE (H + L) conjugated to horseradish peroxidase  was used at 1:100 dilution. Optical densities (ODs) were measured at 492 nm in an Easy Reader . The cut-off (OD = 0.5) was established by calculating the mean value + 3 standard deviations (3 SD) of 12 serum samples from clinically healthy blood donors (negative controls) living in a D. immitis-free area.All samples were further analyzed for the presence of specific anti-All the owners were informed about the present study and consented to participate. The human serum samples were obtained from a previously published study . The prep < 0.05.The data were analyzed using the SPSS Base 20.0 software for Windows. The descriptive analysis of the variables considered was carried out studying the proportions in the qualitative variables. The chi-square test was performed to compare proportions. In all the cases, the significance level was established at p < 0.01) between people allergic or not according to whether the dog was negative or positive to heartworm were reported.The results from the epidemiological survey show that 29.4% (73/248) of clients who went to the Veterinary Teaching Hospital with their dog had some allergy based on information referred by the owners. Of them, 28.8% (21/73) owned a heartworm-positive dog and 11.4% (20/175) of non-allergic clients owned heartworm-positive dogs . StatistD. immitis and WSP (Group A), and 8.1% (3/37) in the seronegative samples (Group B), the differences between dogs being statistically significant (p < 0.05). Median IgE value for Group A was 41.20 IU/mL, with a range of 2.10–1242.00 IU/mL ; median IgE value for Group B was 22.80 IU/mL, with a range of 3.10–83.00 IU/mL .The results from the serological analysis of inhabitants of the Canary Islands show that total IgE concentrations were high (>150 IU/mL) in 34.5% (10/29) of seropositive samples to D. immitis . All of them had high total IgE concentrations (ranging from 152.20 to 1242 IU/mL) and constituted 17.2% (5/29) of the samples of this group. No high specific IgE concentrations were found in the group B (p < 0.05).Five samples from the group A were positive for the presence of IgE against D. immitis and a greater presence of manifested allergies or IgE in humans.For this study, two independent methodologies were carried out, the purpose of which was to analyze possible indicators of a relationship between exposure to D. immitis due to the higher risk of being infected [Although these results are not indicative of causation but, rather, correlation, and the number of allergic and non-allergic owners was similar among owners with heartworm-infected dogs, the epidemiological study showed higher prevalence of allergic owners living with infected dogs. The serological status of these people was not determined, but previous studies have shown that humans living in those areas in which canine heartworm is more prevalent presented higher presence of IgG against infected ,6.D. immitis and anti-WSP IgG, and presence significantly higher of total IgE. Moreover, presence of anti-D. immitis IgE was demonstrated in inhabitants also seropositive to anti-D. immitis IgG. The Canary Islands have a very high incidence of allergic diseases. Although allergic comorbidity is a multifactorial pathology, the existence of other unknown factors that influence the high incidence in the Canaries is recognized [Furthermore, the results obtained in the serological study show a relationship between human seropositivity to anti-cognized ,11.A. lumbricoides, T. canis, T. trichiura, hookworm, and S. mansoni can cause allergic reactions in humans [The measurement of total IgE in serum may be helpful to establish laboratory parameters for the detection of worm diseases. By stimulating type 2 T-helper cells (Th2), IL-4 is released, which induces the synthesis of both monoclonal and polyclonal IgE ,24. Bothn humans ,17,18,19n humans  and specn humans ,33. Whenn humans ,35. Gazzn humans , for insD. immitis IgE response was demonstrated in individuals living in an endemic area [D. immitis and WSP may cause the presence of bronchoconstriction and bronchospasm in the cat, another imperfect host [D. immitis IgG in humans has been described, as a consequence of constant exposure to infected mosquitoes [D. immitis and Wolbachia have an important role in the stimulation of the immune and inflammatory response during animal and human dirofilariasis [D. immitis, and that may contribute as another factor to the development of allergies in inhabitants of hyperendemic regions. Previously, a predominant anti-mic area . Furtherect host ,39. In tsquitoes . D. immilariasis ,41, the lariasis . TherefoD. immitis, in considering that these diseases are multifactorial.The results of this study should be interpreted with caution, as it presents a series of limitations to be taken into account, such as a limited number of samples, a low prevalence of positive subjects, and, furthermore, the relation of correlation but no causation between allergic diseases and D. immitis through the mosquito bite, and the seropositivity to specific anti-D. immitis IgG and IgE found in inhabitants of the Canary Islands, are responsible for the development of allergic reactions in the human host. Furthermore, given the limitations of the study, results should be interpreted with caution. More studies must be carried out in which the number of samples must be increased, and it must be combined with other techniques that allow determining if there is a causal relationship. However, the results presented here encourage further studies to determine a possible relationship between exposure to D. immitis and the development of allergies, in which measurements of allergen-specific IgE levels in the dog owners as well as heartworm parasitic load in the canines would help to elucidate the mechanism of action of this relationship, if any.Despite the results, this study does not demonstrate that contact with


The current state of evidence regarding measures that assess evidence-informed decision-making (EIDM) competence attributes  among nurses is unknown. This systematic review provides a narrative synthesis of the psychometric properties and general characteristics of EIDM competence attribute measures in nursing.The search strategy included online databases, hand searches, grey literature, and content experts. To align with the Cochrane Handbook of Systematic Reviews, psychometric outcome data  were extracted in duplicate, while all remaining data  were extracted by one team member and checked by a second member for accuracy. Acceptability data was defined as measure completion time and overall rate of missing data. The Standards for Educational and Psychological Testing was used as the guiding framework to define reliability, and validity evidence, identified as a unified concept comprised of four validity sources: content, response process, internal structure and relationships to other variables. A narrative synthesis of measure and study characteristics, and psychometric outcomes is presented across measures and settings.n = 31 measures), public health (n = 4 measures), home health (n = 4 measures), and long-term care (n = 1 measure). Half of the measures assessed a single competence attribute . Three measures (9%) assessed four competence attributes of knowledge, skills, attitudes/beliefs and behaviours. Regarding acceptability, overall missing data ranged from 1.6–25.6% across 11 measures and completion times ranged from 5 to 25 min (n = 4 measures). Internal consistency reliability was commonly reported (21 measures), with Cronbach’s alphas ranging from 0.45–0.98. Two measures reported four sources of validity evidence, and over half  reported one source of validity evidence.A total of 5883 citations were screened with 103 studies and 35 unique measures included in the review. Measures were used or tested in acute care (This review highlights a gap in the testing and use of competence attribute measures related to evidence-informed decision making in community-based and long-term care settings. Further development of measures is needed conceptually and psychometrically, as most measures assess only a single competence attribute, and lack assessment and evidence of reliability and sources of established validity evidence.PROSPERO #CRD42018088754. Nurses play an important role in ensuring optimal health outcomes by engaging in evidence-informed decision making (EIDM). EIDM, used synonymously with the term evidence-based practice (EBP)  involvesDespite knowledge of such benefits, competency gaps and low implementation rates in EIDM persist among nurses across diverse practice settings –10. A baEIDM competence attributes of knowledge, skills, attitudes/beliefs, and behaviours have been well defined in the literature. EIDM knowledge is an understanding of the primary concepts and principles of EIDM and hierarchy of evidence –17. SkilMultiple uses for measures assessing EIDM competence attributes in nursing practice and research exist. Such measures can be integrated into performance appraisals  to monitPrevious systematic reviews have focused on EIDM competence attribute measures used among allied health care professionals , 16, 23 The current review aimed to address limitations of existing reviews by: including measures that address a holistic conceptualization of EIDM which includes the use of multiple forms of evidence in nursing practice; focusing on the four EIDM competence attributes of knowledge, skills, attitudes and behaviours; utilizing a modern understanding of validity evidence in which sources based on test content, response process, internal structure, and relations to other variables were assessed according to the Standards for Educational and Psychological Testing ; extractThe objectives of this systematic review were to: 1) identify existing measures of EIDM competence attributes of knowledge, skills, attitudes/beliefs, and/or behaviours used among nurses in any healthcare setting; and 2) determine the psychometric properties of test scores for these existing measures.The protocol for this systematic review was registered (PROSPERO #CRD42018088754), was published  a prioriA comprehensive search strategy consisting of online databases, hand searches, grey literature, and content experts, was developed in consultation with a Health Sciences Librarian. Searches were limited from 1990 until December 2017, as the term evidence-based medicine was first introduced and defined in 1990 . Search Studies were included if they met the following criteria: study sample consists of all nurses or a portion of nurses; conducted in any healthcare setting; reported findings from the use or psychometric testing of measures that assesses EIDM knowledge, skills, attitudes/values, and/or behaviours; quantitative or mixed-method design; and English language. Studies were excluded if the sample consisted of solely other healthcare professionals or nursing undergraduate students, or in which data specific to nurses was not reported separately. As well, studies testing or using measures assessing research utilization were excluded , 24.Titles and abstracts of initial references and full-text records were screened independently by two team members (EB and TB) for inclusion/exclusion. All disagreements were able to be resolved by consensus between those whom extracted the data.Data extraction was piloted using a standard form completed independently by two team members (EB and TB) on five randomly selected references. Data extracted pertaining to study and measure characteristics included: study design, sample size, professional designation of sample, healthcare setting, study country, funding, name of measure, format, purpose of measure, item development process, number of items, theoretical framework used, conceptual definition of competence established, EIDM attributes measured, EIDM domains/steps covered, and marking key or scale for self-report measures. Data extraction on these characteristics was performed by one team member (EB) and checked for accuracy by a second team member (TB/TD).Data extraction of primary outcomes included psychometric outcomes of acceptability, reliability, and validity evidence. Data extracted relating to acceptability consisted of completion time and missing data reported for each measure. Missing data were extracted from reports of incomplete surveys or calculated based on the number of complete surveys included in the analysis. Reliability data extracted for scores of measures related to internal consistency, inter-rater, and test-re-test reliability coefficients. Sources of validity evidence were extracted following guidelines from the Standards for Educational and Psychological Testing . Data weTo determine if study findings supported validity evidence based on relationships to other variables, a review of the literature was conducted and guiding tables on variable relationships were established  were linked  and the remainder of the articles were unique studies. Therefore, the review included 103 studies . Twenty studies were conducted in Europe (57.1%), with 19 (54.3%) taking place in Asia. Two studies were conducted each in Africa, Australia, Canada, and one in New Zealand. Publication years spanned 2004–2017. One additional measure was identified after contacting content experts; its associated study was published in 2018.Of the 103 studies, over half were conducted in the United States (n = 31 measures) followed by primary care (n = 9 measures). Measures were used less often in public health (n = 4 measures), home health (n = 4 measures), and long-term care (n = 1 measure). An overview of measures with identified settings is presented in Table The 35 included measures were used or tested most often in acute care , followed by advanced practice nurses , and licensed/registered practical nurses . A licensure group for 13 of the measures (37.1%) was not specified. Associated population groups are presented for each measure in Table Measures were primarily used or tested among registered nurses  assessed only a single EIDM attribute. Among these single attribute measures, attitudes/beliefs were assessed the most (n = 6 measures) [n = 17 measures), skills (n = 15 measures), and behaviours  , 134–137Overall, missing data related to percentage of incomplete surveys were reported for 10 measures (28.6%). The range of missing data was 1.6%  - 25.6% (EBPQ) and differed across health care settings. Missing data across seven measures yielded percentages below excessive missing data limits of > 10% . ReporteData for completion time were extracted where times were explicitly stated or calculated using time to complete each item if a combined time was reported to complete multiple measures in a study. Completion time was reported for four measures, ranging from 5  - 25 (EBPQ) minutes , 84, 85.Across measures and studies reporting reliability evidence, internal consistency was the most commonly assessed. Inter-rater and test-re-test reliability were also reported, although, for only one measure each.Reliability of scores, reported as Cronbach’s alpha (α), was reported for 21 measures (60%). Cronbach’s alpha values ranged widely across settings of: Acute care 0.45–0.99); primary care (0.57–0.98); public health (0.79–0.91); home health (0.63–0.87); and long-term care (0.79–0.96). Cronbach’s alphas are presented for individual measures and settings in Table 5–0.99; pOut of the 21 measures for which internal consistency was reported, seven measures had multiple study findings reported across unique practice settings. Reported Cronbach’s alphas were varied across and within settings for the same measure as evident by wide alpha ranges  used/tested across three studies, were assigned to Group 1 , 136 se. For theFive measures 14%) used/tested across seven studies, were categorized in group 2 , 82, 137% used/ten = 3 measures). Once again, regarding this source of validity evidence, significant relationships were demonstrated between EBP knowledge, attitudes, skills, and individual characteristics or organizational factors .Six measures 17%) were categorized in group 3 , 80, 120% were can = 19; 54%; see Table n = 12 measures), correlational (n = 11 measures), and ANOVA (n = 8 measures) analyses were primarily conducted. Regression analyses were used less commonly (n = 6 measures). Similarly, as in previous groups, significant relationships between EIDM competence attributes and demographic, organizational factors, and interventions were established  reported validity evidence in the context of acute care settings. For nine measures, validity evidence was reported across multiple settings. For three of these measures , multiple sources of validity (> 1) were more often reported in acute care settings compared to other practice settings where only one source of validity evidence was commonly found. In contrast, one measure (Evidence-based Nursing Attitude Questionnaire) had four sources of validity evidence established in primary and home care settings but not in acute care. While, the same number of validity sources were established for five additional measures  across varied healthcare settings.Most of the measures  compared to other healthcare contexts . This imbalance was also observed in an integrative review of 37 studies exploring the knowledge, skills, attitudes and capabilities of nurses in EIDM [n = 27) were conducted in hospitals, with fewer conducted in primary, community, and home healthcare, and none in long-term care. While there is a large body of evidence to support understanding of the psychometric rigor of EIDM measures in acute care, more attention and investment is required for this type of understanding in community-based and long-term care contexts. Given current trends and priorities in healthcare such as the reorientation toward home care [This review contributes new insight about settings in which EIDM measures have been used or tested that previous systematic reviews have not addressed. This review reveals a concentration on use or testing of EIDM measures in acute care . Very few measures were reported with four (n = 2 measures) or three (n = 5 measures) validity evidence sources established. Employing a similar approach to validity evidence assessment, Squires et al. [As noted, psychometric assessment of the current review was based on the contemporary understanding that the strength of a validity argument is dependent on the accumulation of different validity evidence sources . In thiss et al.  reportedSince existing reviews did not present validity evidence in the context of practice settings, this presents challenges with comparison of results. However, this review presents some insight on contextualizing validity evidence. In the current review, much of the validity evidence was presented in the context of an acute care setting, and in particular, for three measures most widely used , more sources of validity evidence were established by the original developers in acute care practice. Similar to reliability findings, this brings to light a critical gap in nursing research with respect to the use of measures after their original development, and lack of validity evidence assessment in different settings and populations. This demonstrates a call to action for nursing researchers that a consistent level of rigor must be applied to comprehensively re-assess sources of validity evidence for a measure when using it in a new practice setting. This strengthens a cumulative body of validity evidence to support continued use of a measure in varied nursing contexts.Compared to the current review, previous EIDM psychometric systematic reviews , 14, 16 Included studies in this review also limited validity assessment to sources based on test content and relationships to other variables, focusing on construct validity. This appears to be a consistent theme reported across existing reviews as well , 23. A nFindings from the current review and existing literature highlight limitations in assessing validity evidence and the psychometric rigor of existing EIDM measures. Variability in testing and results of validity evidence creates challenges and confusion for end users in research or nursing practice who look to this body of literature to determine appropriate and robust EIDM measures. Scholarly support for the use of a comprehensive and contemporary approach in psychometric development of tools can help to standardize assessments and produce findings representative of a unified understanding of validity evidence.This systematic review can serve as a helpful resource for nursing administrators, frontline staff, or researchers who are interested in using a measure to assess a specific EIDM competence attribute. In selecting measures for nursing practice or research, the specific population and setting in which measures have been previously used or tested, in addition to specific EIDM competence attributes they address, all serve as important considerations. As well, looking to the acceptability of measures, taking into account tool completion time given demands of busy clinical environments and if high rates of missing data > 10% are present , are alsA limitation of this review relates to the absence of quality assessments of included primary studies. Given that traditional quality assessment was not conducted, this may influence the confidence in study findings and thus results are to be interpreted with caution. However, among tools previously used to assess quality of psychometric studies, several limitations exist . These iThere is a diverse collection of measures that assess EIDM competence attributes of knowledge, skills, attitudes/beliefs, and/or behaviours in nurses. Among these measures is a concentration on the assessment of single EIDM competence attributes. Review findings determined that three measures addressed all four EIDM attributes, although with some conceptual limitations, highlighting a need for a tool that comprehensively assesses EIDM competence. More rigorous and consistent psychometric testing is also needed for EIDM measures overall, but particularly in community-based and long-term care settings in which the data is limited. A contemporary approach to psychometric assessment of EIDM measures in the future may also provide more robust and comprehensive evidence of their psychometric rigor.Additional file 1. Electronic database search strategy Identifies key words used for each primary database searched.Additional file 2. Theoretical and empirical literature to guide data analysis of sources of validity evidence Tables used to determine supporting validity evidence for data extracted.Additional file 3. Included studies Description of included studies.Additional file 4. Sources of validity evidence for each measure Identifies supporting data for each source of validity evidence established.


This paper reviews the evidence base for the health impacts of SIL on older adults, the risk factors, and the potential moderators and mediators of those relationships. Substantial evidence indicates that SIL are associated with physical, cognitive, and psychological morbidity; health-related behaviors; and health-related quality of life. Social isolation in particular is associated with a significantly increased risk of premature mortality from all causes. The evidence base for interventions in the clinical setting is also reviewed. Finally, the report’s specific recommendations are discussed, including the need for basic science research, increased funding, key elements in the design and evaluation of interventions, and gap areas (including trends among current younger adults and approaches for specific understudied groups of at-risk older adults). Part of a symposium sponsored by Loneliness and Social Isolation Interest Group.


The patient has always been at the centre of the evidence‐based medicine model. Case‐based critical reviews, such as best‐evidence topics, however, are incomplete reflections of the evidence‐based medicine philosophy, because they fail to consider the patient's perspective. We propose a new framework, called the ‘Shared Decision Evidence Summary’ (ShaDES), where the patient's perspective on available treatment options is explicitly included.Our framework is grounded in the critical appraisal of a clinical scenario, and the development of a clinical question, including patient characteristics, compared options and outcomes to be improved. Answers to the clinical question are informed by the literature, the evaluation of its quality and its potential usefulness to the clinical scenario. Finally, the evidence synthesis is presented to the patient to facilitate the formulation of an evidence‐informed decision about the treatment options.Using three similar but contrasted clinical scenarios of patients with low back pain, we illustrate how considering the patient's preferences on the proposed treatment options impact the bottom line, a synthetic formulation of the answer to the focused question. ShaDES includes clinical and psychosocial components, transformed in a searchable question, with a full search strategy.ShaDES is a practical framework that may facilitate clinical decisions adapted to psychological, social and other relevant non‐clinical characteristics of patients. Some early EBM publications included case scenarios.Failure to incorporate the patient’s perspective into guidelines has been criticized as a major obstacle to successfully implementing EBM with individual patients.In this paper, we review the structure of current BETs and similar case‐based reviews and introduce an alternative approach, called ‘Shared Decision Evidence Synthesis’ (ShaDES). ShaDES improves the currently used approaches by integrating the relevant scientific evidence and the perspective of a patient to choose an acceptable evidence‐based treatment. We illustrate the application of ShaDES using three clinical scenarios.2The typical CAT or BET starts with a clinical scenario, which describes a patient’s complaint, medical history, clinical examination and diagnostic tests, and prognostic or treatment challenges Figure . The sceAnswers to the clinical question are then searched from the literature, by retrieving evidence‐based guidelines, systematic reviews or original studies.3The typical case‐based critical review is adapted to situations where the bottom line proposes a straightforward answer to the clinical question. The bottom line, derived from the evidence in the literature, allows the practitioner to decide whether to prescribe a treatment, or how to interpret results of a test. We believe the current format of BETs and similar case‐based critical reviews is not well adapted to situations where evidence is weak or lacking, or when there are several options among which the practitioner, and therefore the patient, must choose. We present three clinical scenarios of patients with similar clinical history and examination, but different psychosocial  and socioeconomic context . We demonstrate how different patient profiles may result in different evidence‐based therapeutic options and management of the patients.3.1The three patients complain of low back pain (LBP) without specific lesions. They use analgesic and were prescribed exercises by a physiotherapist. These interventions provided moderate benefits. The patients consult their general practitioner (GP) for the next available options. All patients are currently working or willing to work, but they express worries about their ability to continue.3.2Sophie is a 40‐year‐old bus driver in her small French home town and is also responsible for planning work assignments for a team of bus drivers. Her new manager is difficult and not inclined to consult others for their opinions about work organization. Sophie is married to Georges, a bank employee; they have two teenage children. When Sophie comes home from work, she has to supervise the children’s homework and prepare the meal. Georges contributes little to home chores, which sometimes leads to conflicts.Sophie has chronic recurrent LBP. Her most recent episode started six weeks ago while gardening. She felt a sharp pain in her lower back. She takes analgesics and has remained at work. However, her home activities are limited and her husband is worried that she cannot complete her ‘chores’. Sophie feels guilty and fears that her manager believes that she might not be able to do her job appropriately. She believes that there is something wrong with her back and that her pain is caused by pinched nerve due to her occupation. Sophie was prescribed exercises by her physiotherapist and, although she never missed her appointments, she is fearful that doing exercises will harm her back and make her condition worse. She is distressed and depressed.3.3Mary is a 45‐year‐old registered nurse employed in a large Canadian hospital. She recently applied for a head nurse position and is waiting for the decision. Mary is married to Mark, an accountant, and they have three children aged 8, 10, and 12 years. Mary spends most of her spare time building a sailing boat with the help of her spouse and children.She has suffered from recurrent LBP for eight months. Mary uses muscle relaxants and she enthusiastically participated in active physical therapy. These interventions provided moderate benefits. Her pain is particularly intense at the end of the day, and she occasionally experiences sharp bouts of pain at work, which makes her anxious. She knows that chronic LBP is a benign disorder and that fear of pain can be disabling. She has never been on sick leave because of her back, but she now fears that she may not be able to continue, which amplifies her anxiety. She is very concerned that she will not be promoted at work. This makes her even more anxious, because she has been working hard for years to obtain the promotion and has gained the support of her colleagues. She is considering stopping building the boat despite the help of her family.3.4Gloria has been suffering from LBP for the past four years. Her pain started insidiously and has been persistent for the past two years. She is 46‐year‐old, married, with an 18‐year‐old daughter. She was employed as a secretary in a small factory in Switzerland. She also worked as a part‐time cook, and launched a successful blog which publishes her best recipes. However, she has to rest most of the time because of the pain. Her condition has not improved despite various courses of NSAIDs and duloxetine and physical therapy pool‐ and land‐based exercises. She describes her family as supportive but she feels extremely guilty, because she cannot perform the activities she used to do when she was ‘healthy’. Overwhelmed by pain, she is pessimistic and gloomy, invaded by dark thoughts and feelings. She tries to stay active in her everyday life, but she does not succeed. When asked about what gives meaning to her life, she can hardly respond.3.5Current evidence‐based recommendations for the clinical management of chronic LBP are clear and include many options.4ShaDES includes four steps Figure : First, 4.1Implementing ShaDES starts with understanding the clinical scenario by describing the patient, his/her medical and personal history and clinical examination, and identifying diagnostic, prognostic or treatment issues Figure . As seen4.2This part is not specific to ShaDES, and readers can refer to Elwyn et al4.3https://decisionaid.ohri.ca/AZsumm.php?ID=1045 for the decision aid for Spinal Manipulation for Low Back Pain; consulted June 2nd, 2020). In such decision aids, the patient is invited to express his/her feeling by using sliders or cursors through visualization of the relevant dimensions  that are important to the patient.In the next step of ShaDES, the evidence synthesis is presented to the patient to facilitate the formulation of an evidence‐informed decision about the treatment options. To successfully achieve this step, one can use, for instance, O’Connor et al.’s approach to construct decision aids.In ShaDES, we propose to present the evidence in a comparative table Table . The tabThe last part of ShaDES is, as in existing CATs and BETs, the bottom line. To improve the usability of ShaDES, we recommend summarizing the pros and cons of each treatment to assist patients with understanding the trade‐offs necessary to achieve patient‐centred outcomes. For example, the last line of Table 4.4If we now consider how the elements of our proposed model can be applied to the clinical situations described above, the following issues and questions need be emphasized and addressed:Sophie: Sophie was not reassured by her GP, because of her fear of pain or recurrent injury. The clinical and psychological question for Sophie is whether her challenges with her recurrent LBP and the unsatisfactory results of evidence‐based medication and exercise (P) could be better addressed with cognitive‐behavioural therapy and yoga (I & C) directed at pain and function (O). For such conditions, there is strong evidence that CBT is more effective for pain, functional status and behavioural outcomes than placebo/no treatment/waiting list controls. CBT requires the identification of meaningful and realistic goals to allow Sophie to address her catastrophizing with pain and activity and thus improve her readiness to engage in active pain self‐management. Sophie may also consider yoga as she expresses positive expectations towards such a treatment, but limited evidence exists to support its effectiveness compared with standard treatments.Mary: The GP could reassure Mary by addressing her concerns regarding her work. In this instance, the clinical and psychological question is whether her challenges with her recurrent LBP and the unsatisfactory results of evidence‐based medication and exercise (P) could be better addressed with a multimodal programme including spinal manipulation and cognitive‐behavioural therapy (I & C); these interventions would target pain and functional limitation and her expectations regarding what she wants to achieve in both her occupational and personal life (O). Options considered by Mary include manual therapy and CBT. The aims of CBT are to help Mary identify meaningful and realistic goals and learn to cope with pain and stress. Because Mary expressed strong positive beliefs regarding physical treatment, the GP prescribes a short course of spinal manipulation/mobilization.Gloria: The GP felt unable to address adequately Gloria’s pain problems associated to feeling of hopelessness and worthlessness, which also included feelings of self‐depreciation, shame and guild, along with passive suicidal thoughts. Here, the clinical and psychological question would focus on her difficulties with her recurrent LBP and unsatisfactory results of evidence‐based medication and exercise (P) in relation with her depressive disorder. In this instance, a referral to a psychiatrist or psychologist would be indicated to adequately address her feelings and her maladaptive cognitions and behaviours related to movement (I & C), which may contribute to improve pain and function (O). The symptoms here go beyond psychological distress or psychosocial dysfunction and refer instead to a depressive disorder, and referral to a psychiatrist or psychologist in the presence of such orange flags should be considered.5To our knowledge, ShaDES is the first framework that explicitly includes patients’ perspectives in case‐based critical reviews. Our illustration represents real life, where practitioner and patients are usually confronted to more complex situations than are usually depicted in guidelines or clinical scenarios.We focused on including the patient’s perspective. Nevertheless, we still have to consider the practitioner’s experience, or availability of resources,Since the onset of evidence‐based practice, clinicians have struggled to incorporate preferences in shared decision making. Kelly et alFurther research needs to focus on the integration of key characteristics of the clinician’s psychology, such as empathy,6We have proposed a new way to present case‐based critical reviews, which might better reflect the original philosophy of EBM. Our proposition puts a strong emphasis not only on clinical but also on psychosocial components, aimed to point to a question that can be developed into a search strategy. This proposition thus offers a practical framework that may contribute to clinical decisions using relevant psychological, social and other characteristics of the patient and of his/her environment. The applicability and impact of such an approach, which specifically considers values, preferences and needs of patients, remain to be tested.The authors declare they have no conflict of interest.