People are today increasingly relying on health information they find online to make decisions that may impact both their physical and mental wellbeing. Therefore, there is a growing need for systems that can assess the truthfulness of such health information. Most of the current literature solutions use machine learning or knowledge-based approaches treating the problem as a binary classification task, discriminating between correct information and misinformation. Such solutions present several problems with regard to user decision making, among which: (i) the binary classification task provides users with just two predetermined possibilities with respect to the truthfulness of the information, which users should take for granted; indeed, (ii) the processes by which the results were obtained are often opaque and the results themselves have little or no interpretation.ad hoc retrieval task rather than a classification task, with reference, in particular, to the Consumer Health Search task. To do this, a previously proposed Information Retrieval model, which considers information truthfulness as a dimension of relevance, is used to obtain a ranked list of both topically-relevant and truthful documents. The novelty of this work concerns the extension of such a model with a solution for the explainability of the results obtained, by relying on a knowledge base consisting of scientific evidence in the form of medical journal articles.To address these issues, we approach the problem as an We evaluate the proposed solution both quantitatively, as a standard classification task, and qualitatively, through a user study to examine the “explained” ranked list of documents. The results obtained illustrate the solution's effectiveness and usefulness in making the retrieved results more interpretable by Consumer Health Searchers, both with respect to topical relevance and truthfulness. Online Health Information (OHI)   solutions, especially in the area of health  task, and more specifically in that of Consumer Health Search (CHS), i.e., the search for health information by people without special medical expertise  and we illustrate solutions tackling online  misinformation (Section 2.2). In particular, we focus on those solutions that are applicable to the delivery of explainable solutions for identifying truthful information in IR tasks, with special attention to the Consumer Health Search task. First, however, it is necessary to draw attention to the meaning of some concepts that we will use in the article. With regard to the concept of eXplainable Artificial Intelligence (XAI) refers to the ability of an AI system to provide clear and understandable explanations for its decision-making processes and outcomes  provides a wider definition of the purpose of XAI as to “produce more explainable models, while maintaining a high level of learning performance (prediction accuracy)”, and “enable human users to understand, appropriately trust, and effectively manage the emerging generation of artificially intelligent partners”  that produce a ranked list of results that meet a user's information need while trying to uprank truthful results , to improve the transparency of IR systems. While there are similarities between XIR and the broader field of XAI, there are also some notable differences due to the specific tasks, inputs, and output types involved in Information Retrieval, according to the classification provided by Anand et al.  trying to align the predictions of ranking models with certain axioms; and (ii) examining the models to see if they incorporate known relevance factors such as matching, term proximity, and semantic similarity  allowing users to gain a deeper understanding of the search process and the factors that influence the results  as a dimension of relevance in the ranking (described in Section 3.1) to which the explainability strategy proposed in this paper is applied (described in Section 3.2).i) the multidimensional nature of the IR model, so the resulting ranking may be difficult for users to understand; (ii) the fact that information truthfulness is the additional relevance dimension of documents beyond topical relevance, and it would be desirable to inform the user about the extent to which the provided documents are truthful; and (iii) the unsupervised nature of the model does not risk to introduce data bias in the generation of results, allowing us to overlook at least this problem.In Upadhyay et al. , we proptopicality score denoted as BM25 for a query q and a document d. Formally:In the Upadhyay et al.  model, tInverse Document Frequency (IDF) of a term in relation to the entire document collection. Specifically, N represents the total number of documents in the collection, df(t) represents the document frequency for the term t, i.e., the number of documents containing t, tf refers to the term frequency, i.e., the number of times t appears d. To account for differences in document length, length normalization is applied. ld refers to the length d, L represents the average length of documents in the collection, and k1 and b are internal parameters used to adjust the scaling of term frequency and document length, respectively.The left side of the equation calculates the PubMed and PubMed Central (PMC) datasets.Information truthfulness is obtained by comparing the content of documents in the document collection and the content of scientific journal articles (considered reliable sources of evidence), both retrieved for the same query. The relevance of journal articles to queries is also calculated by means of the BM25 model. At this point, two BERT-based textual representation models are used to represent both documents and journal articles. One model is trained on MSMarcocosine similarity, to obtain an information truthfulness score. Formally:Document and journal article textual representations are then compared by means of its refers to the information truthfulness score of the document d for a specific query q, cos is the cosine similarity score, and w1, w2, …, wk are distinct weights assigned to each similarity score, such that ∑wi = 1 and wi ≥ wi+1 (1 ≤ i ≤ k−1). These weights allow assigning greater emphasis to the similarity scores according to the rank of the articles jj retrieved with respect to q, as illustrated in detail in Upadhyay et al. —i.e., the global relevance score—for each document with respect to the considered query. Formally:Finally, both topicality and information truthfulness scores are wtrs is an importance weight assigned to the topical relevance score, and wits is an importance weight assigned to the information truthfulness score. They are used to decide whether to assign more importance in calculating the final value to topicality or truthfulness. Both weights assume values in the  interval.where While the above-mentioned retrieval model have proven to be effective compared to distinct monodimensional and multidimensional IR model baselines, it does not offer explanations to users with respect to how retrieved documents have been estimated to be truthful. However, we can add transparency to such a model by providing users with some information about the employed scientific evidence  supporting the claims in the retrieved documents in the search result page interface. This makes it possible to easily design a first proposal for the explainability of the truthfulness of search results on top of such a model.scientific evidence for truthfulness related to the ranking of documents produced by the model described in Section 3.1. To extract this evidence, as illustrated in query-relevant passages from retrieved documents, i.e., we identify portions of text in each document that are topically relevant with respect to the query. Then, we use these passages to extract passage-based evidence from journal articles that are topically relevant with respect to the query. Both query-relevant passages and passage-level evidence are then shown to users by means of a Graphical User Interface (GUI), which will be illustrated in detail in Section 4.3.1. This should help to increase the user's understanding of the obtained ranking and provide insight into the reasoning behind the truthfulness of each document in the ranked list.The proposed solution aims at providing users with sentence was chosen as the size of a textual passage within a document. The high-level overview of this approach is illustrated in This section details the process of extracting the most important passages from a document in relation to a given query. In fact, the IR model described in Section 3.1 returns a ranked list of documents, which were estimated to be “globally” relevant to a query. In our explainability model, we want to extract from such documents only those text passages that are topically relevant with respect to that query. For the purpose of this paper, one query-relevant passages (sentences) we considered several strategies. The first strategy is based on representing queries and sentences as TF-IDF vectors, whose similarity is calculated by means of cosine similarity, according to which the sentences are ranked. The second strategy is based on using the BM25 model to obtain a ranked list of sentences relevant to the query. The last strategy involves the use of BioBERT to represent queries and sentences and again the use of cosine similarity to obtain a ranked list of sentences. In particular, BioBERT is a leading-edge language model in the biomedical field   , as high-level illustrated in In particular, NER is a process of identifying medication, denoted as μ, and disease, denoted as δ, present in both the query and the considered sentences. In this way, the similarity score between a query and a sentence (obtained either by means of cosine similarity or the BM25 similarity) has been modified so as to decrease it in the absence of correspondence between Named Entities. Formally:In particular, we compared the two Named Entities q, s) indicates the similarity score between the query q and a sentence s, sim indicates the similarity function employed to compute σ, which can be either cos or BM25 depending on the employed model, NERx indicates the Named Entities extracted from x , and wd  is a discount weightq, s) in the case of non-corresponding Named Entities in q and s.where σdmis-lab/biobert-v1.1Python implementation of the sent_tokenise method provided by the Natural Language Processing Toolkit (NLTK version 3.8).anvilPython (version 3.7).To index documents and apply BM25-based retrieval models, we employed the BM25 implementation provided by The objective of quantitative model evaluation is to determine whether the similarity scores between query-relevant passages and passage-based evidence pieces are effective in identifying the truthfulness of retrieved documents with respect to a query. Indeed, the purpose of the article is to provide explanations to users based on such similarity, so they must also prove effective with respect to the task of identifying truthful information as a whole.mean. The second solution considers the maximum similarity score between the query-relevant passage and the different pieces of passage-based evidence as the similarity score.Hence, the similarity scores between a query-relevant passage and pieces of passage-based evidence were computed, and this score was employed to classify documents as truthful or non-truthful. In particular, we considered two solutions to calculate the final similarity score between the query-relevant passage and pieces of passage-based evidence. The first solution considers the similarity scores between the query-relevant passage and different pieces of passage-based evidence and calculates their With respect to both models, we tested query-relevant passage and passage-based evidence extraction models based on TF-IDF, BM25, and BioBERT, with and without the application of NER. We performed the experiments considering a variable number of retrieved documents , a variable number of retrieved scientific journal articles , a variable number of query-relevant passages extracted from the documents . In all cases, the number of pieces of passage-based evidence taken into account was equal to 5.five-fold cross-validation in the following way. Query and document pairs were randomly and independently divided into five folds, with each fold containing a subset of the total data. In each iteration of the cross-validation process, one fold was used as the test set, while the other four folds were used as the training set to train the model. The model was then used to calculate the similarity score between the query-relevant passages extracted from the documents and the pieces of passage-based evidence from the journals, based on the considered queries. This approach allowed us to evaluate model performance using all available data, while ensuring that the evaluation was not biased by using different subsets of data for training and testing in each iteration of the cross-validation process. Performance was evaluated in terms of F1 score (F1), Geometric Mean score (GM), commonly used for imbalanced datasets .In performing experiments with respect to each of these configurations, we applied As mentioned earlier, these results are higher than those using the TF-IDF and BM25 models in extracting query-relevant passages and passage-based evidence. For the sake of conciseness, in Overall, we can observe that the BioBERT model, both with and without the application of NER, outperforms all other models in terms of F1 score, GM, and AUC. Furthermore, incorporating NER generally improves the performance of the models across the board. In addition, the BioBERT model with NER achieves the highest F1 score, GM, and AUC, indicating better performance in misinformation detection with respect to other baselines.user study. This can help improve the proposed model and guide the development of additional tools or techniques to improve the explainability of the results obtained by means of the model.The objective of the qualitative model evaluation is to understand the effectiveness of the proposed explainability strategy by assessing the usefulness of the information and scientific evidence provided to users by means of a Graphical User Interface (GUI). Assessors were given clear guidance on the domain under consideration, how to use the GUI, and what aspects to evaluate.The user study was conducted with 18 human assessors, all doctoral and master's students experienced in NLP and IR, respecting the age and gender balance criteria. The study was performed by means of a specifically-designed tasks, illustrated in Section 4.3.2. Later, users were required to answer a questionnaire, detailed in Section 4.3.3. Based on this questionnaire, it was possible to assess the outcome of user satisfaction with respect to the explainability of the results obtained, as discussed in Section 4.3.4.In the following, the GUI is detailed in Section 4.3.1. By means of this GUI, the users were required to perform some The appearance of the developed GUI is illustrated in Here are visible some key components of the interface, which can be summarized into five main panels, as follows.a) The Query Panel: it presents the set of 12 randomly-chosen queries from those available in the dataset  from which human assessors can choose;(b) The Ranking Panel: it presents the ranked list of the top-5 documents retrieved w.r.t. a query, by using the IR model detailed in Section 3.1. In particular, in this panel, the title associated with these documents are presented. Since in the original dataset, no titles described the content of documents, we employed the T5 model over documents to produce significant titles.Top) and truthfulness score (Tru);(c) The Sentence Extraction Model Panel: it allows human assessors to choose among the list of the three distinct models for extracting query-relevant passages and pieces of passage-based evidence in the form of sentences. As illustrated in Section 3.2.1, the three models are based on TF-IDF, BM25, and BioBERT;(d) The Document Content Panel: by selecting a document from panel (b), this panel shows its content and highlights the query-relevant passages identified by using the sentence extraction model selected in the panel (c);(e) The Top Sentences Panel: this panel illustrates the list of the query-relevant passages extracted for the query selected in panel (a), in the document selected in panel (b), for the extraction model selected in panel (c);(f) The Evidence Panel: it shows human assessors pieces of passage-based evidence from journal articles for the selected sentence in panel (e). Evaluate the Ranking: in this task, assessors were asked to select a query from panel (a), analyze the documents in the obtained ranking against that query and the associated topicality and truthfulness scores in panel (b), and evaluate, based on these and the content of the retrieved documents, which dimension of relevance they believed had the greatest impact on the final ranking;(ii) Evaluate the Query-relevant Passages: in this task, assessors were asked to evaluate, for each document returned in the ranking based on the query chosen in panel (a), what was the best query-relevant passages extraction model. To do this, each assessor had to first choose a document from the ranking in panel (b), choose a model from panel (c), and analyze the highlighted sentences in panels (d) and (e);(iii) Evaluate the Passage-based Evidence: in this task, assessors were asked to evaluate, for each query-relevant passage in panel (e) extracted from each document found in panel (b) against the query in panel (a) and the model chosen in panel (c), the usefulness and reliability of the scientific evidence associated with each step and illustrated in panel (f), to determine whether the supporting scientific evidence was sufficient and clear to determine the truthfulness of the document.(b): for assessing the clarity and influence of topicality and truthfulness in the ranking of the document; to panels (c), (d), and (e): for finding the best method to retrieve sentences and to understand the effectiveness of this choice; and to panels (c), (e) and (f): for assessing the usefulness and quality of evidence provided.The questionnaire was used to collect information on the perceived quality of both query-relevant passage and passage-based evidence extraction models and to understand the users' level of satisfaction with the explainability of the truthfulness of the retrieved documents. In particular, the questionnaire contains a set of questions related to panel (b)—are as follows:Questions related to ranking—panel , (d), and (e)—are as follows:Questions related to sentence extraction (query-relevant passages)—panels  provide sufficient information to determine the truthfulness of the document?− Do you think highlighting a single sentence is enough to capture both the topicality and truthfulness of the document?− c), (e), and (f) are as follows:Questions related to sentence extraction (passage-based evidence)—panels  correctly supported by scientific evidence ?− Does the scientific evidence provide sufficient information to assess the truthfulness of the document?− Do you think the information sources  associated with each highlighted sentence are trustworthy?− yes, no, don't know, or other. Some questions in the questionnaire include multiple-choice questions that allow participants to choose specific methods or ways for document ranks, extracted sentences, and evidence.Some questions in the questionnaire were designed in a way that allows participants to answer inter-rater reliability of the study, we computed Fleiss' kappa measure  and some answering negatively (no or don't know). This suggests that while the majority of users found the highlighted passages informative, others still did not consider them sufficient as meaningful sentences from which to determine the document's truthfulness. It is important to note that this question is complex, as it involves not only the  relevance of the highlighted passages to the query, but also their ability to provide starting points for identifying evidence for or against the document's truthfulness.Regarding question Q5, responses were mixed, with the maximum number of respondents answering affirmatively  relevant passages from documents and corresponding scientific evidence from scientific articles, we used various textual retrieval and representation techniques, with and without the aid of Named Entity Recognition techniques to consider the specificity of certain entities in the health domain. The proposed solution was evaluated both from a quantitative and qualitative point of view. The latter evaluation took place, in particular, by means of a user study, in which users were asked to perform tasks and answer a questionnaire.Through this questionnaire, we were able to obtain valuable information from the assessors regarding their perception of the explainability of the results obtained. In particular, with respect to the ranking obtained and the effectiveness of the relevance dimensions, the extraction of textual passages from documents and scientific evidence from scientific articles and their usefulness in explaining why a document found was actually judged as satisfactory by the majority of respondents. We analyzed responses using the Fleiss' kappa score to assess the inter-rater reliability of the questionnaire and found that the level of agreement among raters was generally high.However, the results of our user survey also revealed some limitations and room for improvement with respect to the proposed solution. For example, it appears that identifying textual passages in the form of single sentences within documents may not always be sufficient to provide a good starting point for assessing both the topical relevance and truthfulness of a document; some psychological factors of the users or other factors related to the dataset should be further investigated for a better understanding of the actual impact of the different dimensions of relevance; however, some assessors found it difficult to estimate the reliability of the information sources ; moreover, the quantitative evaluation has given encouraging albeit not excellent results. We, therefore, plan to address these limitations and further improve our approach in future work.https://github.com/ikr3-lab/explainableCHS-frontiers/. Further inquiries with respect to the data used and their availability can be directed to the corresponding author.Code and documentation related to this original work can be found at the following link: RU, PK, GP, and MV contributed to the conception and design of the study. RU developed the software for model implementation and the Graphical User Interface and performed statistical analysis on quantitative results. RU and MV designed and followed the human assessor evaluation process and wrote the first draft of the manuscript. All authors contributed to the manuscript revision, read, and approved the submitted version.


Health-care decision making should consider the best available evidence, often in the form of systematic reviews (SRs). The number of existing SRs and their overlap make their identification and use difficult. Decision makers often rely on de novo SRs instead of using existing SRs. We describe two cases of duplicate reviews  and one case of duplicate primary data analysis . All cases have in common that unintended duplication of research occurred between health authorities and academia, demonstrating a lack of communication and coordination between them.It is important to note that academia and health authorities have different incentives. Academics are often measured by the number of peer-reviewed publications and grants awarded. In contrast, health authorities must comply with laws and are commissioned to deliver a specific report within a defined period of time. Most replication is currently unintended. A solution may be the collaboration of stakeholders commonly referred to as integrated knowledge translation (IKT). The IKT approach means that research is conducted in collaboration with the end users of the research. It requires active collaborations between researchers and decision-makers or knowledge users  throughout the research process. Wherever cooperation is possible in spite of requirements for independence or confidentiality, legal regulations should facilitate and support collaborative approaches between academia and health authorities. Health-care decision making should consider the best available evidence. In the spirit of evidence-based medicine, it is recommended to obtain such evidence by relying on high-quality systematic reviews (SRs).The number of published SRs is growing exponentially: In 2010, Bastian et al. , and whiNot surprisingly, this comes at the cost of overlapping SRs, i.e., multiple SRs dealing with the same or similar question , 7. ReplThis article aims at encouraging a discussion on unintended duplication of systematic reviews or analyses by different health authorities and academia resulting from poor communication and coordination between the two worlds. For illustration, three examples are presented that raise the question of useful replication or research waste.Federal Joint Committee is the highest decision-making body in the German health care system. It regularly commissions the Institute for Quality and Efficiency in Health Care (IQWiG) with systematically reviewing the evidence on drugs, diagnostic, or therapeutic procedures as a basis for their decision-making purposes. IQWiG is scientifically independent. There is a legal foundation in the German Social Code Book V  of this sharing of responsibilities. Decisions made by the Federal Joint Committee are sometimes subject of court proceedings. IQWiG’s rigorous approach has resulted in the recognition of the trustworthiness of their evidence reports by German jurisdictions. IQWiG preferably synthesises evidence from RCTs and other clinical trials according to their own methodology instead of relying on already existing evidence syntheses. This inevitably increases the number of SRs and thus risk of duplicate SRs. In addition, there is no pre-registration of IQWiG reviews in databases of SRs, such as PROSPERO (but review protocols are published on the website). As part of its reviews, IQWiG also searches for pre-existing SRs and refers to them in the results or even uses them instead of primary studies; however, IQWiG is required by law to perform independent assessments (and reviews) with participation of clinical or methodological experts and as a matter of fact, usually relies on primary trial results. The Institute for Quality Assurance and Transparency in Health Care (IQTIG) is responsible for statutory quality assurance in the health care system. The Federal Joint Committee commissions IQTIG for the development and implementation of quality assurance procedures. The Federal Office for Radiation Protection is responsible for the safety and protection against radiation damage to the environment and population health. Therefore, its mandate includes assessing health-related risks from radiation  to advise the Federal Ministry for the Environment and other health authorities.This section presents German health authority organisations, which is relevant for understanding the following three cases. The Below, the authors present three cases of unintended, publicly funded, duplication.One example for unintended duplication of evidence synthesis by academia and health authorities is related to “minimum volume standards” and the hospital volume-outcome relationship for total knee arthroplasties. There was no high-quality SR on this topic and thus no evidence for a minimum volume standard. Yet, German hospitals need to perform at least 50 total knee arthroplasties annually to get reimbursement for this procedure . TherefoVarious randomized controlled trials (RCTs) on lung cancer screening in heavy smokers have been completed within the last years. In many of these studies, computed tomography (CT) was found to reduce lung cancer mortality. SRs and clinical guidelines therefore recommended low-dose-CT screening . The topUnintended duplication of efforts could potentially have been avoided if both agencies  had better communication processes in place, allowing them to join efforts. From a scientific perspective, it would require fewer resources either if both agencies collaborated directly, or if one agency built on the previous work by the other. However, legal reasons require that both assessments are done independently from each other. Issues of confidentiality and independence allow only minimal scientific exchange between both agencies. The current workflow is stipulated by national law, which follows the principle of independent assessments without specifically aiming at replication of results.Another example for unnecessary duplicate work in the context of evidence syntheses is the analysis of the relationship between volume and outcome in transcatheter aortic valve implantation (TAVI). In contrast to the other examples, it does not refer to multiple SRs but to primary data analyses.Specifically, in 2021, IQWiG published an evidence report on the association between hospital volume and quality for TAVI . The avaIn the sense of evidence-based research, the example may be viewed positively, as it was performed in response to a research gap identified in an evidence synthesis. However, it illustrates that research to fill such knowledge gaps should be coordinated.We described two cases of duplicate reviews  and one case of duplicate primary data analysis (TAVI) as additional analyses for an evidence synthesis. All cases have in common that two institutions  performed very similar analyses, where one analysis could have easily replaced the other, at least partly, to inform decision-making. Duplication of reviews occurs in other countries as well. Screening mammography, for example, was covered by two funded reviews (with slightly different questions) , 30, altThere are certain reasons to consider several high-quality publications as useful replication and reasons that justify the conduct of more than one SR . If seveTo prevent unintended duplication, which can contribute to research waste in some cases, institutions and academia first need to be aware of each other’s ongoing and planned work and to use prior SRs when planning new studies . EvidencA solution may be collaboration of stakeholders commonly referred to as integrated knowledge translation (IKT). The IKT approach means that research is conducted in collaboration with those who will use the results of the research (end-users). Therefore, IKT requires active collaboration between researchers and decision-makers or knowledge users  throughout the research process . BenefitResearch waste is known to be an issue in particular with SRs. Intended replication makes sense, while unintended duplication should be avoided. Collaborative approaches are needed to improve the situation. Awareness of ongoing (or even better: planned) projects is a prerequisite to this. Where possible, legal regulations need to allow for and facilitate collaborative approaches between academia and health authorities as well as between different health authorities.


In this era of evidence-based medicine, the randomized controlled trial (RCT) has become the gold standard in determining whether a new intervention has beneficial effects. Although in recent years the RCT has given way to more flexible approaches, the strong reliance on this type of decisive study design in evidence production has had unintended consequences . An examIn the current debate about prevention, there is a strong plea for a shift in content and mode of delivery of prevention, specifically targeting the environments in which disadvantaged groups live and work . While tThere is compelling evidence that psychosocial work factors may introduce health effects . A recenScandinavian Journal of Work Environment and Health, Aust and colleagues (In this issue of the lleagues  have undThis editorial is not the place to summarize the evidence of a meta-review, which itself summarizes the evidence of 52 reviews. Read the article yourself and be surprised by the quality and density of information on the evidence of organizational-level interventions. However, the meta-review shows some findings that should challenge the research community.First, 28 out of 52 reviews focus on the healthcare sector. Healthcare organizations are apparently easily accessible and reachable, and have plenty of study participants. The feasibility of a research project seems more important than scientific or societal considerations. Hence, the available evidence is extremely biased towards the specifics of work environments in healthcare with low generalizability to other workplaces. We must ask ourselves the question whether our research priorities reflect sufficiently societal needs.Second, the synthesis of evidence presented in the 52 reviews seldom demonstrates that improvements in the psychosocial work environment are causally linked to improvements in workers’ health. In line with the terminology of the authors, it remains to be seen in many interventions whether proximal effects are associated with distal ones. The noticeable exceptions were : interveThird, linked to the discussion about the appropriate study design for evaluating effectiveness of interventions in occupational health, in most reviews the majority of original studies had some type of control group, but the use of an RCT design was low. This illustrates the intrinsic difficulty of randomization of workplaces for many different reasons . The disThe meta-review of Aust and colleagues is not only of interest because of its specific content, it also raises important considerations for intervention research. I propose the following five guiding principles for intervention research on the psychosocial work environment:1.In primary prevention strategies, the essential choice is between selective or universal prevention . An orga2.In intervention studies with a short follow-up period, it is sensible to focus on proximal endpoints, ie, changes in the psychosocial work environment, rather than distal endpoints such as sickness absence or workers’ health.3.When the proportion of workers’ health attributed to the risk factor of interest is modest then the reduction in the risk factor due to the intervention must be large to have a discernable impact on workers’ health. Remember that most workers are quite healthy, thus, large effects in universal interventions cannot be expected.4.We often lack insight into whether an organizational intervention introduces improvements in the psychosocial work environment, and, consequently, that through these improvements the beneficial effects on workers’ health are achieved. Without insight into the pathway of effectiveness, interventions will remain a black box.5.It is a misconception that the effectiveness of an intervention is primarily determined by its content and quality of delivery. The implementation and specific context in the organization are equally as important. New analytical evaluation methods may be required, acknowledging that individual behavior and circumstances, specific working conditions, and higher-level contextual factors interact continuously.


This review examines the pharmacotherapy and lifestyle recommendations of the most recent iterations of the Canadian Cardiovascular Society (CCS) / Canadian Heart Failure Society (CHFS), the European Society of Cardiology (ESC), and the American Heart Association (AHA) / American College of Cardiology (ACC) / Heart Failure Society of America (HFSA) heart failure (HF) guidelines, which all have been updated in response to therapeutic developments across the spectrum of left ventricular ejection fraction. Identified areas of unanimity across these guidelines include the following: recommending quadruple therapy for patients with HF with reduced ejection fraction ; intravenous iron administration for patients with HFrEF and iron deficiency; and sodium restriction for patients with HF. Recent evidence regarding the harms of HFrEF medication withdrawal in patients with HF with improved ejection fraction has prompted subsequent guidelines to recommend against withdrawal. Due to the lower quality of evidence, there are disagreements regarding management of HF with preserved ejection fraction and uncertainty regarding management of HF with mildly reduced ejection fraction. Practical guidance is provided to clinicians navigating these challenging areas. In addition to these clinically focused comparisons, we describe opportunities for guideline improvement and harmonization. Specifically, these include opportunities regarding HFrEF sequencing, the need for timely updates, shared decision-making, Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework adoption, and the creation of recommendations where high-quality evidence is lacking. Although these guidelines have broad agreement, key areas of controversy remain that may be addressed by emerging evidence and changes in guideline methodology. Over the past decade, major developments have broadened available treatment options across the spectrum of left ventricular ejection fraction (LVEF). This expansion includes advancements in the management of HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF), and the more recent introduction of HF with mildly reduced ejection fraction (HFmrEF) and HF with improved ejection fraction (HFimpEF).,,The most recent comprehensive HF guideline document by the Canadian Cardiovascular Society (CCS) was published in 2017,Here, we compare the pharmacotherapy and lifestyle recommendations of the latest CCS, ESC, and AHA/ACC/HFSA HF guidelines and discuss supporting evidence to inform clinicians seeking practical guidance amidst areas of uncertainty and disagreement. This review adds to an existing article that compared the ACC/AHA/HFSA and ESC heart failure guidelines,Societies differ in their guideline methodology for determining certainty  of evidence and the strength of recommendations .15, 16, Although the CCS HF guidelines last defined LVEF terminology in the 2017 update, all 3 guidelines have adopted LVEF categories consistent with the 2021 Universal Definition of HF: HFrEF (LVEF ≤ 40%); HFmrEF (41%-49%); HFpEF (≥ 50%); and HFimpEF , with the exception of the ESC, which reserves the category of “HFimpEF” for HF with LVEF ≤ 40% improved to ≥ 50%.de novo initiation.Management of patients with HFrEF is the area in which the 3 guidelines have the greatest consensus . The guiBoth the CCS and the AHA/ACC/HFSA guidelines strongly recommend titrating standard therapies to target doses, whereas the ESC guidelines advise the same without providing formal recommendations on the best approach to achieve this end. All 3 guidelines provide tables of evidence-based drugs and doses, which have minor differences . Nebivol,,,Despite their consensus on what constitutes standard pharmacotherapy for HFrEF, all guidelines have stopped short of proposing a specific sequence to initiate and titrate medications. This reflects the lack of direct evidence to guide such recommendations, as each new class of medication historically has been compared with placebo in addition to the standard of care in the era when the trial was conducted. However, evidence and recognition are increasing that the benefits of HFrEF pharmacotherapy are additive to and independent of background medications, and that the pharmacologic effects of some medications may offset the adverse effects of others. For example, SGLT2i’s have similar efficacy irrespective of background medication use, including ARNIs and MRAs, and they can reduce the risk of hyperkalemia from renin-angiotensin-aldosterone system inhibitors.A recent study by Shen et al. compared 13 potential sequences for standard HFrEF pharmacotherapy initiation, using a simple Markov model, based on data from 6 RCTs.Safety, Tolerability and Efficacy of Up-Titration of Guideline-Directed Medical Therapies for Acute Heart Failure (STRONG-HF) trial results.This modeling study offers several insights. First, the simple act of changing the order of medications without altering the final combination  could impact patient outcomes. Second, the conventional sequences implicitly mandated by insurance companies by requiring special authority and/or prior authorization do not represent those that provide the best efficacy outcomes, and such barriers may stall optimal implementation strategies. If the most-effective sequences cannot be implemented due to coverage considerations , the shorter titration schedules could still be implemented . Third, at the individual level, all 8- to 12-week sequencing strategies modeled in this study produced comparable results (with the exception of the less-effective “direct ARNI” sequence [ARNI → beta-blocker → MRA → SGLT2i]), and decisions therefore should be informed by individual patient factors, a context in which the “spending function” framework can be useful for decision-making.In general, consensus has been reached regarding the use of other therapies for patients who remain symptomatic after optimization of standard therapies, coined as the term “individualized therapies” in the CCS guidelines . The guiSystolic Heart Failure Treatment with the IF Inhibitor Ivabradine Trial (SHIFT) trial. Notably, the Health Canada-approved indication for ivabradine is in patients with New York Heart Association (NYHA) class 2-3 HF with LVEF ≤ 35% and a resting heart rate ≥ 77 beats per minute, and many provincial drug plans reflect these criteria for coverage.Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction (VICTORIA) trial.African-American Heart Failure Trial (A-HeFT) trial inclusion criteria, from which these recommendations are derived.Gruppo Italiano per lo Studio della Sopravvivenzanell’Insufficienza cardiaca-Heart Failure (GISSI-HF) trial, with the CCS guidelines further noting the high variability in omega-3 content of over-the-counter products.Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial.Unanimously weak recommendations are given for the use of digoxin in this population, reflecting the aging evidence, lack of mortality benefit, and risk of toxicity with this agent. Ivabradine is also recommended in patients with symptomatic HFrEF in sinus rhythm with a resting heart rate ≥ 70 beats per minute, with both the ESC and AHA/ACC/HFSA guidelines further specifying that LVEF should be ≤ 35%, which more strictly adheres to the inclusion criteria of the t Feasibility Study in Recovered Heart Failure (TRED-HF) trial, the ESC guidelines advise  and the AHA/ACC/HFSA guidelines recommend that patients with HFimpEF should continue to receive their HFrEF medications indefinitely.Dapagliflozin in Heart Failure with Preserved and Mildly Reduced Ejection Fraction (DELIVER) trial demonstrated a statistically significant reduction in the primary outcome of cardiovascular death or worsening HF with dapagliflozin, compared to placebo, consistent with its effect across the LVEF spectrum and further affirming the efficacy of medications used for HFrEF in the HFimpEF population.All guidelines acknowledge HFimpEF as a distinct category, consistent with the Universal Definition of HF.Prior to the availability of the TRED-HF or DELIVER trial results, the CCS 2017 guidelines described  select populations in which consideration could be given to withdraw HF medications after 6-12 months of therapy with normalization of LVEF and left ventricular dimensions in asymptomatic (NYHA class 1) patients. Although neither the TRED-HF nor DELIVER trial results directly contradict this guidance, they do suggest that caution is warranted with this approach. This situation highlights an issue common to all guidelines, which is that their recommendations and discussions often become outdated as new evidence emerges. Given that clinicians who rely on these guidelines may not evaluate emerging evidence or keep up with guidelines from other countries, this may result in suboptimal care in the period between guideline revisions and their dissemination. Consequently, guideline-development processes could be improved by implementing systems to update their content upon the publication of major evidence. At a minimum, guidelines could update such recommendations with a disclaimer regarding the presence of new evidence (with a link to said evidence or to newer guidelines incorporating this evidence) in these cases. The World Health Organization living guidelines for the management of COVID-19 provide an ambitious example of GRADE-based guidelines that have been updated continuously to incorporate rapidly evolving evidence.Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM-Preserved) trial to evaluate pharmacotherapy in patients “without reduced LVEF,” defined as HF and an LVEF > 40%.The term “HFpEF” was first used in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist [TOPCAT] trial) in patients with HFpEF.Irbesartan in Heart Failure with Preserved Ejection Fraction Study (I-PRESERVE) trial.,Both the CCS 2017 and the AHA/ACC/HFSA guidelines give weak recommendations for an ARB  and/or an MRA  trial comparing use of ARNIs to use of ARBs in patients with HF and LVEF ≥ 45%, the CCS and ESC guidelines did not make any formal recommendation for use of ARNIs in HFpEF, awaiting further analyses or trials for more conclusive findings.P = 0.056), along with subgroup differences indicating benefit in women or patients with an LVEF of 45%-57%.Based on the inconclusive results of the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved) trial, which included patients with HF and LVEF > 40% , were presented and published on the same day as the ESC guidelines (and subsequent to publication of the CCS 2021 guidelines). Given this timing, only the AHA/ACC/HFSA provide recommendations for SGLT2i’s for HFpEF.Results of the The overarching differences in recommendations for HFpEF between guidelines reflect the lowlevel of certainty of evidence for medications in this condition. Clinicians may be left confused when guideline recommendations differ and in cases in which multiple medications have weak recommendations, without clear guidance on their relative or cumulative benefits. The utility of “weak/conditional recommendations” could be improved by embracing the role of shared decision-making. To that end, every weak recommendation should be accompanied by sufficient information to facilitate shared decision-making with patients, ideally in the form of a decision aid. In cases in which no decision aids exist (as with HFpEF/HFmrEF pharmacotherapy at the time of this writing), guidelines should describe the uncertainty of the evidence and provide a synopsis of known benefits, harms, and other information needed to make a shared decision. So, rather than patients with the same condition being treated differently based on which guideline their clinicians follow, they could receive treatment that is individualized according to their values and preferences, no matter where they reside.CCS guidelines have not yet broached specific recommendations for HFmrEF pharmacotherapy, although the 2017 guidelines highlighted this as an area for future research. In general, evidence for managing HFmrEF is derived from subgroup analyses from landmark trials of “HFpEF” (many of which included patients based on their having an LVEF > 40% or ≥ 45%). Recognizing this limited evidence, the ESC and AHA/ACC/HFSA guidelines weakly recommended ACEI/ARBs, ARNIs, MRAs, and beta-blockers in patients with HFmrEF . As prevThe HFmrEF recommendations highlight a key issue with the methodology used to rate quality of evidence by both the AHA/ACC/HFSA and ESC guidelines. The AHA/ACC/HFSA recommendations rate the level/certainty of evidence for SGLT2i and the other medications  as “moderate quality” . However, the SGLT2i recommendation is based on the high-quality EMPEROR-Preserved trial , whereas the evidence for the other medications is an amalgamation of post hoc subgroup analyses and secondary analyses from trials with initially neutral primary outcome results. As noted, the ESC provided similar HFmrEF pharmacotherapy recommendations, but without providing a clear explanation for their difference in approach compared to the skepticism shown toward HFpEF evidence. As discussed below, the incorporation of use of the GRADE framework would enhance transparency and help clarify the reasoning behind such recommendations.These idiosyncrasies could be better understood by universally incorporating use of the GRADE framework, which would facilitate transparent reporting of recommendation rationale, as well as reasons to downgrade the rating of level of certainty of evidence.Iron deficiency is associated with worse quality of life, survival, and risk of hospitalizations among patients with HF, irrespective of their anemia status.A Randomized, Double-blind Placebo-controlled Trial Comparing the Effect of Intravenous Ferric Carboxymaltose on Hospitalizations and Mortality in Iron-deficient Subjects Admitted for Acute Heart Failure (AFFIRM-AHF) trialIntravenous Iron Treatment Versus Standard Care in Patients with Heart Failure and Iron Deficiency (IRONMAN) trial. This study, which was larger than the aforementioned ferric carboxymaltose trials, demonstrated the efficacy of another iron formulation  for this indication.The evidence cited for these recommendations includes a meta-analysis of patients with iron deficiency and HF with LVEF < 45% for criterion 1,Despite this broad consensus concerning intravenous iron use, little emphasis is placed on this intervention, despite the fact that it provides greater quality-of-life improvements than any other pharmacologic intervention in patients with HFrEF.The importance of such quality-of-life improvements is demonstrated in a scoping review that examined the values and preferences of patients with HFrEF41Guidelines are unanimous in advising sodium restriction, but they differ in their target range or limit. The 2017 CCS guidelines make a weak recommendation to restrict dietary sodium intake to 2-3 g/d in patients with HF. The ESC guidelines did not make a formal recommendation, but suggested avoiding excess sodium intake (> 2 g/d). The AHA/ACC/HFSA guidelines make a moderate-strength recommendation that “excess sodium” be avoided, with no particular limit suggested. However, separate from the HF guidelines, on their website, the AHA does advise most adults to consume ≤ 2.3 g/d of sodium, with an “ideal limit” of ≤1.4 g/d.Study Of Dietary Intervention Under 100 mmol in Heart Failure (SODIUM-HF) trial, published in 2022, may guide future sodium restriction recommendations.The Whether this trial alone will lead to revised recommendations in future guideline iterations remains to be seen. In contrast to the uncertainty regarding HFmrEF and HFpEF pharmacotherapy, which pertains to imprecision around the effect estimate, the uncertainty reflected by different sodium-restriction targets is related to the direction of effect. The fact that the ESC and AHA/ACC/HFSA are hesitant to make formal recommendations under such circumstances is not surprising. Nonetheless, a reasonable proposal may be for a weak recommendation that patients aim for a range of sodium intake of ∼1.4-3 g/d . The use of a range  reflects the uncertain state of evidence and could also harmonize current guideline recommendations. Additionally, irrespective of consensus on a specific range, guidelines could still make strong recommendations in favour of shared decision-making in such instances. For example, a strong recommendation could be made in favour of having discussion with patients regarding the fact that the benefits of sodium restriction targets are uncertain, but that stricter restrictions  may reduce symptoms, hospitalizations, and loop diuretic requirements, compared to more-liberal restrictions . Also part of the discussion should be the fact that some patients find that stricter restrictions result in a diet that is less enjoyable, more time-consuming, or more expensive .This comparison of 3 major international HF guidelines demonstrated broad agreement among the 3, but it also identified several key areas for improvement. First, the unanimous uncertainty surrounding optimal HFrEF treatment sequencing could be informed by model-based estimates in the absence of RCT data. Second, to ensure that guidelines are transparent and up-to-date, adoption of use of the GRADE framework, along with mechanisms to rapidly update recommendations based on emerging evidence, is needed. Third, guidelines could facilitate shared decision-making by providing syntheses of the benefits and harms of treatments that informed the recommendations. Fourth, the relative importance of different therapies could be more accurately identified via further considerations of patient values and preferences. Finally, to improve the quality of recommendations when the level of certainty of evidence is low, guidelines could make nuanced weak recommendations and transparently disclose such uncertainties. Additionally, the review provided therapeutic guidance to clinicians navigating the complexities of HF management. Adoption of these recommendations for guideline developers could further assist clinicians in providing evidence-based collaborative care for patients with HF.


People with intellectual disabilities and behaviours that challenge others are living longer. This review aimed to explore what is known about the health and social care needs, experiences, service interventions and resources of and for this population as they transition to different care contexts in the UK.A rapid scoping review of published and unpublished literature was conducted based on collaborative working with key stakeholders and using systematic methods of data searching, extraction and analysis.Consistent social work support, skilled staff, suitable accommodation, creative engagement with individuals and families to plan ahead, and timely access to quality healthcare are all required to promote successful transitions as people age, and to avoid unwanted/inappropriate transitions at points of crisis.More research is needed to assess the types of services that this population can and do access as they age, the quality of those services, and the extent to which local commissioners are planning ahead for people with intellectual disabilities and behaviours that challenge others. In lineAlthough the means by which the above estimates are calculated vary, using different ways to count people and at different points in time, the numbers highlight that the needs of older people with intellectual disabilities across the UK four nations  require attention from policy‐makers, commissioners and service providers. In addition, they are likely to underestimate the true levels of need, as many people with intellectual disabilities are not known to health or social services , UK based studies have for some years found that older people with intellectual disabilities experience more health‐related problems than the general population, with these issues often occurring at a younger age  becoming unable to continue to provide care  evidencing the support for older people with intellectual disabilities and behaviours that challenge others, and their family carers.2Our review was intentionally inclusive and exploratory, designed to capture a broad range of evidence. We therefore undertook a scoping review, enabling the systematic synthesis of evidence from diverse sources according to its nature, features, and findings/outcomes , policy‐makers and consultants (n = 7), commissioners (n = 2), service providers (n = 3) and a patient and public involvement (PPI) adviser (n = 1); and a PPI advisory group, which included one person with intellectual disabilities and her support worker, two parent carers and one sibling carer. Advisors were all invited to contribute to these groups on the basis of their knowledge, expertise and experience in supporting older people with intellectual disabilities and behaviours that challenge others, and/or growing older themselves. While there were more people with intellectual disabilities involved in the two groups, they agreed amongst themselves to ‘play to their strengths’ and focus time and energy on particular strands of project activity. Thus, one person opted to work on the review, while others focused their attention on supporting empirical work packages. Both groups contributed ideas, discussed ongoing findings, and helped to ensure clarity and relevance of analysis. Specifically, we liaised with the groups to finalise our search strategy; to consider the initial full screen returns; and to discuss our preliminary data analysis. The groups therefore contributed to analytic thinking regarding the codes and development of key themes.Throughout the review we consulted with members from our two expert advisory groups: a professional group, which included health and social care professionals , to consider the status of transition‐related care and support for older people with intellectual disabilities and behaviours that challenge others, drawing out implications for how this care and support might be most effectively planned and undertaken to fit with their needs and preferences.2.2Valuing People White Paper for England and Wales  literature, including research articles, reports, and guidance. Within the published research we included primary  and secondary  level evidence. To enhance the relevance of our review findings, we included evidence made available after 2001, to coincide with the publication of the Government's ts Bell, . With thPublished/made available in English after 2001Concern older (40+)Concern the health and social care needs, experiences, service interventions and resources of and for these older adults transitioning to different care contexts, for example, from family care to service care; from one context of service care to another ; and, from one context of family care  to another .Using the population, concepts and context (PCC) framework , as a means of determining those (academic and grey literature) most likely to yield relevant evidence. We then identified and searched the following priority electronic databases: Cumulative Index to Nursing and Allied Health Literature (CINAHL) (Ebsco); Healthcare Management Information Consortium (HMIC) (Ovid); NHS Evidence (NICE); Scopus (Elsevier); Turning Evidence Into Practice (TRIP); Web of Science (WoS) (Clarivate); Google (first five pages); and, Google Scholar (first five pages).We generated search terms , combined using the Boolean operators ‘and/or’ and appropriate truncation and phrase symbols to form initial search strategies, which we piloted against selected key databases. On the basis of the insights gained concerning the sensitivity and specificity of our terms, we confirmed our final search strategies to be used for each database, as well as the Google search strings, limited by file type (PDF) , all records were screened by Researcher One, with Researchers Two, Three and Four also independently screening a selection. Any discrepancies were discussed between Researcher One and the other three researchers as appropriate, and in a majority of cases, a final decision reached, in all cases without recourse to a third researcher. In a minority of cases, a decision could not be made until additional information, unavailable in either the title or abstract, was obtained. This process enabled the exclusion of evidence that clearly did not meet the inclusion criteria and identified evidence for full text review.All full text records were read by Researcher One, with Researchers Two, Three and Four also independently reading a selection. To reduce the potential for bias and promote transparency and consistency in decision‐making, a standardised tool was used  appraisal in scoping and rapid reviews is generally considered optional  people with intellectual disabilities and behaviours that challenge others. Such diversity necessitated a flexible approach to bringing together the evidence in its entirety. Key characteristics of included evidence were summarised in a table of characteristics  findings. Thus, we sought to generate new conceptual understanding, set out as analytical themes . To do so, data were analysed deductively and inductively. Deductively, we took the focus of the review—transitions—as our point of entry into the data. Practically, this meant that the question ‘What does this evidence mean for transition for older people with intellectual disabilities and behaviours that challenge others?’ underpinned all interpretation. Inductively, we followed a three‐stage process Table , meaning33.1Database searches yielded 261 returns, of which 223 were excluded on the basis of initial screening (using titles/abstracts). Of the remaining 38 read in full, 32 were excluded and six were identified for inclusion. A total of 37 returns were identified from the reference lists of database included articles, all of which were read in full. Of these, one article was included. A total of 40 items of evidence were identified by the research team and/or our advisory group, all of which were read in full. Of these, two were included. Therefore, a total of nine items of evidence were included in our review , Slevin et al.  conclude3.4.3This section focuses on the service infrastructure within which the interventions outlined above, as well as other relevant care and support, are delivered. Slevin et al.  state th3.5This section continues consideration of the collective evidence about factors that are important in promoting or impeding successful transition for older people with intellectual disabilities and behaviours that challenge others. The focus is on factors relating to the immediate run‐up to, point of and period following transition.3.5.1In line with the evidence regarding the value of specialist community teams (3.4.3), included studies confirm the benefits of specialist involvement at the point of transition. Leaning and Adderley , for exa3.5.2In this section we concentrate on the importance of staff skills and attitudes in supporting a successful transition. Hubert and Hollins  examinedThese findings are supported by Bissell et al.'s  longitud3.6Our review found no targeted resources to guide older people with intellectual disabilities and behaviours that challenge others, their families, or professionals (both front‐line and planners/commissioners), in planning and decision‐making. We did find some generic resources, some of which included limited relevant content. Most likely as a result of their lack of contemporaneity, we were unable to access the majority of those identified. Table 4We have identified a diverse range of evidence, which, collectively, suggests the same core message, namely, that transition‐related care and support of older people with intellectual disabilities and behaviours that challenge others remains lacking in crucial respects. The review has also highlighted a number of factors which appear to be critical in: (i) supporting this population as they transition from one context of care to another; and (ii) avoiding unnecessary transitions, notably at points of crisis, which are now discussed.4.1In terms of supporting effective transition, we identified a number of systems issues that need to be addressed. The importance of proactive preparation and planning across multiple areas of activity is clear. These areas include: professional involvement in supporting transition planning amongst people with intellectual disabilities and their family carers ; and, firmly embedding people in local communities . These principles foreground the  Hollins  associat Hollins .all involved within particular inter‐personal, organisational and systems contexts of interaction. As our analysis has demonstrated, it is these social dynamics that are critical to promoting and impeding effective transitioning. In this context, although the need for appropriate training and support of professional staff is indubitable, equally the care delivered by those staff, and the organisations and systems within which they work, must be predicated on values that promote the human rights of those for whom they care  as opposed to specific conditions that may be associated with behaviours that challenge others  and/or specific forms of behaviour  runs the risk of having missed articles that pertained to our population of interest. However, a trial of that alternative approach returned a vast number of returns that would have been unmanageable for the purposes of a rapid scoping review. Moreover, an initial scan of the returns showed no relevance to our research question. Therefore, we made a pragmatic decision to build a search strategy around the key terms of ‘intellectual disability’, ‘challenging behaviour’ and ‘ageing’.n = 5 studies), followed by mental ill‐health (n = 4 studies), epilepsy (n = 2 studies), genetic conditions (n = 1 study) and cerebral palsy (n = 1 study). As ‘mental ill‐health’ was not further defined, we are unable to determine its particular presentation. Therefore, we can say that our findings are broadly relevant to the population of older people with intellectual disabilities and behaviours that challenge others, including in respect of gender, degree of intellectual disability and health status generally. Such breadth means that our findings may have less relevance to a particular population of people with intellectual disability, for example, those not addressed by our included evidence  and/or those whose degree of intellectual disability and/or attendant health status may prompt a need for specific care and support.Our included evidence encompassed male and female participants, assessed across mild to severe/profound intellectual disability, and with a range of physical and mental health conditions. Autism was most frequently cited  has highlighted the need for social care staff training to facilitate more nunaced and proactive approaches to support people as they grow older  under its Health Services and Delivery Research Programme (NIHR129491). The views expressed are those of the authors, and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.The authors declare no conflicts of interest.Appendix 1: Search Strategies.Appendix 2: Study inclusion screening form.Appendix 3: Data extraction form.Click here for additional data file.


Klebsiella pneumoniaie and plays a crucial role in the development of antibacterial resistance. Mur enzymes are also important alternative drug targets in addition to blaNDM-1 which are crucial for thesurvival of the bacteria. Vitex negundoi is an aromatic medicinaltree with proven antibacterial properties. Fifteen compounds from V. negundo were evaluated for their inhibitory effects on the target proteins blaNDM-1,Mur C, Mur E and Mur F of K. pneumoniae through molecular docking using the Glide (xp) module of Schrodinger. ADME toxicity was also predicted for all the fifteen compounds in the QikProp module. The docking results revealed that thecompounds agnuside, negundoside and isoorientin showed promising inhibitory effects on all four targets blaNDM-1, Mur C, Mur E and Mur F of K. pneumoniae with docking scores greater than -7 kcal/mol and reasonable hydrogen bond interactions.The findings of this study provide a lead for developing novel drugs against potent multidrug-resistant K. pneumoniae.Antimicrobial resistance among bacterial strains has emerged out to be a serious threat and contributes to the loss of effectiveness of the common antibiotics. New Delhi metallo-β-lactamase-1 (blaNDM-1) is an enzyme present in several pathogenicbacteria with a high incidence in  E. coliand Klebsiella pneumoniaie which accounts for 60% and 16% of the infection respectively  and their structures were retrieved from PubChem compound database. The obtained structures were imported into the glide window and converted into maestro format. Itwas then prepared using the LigPrep module . The ligands were geometry optimized using OPLS-2005 force field.Fifteen bioactive compounds namely Negundin A, Negundin B, Indomethacin, Isoorientin, Isovitexin, Lyoniresinol, Mussaenosidic Acid, Agnuside, Negundoside, Pinoresinol, Vitexin, Vitedoamine A,Vitedoin A, Vitedoin B, Vitexicarpin reported from the leaf extractof V. negundo were predicted using QikProp program , which alsoanalyses the pharmaceutically relevant properties for indispensable lead generation and lead optimization.Unfavourable absorption, distribution, metabolism, excretion and toxicity (ADME Toxicity) properties for all the fifteen compounds of V. negundo compounds in the active sites of four targets , molecular docking analysis was carried out in Glide module .Initially, the docking area was defined by a grid box using receptor-grid generation protocol . The molecular docking experiments were carried out with default parameters (Glide protocol) using XP docking module. The resultsof the molecular docking gives information about the drug like molecules of V. negundo that interact with the putative binding sites blaNDM-1, Mur F, Mur E and Mur C of K. pneumoniae . The docking results were interpreted basedon docking score, glide energy and number of Hydrogen bond interactions.To examine the binding conformation of the fifteen Escherichia coliUdpmurnac-Tripeptide D-Alanyl-D-Alanine-adding Enzyme (Mur F) at 2.3 Angstrom Resolution (PDB ID: 1GG4) had 82.04% sequence identity for Mur F with 99% query coverage and 0% gaps. The structure of UDP-N-acetylmuramyl tripeptide synthetase fromE. coli (Mur E) (PDB ID: 1E8C) had 89.27% sequence identity, 99% query coverage and 0% gaps for Mur E and Escherichia coli Mur C (PDB ID: 2F00) had 89.98% sequence identity, 99% query coverage and 0% gaps for Mur C.They were identified as suitable templates. In modelling algorithm, if a protein sequence shares more than 30% identity they were structurally similar. This evidence provides 1GG4, 1E8C and 2F00 as appropriate templates for structure prediction ofMur F, Mur E and Mur C through modelling techniques. The three-dimensional structures predicted using Swiss model for Mur F, Mur E and Mur C are shown in Figure 1(see PDF).A high percentage of sequence similarity between the target sequence and template structure produces reliable three-dimensional structure of the proteins. Protein Blast showed that the Crystal structure of Validation of the models by Phi and Psi angles through Ramachandran plot reveals that the models generated were in a more acceptable range. The overall main chain and side chain parameters of Mur F, Mur E and Mur C were validated through RAMPAGE. It indicates97.5% residues in the core region, 2.2% of residues in the allowed region and 0.2% residues in the disallowed region for Mur F, 96.5% residues in the core region, 3.1% of residues in the allowed region and 0.4% residues in the disallowed region for Mur E and96.6% residues in the core region, 2.8% of residues in the allowed region, and 0.6% residues in the disallowed region for Mur C . These results indicate that the predicted structures are of reasonably good structural parameters.The best site for the docking approach has been chosen based on the site score and hydrophobic / hydrophilic regions predicted using site map protocol. Figure 3(see PDF) shows the binding cavity of the protein structures for blaNDM-1, Mur F, Mur E andMur C.V. negundo compounds were analysed to determine the pharmacokinetic properties using QiKprop module in the Schrodinger suite. The pharmacokinetic properties such as QPPMDCK (Predict apparent MDCK permeability), QplogHERG , QPPcaco (Predict apparent Caco-2 cell permeability), Rules of 5 (number of violations of Lipinski's rule of five), Molecular weight and stars  are presented in Table 1(see PDF).The 15 V. negundo compounds in the active site of blaNDM-1, Mur F, Mur E and Mur C were performed. The receptor grid generation was recorded which indicates good interaction between proteins and the smallmolecules. The docking results of all the active compounds are reported in Table 2(see PDF). The ranking of the docking results is based on the docking score, glide energy and number of hydrogen bond interactions. The best docked ligand molecules in theactive site of blaNDM-1, Mur F, Mur E and Mur C are shown in the Figure 4(see PDF). All the small molecules having interaction with the binding cavity in various conformations differ in their docking score and glide energy. Among all the bioactive compounds,Isoorientin showed the best binding affinity for blaNDM-1 with docking score -7 kcal/mol, glide energy -64.8 and 5 hydrogen bonds. Agnuside showed best binding affinity for Mur F and Mur C with docking score -6.7 kcal/mol and -7.5 kcal/mol, glide energy -59and -62.5 respectively with 11 hydrogen bonds. Negundoside showed best binding affinity for Mur E with docking score -10.7 kcal/mol, glide energy -81 and 9 hydrogen bonds. Thus agnuside, isoorientin and negundoside showed promising inhibitory effect in theactive site of all the target proteins. The results indicate that V. negundo derivatives have potential applications towards blaNDM-1, Mur F, Mur E and Mur C of K. pneumoniae.Molecular docking analysis of the K. pneumoniae, 2 strains of E. coli and 8 strains of A. baumannii [K. pneumoniae were selected as alternative targets in addition to blaNDM-1 for this study. Mur enzymes are primarily involved in the peptidoglycan biosynthesis essential for thesurvival of the bacteria. To develop new molecules against the target proteins blaNDM-1, Mur C, Mur E and Mur F of K. pneumoniae, an aromatic medicinal tree V.negundo that has been used traditionally owing to its antibacterial properties wasselected for the study. Herbal medicines are becoming popular worldwide because of their minimal side effects [V. negundo compounds on K. pneumoniae proteins that would collapse the survival of the bacteria. Docking was performed using the Glide (xp) module of Schrodinger with fifteen reported compoundsof V. negundo against the four targets of K. pneumoniae. The results revealed that agnuside, isoorientin, and negundoside showed promising inhibitory effect against all the four target proteins of K. pneumoniae.analysed. Findings of the present study could provide a lead for developing novel drugs against multidrug resistant K. pneumoniae.Antibiotics work by either killing or inhibiting the growth of the bacteria . The indaumannii . There a effects , 25. Mol


The COVID-19 pandemic highlighted some potential limitations of transmission-based precautions. The distinction between transmission through large droplets vs aerosols, which have been fundamental concepts guiding infection control measures, has been questioned, leading to considerable variation in expert recommendations on transmission-based precautions for COVID-19. Furthermore, the application of elements of contact precautions, such as the use of gloves and gowns, is based on low-quality and inconclusive evidence and may have unintended consequences, such as increased incidence of healthcare-associated infections and spread of multidrug-resistant organisms. These observations indicate a need for high-quality studies to address the knowledge gaps and a need to revisit the theoretical background regarding various modes of transmission and the definitions of terms related to transmission. Further, we should examine the implications these definitions have on the following components of transmission-based precautions: (i) respiratory protection, (ii) use of gloves and gowns for the prevention of respiratory virus infections, (iii) aerosol-generating procedures and (iv) universal masking in healthcare settings as a control measure especially during seasonal epidemics. Such a review would ensure that transmission-based precautions are consistent and rationally based on available evidence, which would facilitate decision-making, guidance development and training, as well as their application in practice. Standard and transmission-based precautions are essential elements of infection prevention and control (IPC) practices ,2. TransEmerging scientific evidence and revisiting previously available studies support the argument that the distinction between droplets and aerosols is artificial, and dogmatic size thresholds for ‘large droplets’ and ‘aerosols’ are not fully consistent with the physical properties that are relevant for the transmission of respiratory viruses -7. WhileMycobacterium tuberculosis, and the measles and varicella-zoster viruses, have traditionally been considered as being transmitted obligatorily or preferentially through the airborne route, thus necessitating precautions against airborne transmission, including the use of respirators and hospitalisation in single rooms with negative pressure [Only a few microorganisms, such as pressure . These rpressure ,12.Altogether, the relevant role of various routes of transmission, which includes the physical transport of an infectious particle leading to infection, has been challenging to assess. Efforts to define criteria of proof for each transmission route have been useful but it is difficult to draw any conclusion with certainty ,14. The Furthermore, the quality and certainty of evidence on the effectiveness of various elements of PPE used for transmission-based precautions remains low, as the evidence is based mostly on observational studies and only a few randomised controlled trials. Several systematic reviews and meta-analyses have been published but the certainty of the conclusions is limited by the bias of the underlying studies . This meLater variants of SARS-CoV-2 are characterised by higher transmissibility than previous variants . On the These observations indicate a need to revisit transmission-based precautions and their effectiveness for preventing transmission of SARS-CoV-2 in particular and other respiratory viruses in general, as well as a need to fund, design and execute high-quality studies to fill the evidence gaps for transmission-based precautions .On 16 March 2022, the European Centre for Disease Prevention and Control (ECDC) convened a group of 11 IPC experts to explore whether modifications in transmission-based precautions would be needed to address what we learned during the COVID-19 pandemic and to identify knowledge gaps and research needs. Experts were selected as a convenience sample from the ECDC Expert Directory based on declared expertise in hygiene and infection control. The discussion was structured based on the following elements of the Evidence to Decision (EtD) framework : (i) HowBoxA review of the theoretical framework, and definitions of terms, for modes of transmission underpinning the IPC paradigm;Risk assessment parameters for IPC measures based on risk of infection transmission inclusive of: transmissibility of infection, impact of infection, patient factors, staff risk factors, practice/procedure factors and environmental factors, while taking into consideration: healthcare workers’ preference, desirable and undesirable anticipated effects and the balance between them, overall certainty of the evidence of effects, acceptability and ease of implementation;Design and implementation of high-quality applied clinical research to inform:- The use of respirators and medical face masks in various risk scenarios,- The impact of gowns, aprons and eye protection as part of transmission-based precautions,- Optimal masking strategies to reduce risk of transmission inclusive of sessional vs risk-targeted, wider masking policy, including behavioural insights to adherence, any unintended consequences for staff and patient safety, and staff preferences,- A risk-based approach to the selection of personal protective equipment considering the time of exposure, the proximity to the patient and the procedure/task.IPC: infection prevention and control.Given that neither the current droplet nor the airborne precautions address the role of aerosols at short distances, various options could be considered for adapting current transmission-based precautions. Droplet precaution measures could be expanded to address the theoretical risks linked to inhalation of short-range aerosols. A two-tiered risk-based approach could be applied, based on proximity, length of exposure, type of symptoms and type of care: (i) contacts with prolonged, close proximity to the patient, including the performance of high-risk procedures, are associated with higher risk and justify the use of high-efficacy respiratory protection; (ii) for contacts without prolonged, close proximity to an infectious patient in adequately ventilated spaces, the effectiveness of medical face masks would be sufficient.Gloves are part of contact precautions that have been recommended for the prevention of the transmission of respiratory viruses such as influenza and SARS-CoV-2. However, hand hygiene, including alcohol-based hand rubs, is an effective measure against SARS-CoV-2 and other respiratory viruses ,30, as wWhile the desirable anticipated effects from the use of gloves and gowns/aprons are small, the undesirable anticipated effects are at least moderate. Therefore, the balance of desirable and undesirable effects does not favour the routine use of gloves or gowns/aprons for the prevention of COVID-19 and other respiratory virus infections. An exception may be prolonged, close exposure to a case, especially a patient who is coughing or sneezing heavily, when high-risk procedures are required, or in cases when there is a high risk of exposure to infectious body fluids - as stipulated by standard precautions.There is emerging evidence that the increased risk of infection from some aerosol-generating procedures may be more related to proximity with the patient than to increased generation of aerosols by the procedure itself . SeveralGiven that the risk of transmission is related not only to the microorganism, but also to the duration and proximity of contact, the applied transmission-based precautions should ideally be selected following a point-of-care risk assessment, taking into account proximity, duration of exposure, risk of aerosol production and the type of task performed.Various forms of continuous face mask use, such as universal masking, applying to healthcare workers, patients, visitors and persons accompanying the patient, and targeted continuous masking, applying to healthcare workers , especiaThe eyes have been identified as potential routes of entry for respiratory viruses either directly, by infection of the ocular mucosa, or by transfer to the nasopharynx through the nasolacrimal duct . AvailabA limitation of the above suggestions is the low level of available evidence in epidemiological studies or clinical trials for the effectiveness of specific elements of transmission-based precautions, including elements of PPE. Emerging evidence may increase our certainty in the magnitude of their effectiveness. A better understanding of the physical processes of exposure does not automatically translate into more effective prevention measures, as infection is a more complicated process than the transfer of infectious particles, involving immune processes and the suitability of various exposed host tissues for the entry of viruses. The applied preventive measures aim at mitigating the risk of infection to an acceptable level, taking into account the assessed risk but also other parameters such as preferences, ease of implementation and unintended consequences. Studies which use various forms of modelling and laboratory experiments to investigate the role of procedures and behaviours in generating and dispersing respiratory particles are limited and ultimately do not provide adequate evidence to address transmission in the complex healthcare environment. There is a need for applied clinical research on the effectiveness but also the unintended consequences of preventive measures to support the development of evidence-based recommendations for guidance. Furthermore, human challenge studies, taking carefully into consideration any ethical issues , may proTransmission-based precautions are important but are not the only measures to control SARS-CoV-2 transmission in healthcare. It should be noted that PPE is only one among several control measures in the hierarchy that includes elimination and substitution, engineering and administrative controls . TransmiMeasures to prevent and control an infection with high morbidity and case fatality and without treatment options are influenced by the assessed risk of adverse outcome  and ofteThe ECDC expert panel suggested that the IPC community should consider revisiting the current transmission-based precaution framework, including the theoretical background regarding various modes of transmission and the definitions of terms related to transmission, to account for available and emerging scientific evidence and the role that the consequence of infection plays on the choice of the precautions. Such a review would ensure that transmission-based precautions are consistent and rationally based on available evidence, which would facilitate decision-making, guidance development and training, as well as their application in practice to prevent transmission of SARS-CoV-2 and of other respiratory viruses. High-quality studies are imperative to address the current knowledge gaps and strengthen the evidence for any future revision of transmission-based precautions.


Chiropractors use a treatment strategy called maintenance care with the intent of secondary and tertiary prevention. The Nordic Maintenance Care Program provides evidence of when and for whom maintenance care should be offered. Dissemination has occurred through articles, workshops, social media, conference in Europe and internationally. However, little is known about chiropractors’ awareness and use of this evidence. This study explores chiropractors’ attitudes, skills, and use of evidence on maintenance care, as well as study their association with general evidence-based practice and demographic characteristics. Moreover, barriers and facilitators of evidence access are also examined.Questions pertaining our research aim were included in the anonymous and digital Evidence-Based practice Attitude and utilization SurvEy, which was distributed to all members (n = 770) of the Norwegian chiropractic association in the fall of 2021.skills to identify suitable patients, and 45% had used published information in the past month. Strong alignment was observed between Norwegian chiropractors’ attitudes, skills, and utilization of evidence-based maintenance care and general evidence-based practice. Maintenance care skills were significantly associated with age (those between 40 and 59 years being less likely to report having high skills), clinical setting  and country of education . Moreover, maintenance care use was significantly associated with country of education . Access to resources was a barrier, whereas knowledge of patient suitability facilitated evidence-based maintenance care.The response rate was 41% (n = 312). Regarding attitudes towards evidence-based maintenance care, 26% agreed they needed tools to recommend this care to patients. Approximately half (57%) believed they had Norwegian chiropractors had neutral attitudes towards maintenance care, but generally reported moderate skills. Most had not used evidence about maintenance care in the previous month. Access to useful resources about the evidence regarding maintenance care was a barrier, and knowledge of who responds to maintenance care was a facilitator.The online version contains supplementary material available at 10.1186/s12998-023-00502-3. Chiropractors traditionally use a secondary and tertiary preventive strategy known as Maintenance Care (MC) to manage recurrent and persistent musculoskeletal pain . MaintenDuring the past 10 years, a research program in the Nordic countries has investigated the concept of MC: its prevalence, indications, and effect , 5. In aWork in the Nordic Maintenance Care Program is ongoing to develop stratified care pathways and implement the knowledge acquired from the past decade of research. The psychological profile tool used to identify patients with likely positive and negative outcomes from MC  is a comprehensive questionnaire needing statistical software to be scored according to a complex clustering procedure and not very clinic-friendly . At the In Scandinavia and Europe, the results from the Nordic Maintenance Care program have been communicated in short videos that have been published in specific social media forums, in podcasts and interviews, as well as in workshops and lectures online and in person , i.e. the integration of the best available research evidence into clinical practice to improve both health outcomes and quality of care for individual patients , 9. To tThis knowledge is necessary if optimal patient management through the utilization of EBP is the goal. Thus, the results may influence future research communication and implementation concerning MC evidence.The aim of this study was to explore chiropractors' attitudes, skills, and use of available evidence on maintenance care and to study if these are associated with attitudes, skills, and use of evidence in general and with demographic factors. Moreover, if barriers and facilitators of access to such evidence exist.What are chiropractors' attitudes towards the usefulness of resources/tools for prescribing MC in clinical practice?Do chiropractors think they have the skills to identify patients likely to respond positively or negatively to MC? Do chiropractors often use published information to identify patients suitable for MC?Do chiropractors consider that barriers exist regarding access to useful resources to evaluate if MC is appropriate? Do chiropractors believe it is a facilitator to have knowledge of which patients are likely to respond positively or negatively to MC? What are the associations between attitudes, skills, and use of EBP in general and attitudes, skills, and use of evidence relating to MC?. What are the associations between attitudes, skills, and use of evidence relating to MC and the chiropractor’s demographic factors?The objectives of the study were to explore the following questions:The study was based on data from an online, cross-sectional survey conducted in Norway. No identifying data were collected, and results were reported as aggregated data, thus maintaining participant anonymity. Study participation was voluntary, and no ethical approval was needed according to Norwegian law . The stuAll chiropractors (n = 770) registered as members of the Norwegian Chiropractors’ Association in 2021 were eligible and invited to participate. In Norway, this is approximately 90% of all licenced chiropractors .In the fall of 2021, a questionnaire survey was conducted using an online system called 'Nettskjema' developed at the University of Oslo, Norway. The survey link was distributed via email to 770 practicing chiropractors who were members of the Norwegian Chiropractors' Association. Various methods were used to encourage participation, including social media posts, emails, and personal reminders. Verbal advertisements and encouragement were also provided during the National Norwegian chiropractic Conference. Data collection took place between October and November 2021, and participants were provided with information on the study's purpose, the meaning of their consent, data storage, reporting of results, and ethical considerations. Multiple reminders and messages were sent through email and social media groups to encourage completion of the survey.The questions for this study (described below) were added to a more extensive questionnaire called The Evidence-Based practice Attitude and utilization SurvEy (EBASE), which has shown good internal consistency, construct and content validity and demonstrated acceptable test–retest reliability , 13. TheA. EBP attitude; scores ranging from 8 (predominantly ‘strongly disagree’) to 40 (predominantly ‘strongly agree’); the subgroups were labelled ‘Disagree’ (sub-score < 32) and ‘Agree’ (sub-score >  = 32),B. EBP skills; scores ranging from 13 (primarily ‘low-level skill’) to 65 (primarily ‘high-level skill’); the subgroups were labelled ‘Poor-average’ (sub-score <  = 39) and ‘Average-good’ (sub-core > 39), and.C.: EBP use; scores ranging from 0 (mainly ‘infrequent use’) to 24 (mainly ‘frequent use’); the subgroups were labelled ‘Never-rarely’ (sub-score <  = 8) and ‘Sometimes’ (sub-core > 8).For parts A, B, and D of EBASE, scores were generated and dichotomized for objective six as follows:Part G of EBASE were used to describe the study participants, and to investigate associations between MC attitudes, MC skills and MC use and demographic factors for objective 7. The selection of candidate factors to investigate associations was based on the literature of identified demographic factors , 16. TheFor this study, we included five specific questions and answer options specifically pertaining to MC:For objective 7, the responses to the questions regarding MC attitudes, MC skills and MC use items were dichotomized.MC attitudes were dichotomized into ‘Disagree’ , and ‘Agree’ (including the responses ‘Agree’ and ‘Strongly agree’).MC skills were dichotomized into ‘Low skills’  and ‘High skills’ (including the responses ‘Medium–high’ and ‘High Skills’). MC use were dichotomized into ‘no use’ (including response options ‘0 times’) and ‘use’ .Survey responses were exported directly into and analyzed with STATA/SE 16 . There were no missing data, as all items were made compulsory.Categorical data were described using frequency distributions and percentages. Cross-tables were used to analyze the association between EBP attitudes, EBP skills, and EBP use and MC attitudes, MC skills, and MC use.The associations between MC attitudes, MC skills, and MC use as outcomes and the selected demographics as independent variables were investigated by logistic regression analysis. The result is presented as odds ratios (OR) with a 95% confidence interval.The response rate for the survey was 41% (n = 312) of the target sample. Of the participating chiropractors, 174 (56%) were male , see Table In the EBP skills subgroups, among chiropractors who rated their skills as ‘average-good’, access to instruments to subgroup patients suitable for MC were mainly found to be a minor MC barrier, whereas those rating their EBP skills as ‘poor-average’, found it to be a moderate barrier, see Table In the EBP use subgroups, more chiropractors reporting to use EBP ‘sometimes’ compared to those reporting ‘never-rarely’ answered that they had used scientific literature during the past month (MC use), see Table Logistic regression analysis showed that MC attitudes were not significantly associated with any of the demographic factors Table .Table 4AMC skills were significantly associated with age, clinical setting, and country of education. Thus, chiropractors in the age range 40–59 who were working with conventional health providers were less likely, in contrast to those educated in the USA and Australia that were more likely, to report that they have ‘medium’ to ‘medium–high’ skills to identify patients that respond positively or negatively to MC , providing information through channels other than those tried already (as access to information was considered a barrier). Educational programs at schools should be targeted for this knowledge to be translated to students.The response rate was only 41%, but still better than that of a recent equivalent Swedish study in the EBP field . It is gThis EBASE study is a direct replica of a recently conducted Swedish study among manual therapists , and simNorwegian chiropractors generally had neutral attitudes towards the tools available to utilize the evidence of MC; they reported moderate skills, and most had not used evidence about MC the previous month. Access to useful resources about evidence of MC was a barrier for most chiropractors, although most thought that knowledge of responses to MC was a facilitator.Additional file 1. Communication of the Nordic Maintenance Care program.