The "Law on Doctors of the People's Republic of China," which was officially implemented on March 1, 2022, emphasizes the requirements for rational drug use and the necessity for appropriate management of off-label drug use. The safety and ethical considerations related to off-label drug use are different in children than in adults. There is so far no management guideline for pediatric off-label use of drugs in China, and the applicability of foreign guidelines is limited. Establishing a localized evidence-based management guideline for pediatric off-label use of drugs to support the national legislation and clinical practice is of critical importance.We established a guideline working group, including experts from a broad range of disciplines and developed recommendations following the guidance of the World Health Organization Handbook and the Chinese Medical Association. The following themes were identified by questionnaires and expert interviews to be of great concern in the management of off-label drug use in children: general principles and characteristics of management of pediatric off-label drug use; establishment of expert committees; evidence evaluation; risk–benefit assessment; informed consent; monitoring and assessment of the risk; and monitoring and patient education. Two rounds of Delphi surveys were organized to determine the final recommendations of this guideline. We graded the recommendations based on the body of evidence, referring to the evaluation tool of the Evidence-based management (EBMgt) and the Oxford Center for Evidence-Based Medicine: Level of Evidence (March 2009).We developed the first guideline for the management of pediatric off-label use of drugs in China.The guideline is to offer guidance for pediatricians, pharmacists, medical managers, policymakers, and primary care physicians on how to manage off-label drug use in pediatrics and to provide recommendations for Chinese healthcare policy in the future.The online version contains supplementary material available at 10.1186/s12887-022-03457-1. Off-label use refers to the use of drugs beyond the scope of the drug instructions and labels provided by the manufacturer and approved by the National Medical Products Administration of China . DiffereThis guideline was developed by the Chinese Society of Pediatric Clinical Pharmacology, the Chinese Medical Association, the National Clinical Medical Research Center for Child Health and Disease , and the Chinese GRADE Center. Methodological support was provided by the Chinese GRADE Center, the World Health Organization (WHO) Collaborating Center for Guideline Implementation and Knowledge Translation, and the Institute of Health Data Science, Lanzhou University. The guideline was launched on April 12, 2021, and finalized on December 24, 2021. The guideline followed the methodology proposed by WHO  and the Experts from a broad range of disciplines including pediatrics, pharmacy, management and health policy, and evidence-based medicine, as well as parents of children participated in the development of the guidelines. The participants were divided into the steering committee, a secretarial team, an evidence team, a consensus team, and an external review team. A full list of members is provided at the end of this article. All members completed a declaration of interest form and stated that they had no economic conflicts of interest directly relevant to this guideline.This guideline is registered at the International Practice Guideline Registry Platform (Registration no. IPGRP- 2021CN088). The guideline protocol is available on request from the registration platform.The target audience of this guideline includes pediatricians, pharmacists, medical managers, policymakers, and primary care physicians. The management population of the guideline is children and their guardians.The themes of this guideline were determined during one round of a questionnaire-based survey and two rounds of expert interviews. At the beginning, the working group identified 11 themes by analyzing published guidelines relevant to the topic and interviewing pharmaceutical specialists. Subsequently, we developed a questionnaire to evaluate the importance of these themes and ask suggestions for additional themes. Sixty-six themes were obtained through the feedback from the survey. After de-duplication, merging, and discussion with the consensus team meeting, eight themes were finally selected to be included.We performed a systematic literature search for each question through PubMed, Web of Science, Embase, China Biomedical Literature Database (CBM), WanFang Data, and China Knowledge Network database (CNKI) to identify literature published from inception to August 13, 2021. We used the search terms "pediatric*", "paediatric*", "child*", "infant*", "adolescent*", "neonat*", "newborn*", "teen*", "off-label", "off label use*", "unlabeled use*" and "unlicensed medicines"   combinedBased on the summary table of the available evidence for each theme and consideration of patients' preferences and values, fairness, and the implementation ability of the management measures, we drafted initial recommendations on off-label drug use for children. Two rounds of Delphi surveys on recommendations were then conducted on November 4, 2021, and November 8, 2021, respectively, and a total of 19 suggestions from experts were collected. Recommendations were considered to have reached a consensus when 80% of the voters agreed to the recommendation.The secretariat prepared the first version of the guideline in accordance with the RIGHT checklist and sent the full text to the external review committee. All opinions and recommendations of the review committee were taken into consideration in the revision and creation of the final draft of the guideline.This guideline is planned to be updated within three to five years based on emerging relevant evidence, following the Reporting Items for Updated Clinical Guidelines: Checklist for the Reporting of Updated Guidelines (CheckUp ) checkliThe guideline entitled "Management Guideline for the Off-label Use of Drugs in China 2021)" focuses on the definition of off-label use of drugs, evidence grading standards, management of informed consent, monitoring of adverse drug reactions and adverse events, main responsibilities of hospitals and manufacturers, conditions for reimbursement by social health insurance, and the national approval system, resulting in recommendations in nine thematic areas  of health care workers did not follow the “Expert Consensus on Off-label drugs in pediatrics in China” guidance document, with 52.6% of the reasons being "no expert group on off-label use" .To ensure the rationality of off-label use of drugs to treat children, the process of protocol development and safety monitoring requires the discussion and collaboration of experts from various disciplines, including pediatricians, pharmacists, and nurses –17. In aGuidelines and consensus statements on the management of off-label use of drugs for children from China and abroad emphasize that off-label drug use should be evidence-based. Most clinicians, however, lack the necessary skills and time to conduct systematic reviews of existing evidence . EvaluatClinical experts in the corresponding diseases.Non-clinical experts in medical technology, such as professionals in clinical testing, pathology, imaging, or ultrasound.Experts in the field of essential medicine, such as biologists and pharmacologists. In complex clinical cases involving, the expert committee can be expanded if the expertise of the regular committee does not cover all aspects related to the actual situation of the patient. Under the principles of individualized medical model and precision medicine, we suggest that the expert groups should be expanded on a case-by-case basis to include non-clinical medical technologists and basic medicine specialists when discussing off-label treatment of children who have comorbidities or need to take multiple drugs off-label at the same time. For example, we suggest including microbiologists for questions regarding the off-label use of drugs to treat infectious diseases; and radiologists for questions related to ultrasound and MRI contrast agents in children.Formulating and regularly updating the list of drugs commonly used off-label for children in their respective medical institution;Participate in consultations for off-label drug use in children;Promptly release data on serious adverse events or adverse reactions(ADRs) related to off-label drug use. Evidence from adults can be used as indirect evidence;In the lack of high-quality pediatric clinical evidence, an extrapolation of evidence from adult trials can help mitigate the impact of limitations caused by insufficient sample size, disruption of equilibrium, and heterogeneity in pediatric clinical trials . Both thWe suggest assessing the evidence by systematic reviews in cases when there are not yet any approved indications for children, but there is evidence for both adults (in China) and children (anywhere).When there exists evidence only from Chinese adults evidence and no high-quality evidence is available for the pediatric population, we suggest using these findings with caution. A comprehensive analysis of all available information and data is required prior to use, including differences in organ function in specific age groups, the impact on pharmacological characteristics, knowledge of the disease, epidemiological conditions, non-clinical trial data, pharmacokinetics (PK), pharmacodynamics (PD), clinical effectiveness, and safety differences between adult and pediatric populations for drugs with the same or similar mechanism.Evidence from similar diseases in children can be used as indirect evidence;Evidence from pharmacokinetic or pharmacodynamic equivalency modeling studies on pediatric populations can be used as indirect evidence.Evidence from similar diseases may need to be considered for some specific types of disease, such as rare diseases in children , 30 or pIt is not suitable to adopt the adult dose directly for children based on the child's age and weight alone . InsteadBenefit and risk assessment is an appropriate method to judge the rationality of off-label drug use , 5. In rThe severe shortage of drugs for neonates is a worldwide problem , 40, maiCompared with adults, assessing the benefit-risk of off-label use of drugs in children is more complicated . BecauseInformed consent is a crucial tool for doctors and patients to defend their legitimate rights and interests. Although children have a limited ability to estimate risks, signing informed permission is vital for children's mental health and treatment participation. Article 19 of the Civil Code of the People's Republic of China  stipulatEvidence-based drug databases and drug directories, such as the Micromedex Pharmaceutical Database, the British National Formulary for Children (BNF-c) , the DutCurrently, awareness on the principles of adequate off-label drug use is poor among clinicians . For halThe World Health Organization  categoriCurrently, adverse drug response events are being monitored and reported through the National Adverse Drug Reaction Database of the State Drug Administration in China . HoweverWhile clinicians, pharmacists, and nurses should individually assess the risk of children taking off-label drugs during the process of monitoring adverse drug reactions, we suggest seeking help from parents or guardians of children, especially of children who are incapable of autonomous behavior , 72.Pediatricians should consider whether or not their child patients have the ability to be independent during drug education. 83.5% of medical working groups believed that the family members or guardians of children should be informed when they use off-label drugs . As a reComprehensive drug education is essential to the safety of off-label use of drugs for children. For example, for children and adolescents who use psychotropic drugs beyond the label, a list of information on overdose drug instructions is required . The druEffective drug education enhances doctor-patient communication, promotes public knowledge of safe drug use, and reduces misunderstanding-related doctor-patient confrontations , 81. BecAlthough the guideline is the first Chinese evidence-based guideline for the management of pediatric off-label use of drugs, there were certain difficulties in the application of evidence-based methodology in the area of health care. Because of the diversity and heterogeneity of the types of research on each topic, we were unable to produce systematic reviews of evidence.Off-label use of drugs in children is common globally, also in China. This guideline provides 21 recommendations grouped into 8 themes and a list of evidence on the common types of off-label use of drugs in children, in order to assist the management of pediatricians, pharmacists, medical managers, policymakers, and primary care physicians on off-label use of drugs in pediatrics, as well as provide recommendations for future healthcare policies in China.Additional file 1: Supplementary 1. Management Guideline for the Off-label Use of Drugs in China (2021). Supplementary 2. A list of common types pediatric off-label use of drugs, evidence levels, and recommendations.


The method has also been implemented as a web tool that allows users to explore the effects of excluding different points of evidence, and indicating relative preferences on the endpoints.Evidence-based medicine propagates that medical/clinical decisions are made by taking into account high-quality evidence, most notably in the form of randomized clinical trials. Evidence-based decision-making requires aggregating the evidence available in multiple trials to reach –by means of systematic reviews– a conclusive recommendation on which treatment is best suited for a given patient population. However, it is challenging to produce systematic reviews to keep up with the ever-growing number of published clinical trials. Therefore, new computational approaches are necessary to support the creation of systematic reviews that include the most up-to-date evidence.We propose a method to synthesize the evidence available in clinical trials in an ad-hoc and on-demand manner by automatically arranging such evidence in the form of a Through two use cases, our method was shown to be able to generate conclusions similar to the ones of published systematic reviews. To evaluate our method implemented as a web tool, we carried out a survey and usability analysis with medical professionals. The results show that the tool was perceived as being valuable, acknowledging its potential to inform clinical decision-making and to complement the information from existing medical guidelines.The method presented is a simple but yet effective argumentation-based method that contributes to support the synthesis of clinical trial evidence. A current limitation of the method is that it relies on a manually populated knowledge base. This problem could be alleviated by deploying natural language processing methods to extract the relevant information from publications. The evidence-based medicine (EBM) paradigm fosters the use of the best available evidence when making decisions in treating individual patients . Best evdimension tree in which the nodes correspond to standard primary and secondary endpoints considered in a given therapy area . Our proposed methodology generates such a hierarchical, tree-shaped argument from a given knowledge base automatically, but most importantly makes the process of generating such a conclusion interactive and dynamic. By changing the weights, and thus the relative importance of each comparative dimension , a user can perform a sensitivity analysis to understand under which conditions and assumptions a certain treatment can be assumed to be superior to another one. The method is also dynamic in the sense that it can incorporate new evidence as it becomes available instantly, and the users can inspect how the newly added evidence affects the overall conclusion. We thus call our method Dynamic Interactive Argumentation Trees (DIAeT).In order to help reduce the effort in aggregating evidence as a crucial step in elaborating a systematic review, in this paper we present an argument-based approach that automatically generates a conclusion from a given body of semantically captured clinical trials. The main goal of a systematic review is to identify which of a number of existing treatments is superior to other treatments. Therefore, our methodology automatically generates a conclusion together with a justification in how far one treatment can be seen as superior to another one, where the backing evidence comes from a knowledge base in which clinical trials are semantically described. The conclusion and corresponding justification are provided in the form of a tree consisting of an overall conclusion on the superiority of one treatment over another at the root of the tree, and interim conclusions regarding the hierarchically ordered sub-dimensions along which the treatments can be compared. The sub-dimensions are ordered in a Little work exists on addressing reasoning through argumentation on the analysis and synthesis of clinical trial information. There have been efforts on using argumentation theory in the biomedical domain that rather focus on decision-making and the explanation of individual treatments e.g., , 5), but, but5]),In contrast to Hunter and Williams’ approach, our method does not rely on abstract argumentation but rather on Toulmin-style argumentation , which iOther methods to synthesize clinical trial evidence that do not follow an argumentation-based approach use statistical approaches. For example, the Aggregation Data Drug System (ADDIS)  supportsWhile ADDIS and Hunter and Williams’ framework are formally rigorous, we believe that the conceptual simplicity of our method is a useful feature as it is easy to adapt to other types of interventions and health conditions and it is straightforward to specify preferences between dimensions via weights on the single dimensions.In this paper, we describe the method sketched above for the automatic generation of conclusions that summarize the evidence available in a set of clinical trials. We describe the method technically, in particular showing that it supports sensitivity analysis. As a proof-of-concept, we demonstrate that the main conclusions of two published systematic reviews can be reproduced with our approach. We further present the results of a usability study showing that medical practitioners find the tool easy to use, and they understand how conclusions are generated from the available evidence.Our method generates a conclusion from the existing evidence with respect to the superiority of a given treatment in comparison to another treatment. While we focus on the direct comparison between two treatments in our exposition of the method, the approach can be extended to comparing multiple treatments.↦IGlar is overall superior to NPH insulin in terms of safety  and efficacy (considering HbA1c reduction) when weighted equally.⇒→Benedetti et al.  show tha→Hsia et al.  show tha→n other arguments from corresponding studies” show that IGlar is superior to NPH insulin in reducing HbA1c.“IGlar is superior to NPH insulin in terms of efficacy. ⇒→Benedetti et al.  shows th→No study shows that IGlar is NOT superior to NPH insulin in terms of nocturnal hypoglycemia.→n other arguments from corresponding studies” show that IGlar is superior to NPH insulin in terms of nocturnal hypoglycemia.“IGlar is superior to NPH insulin in terms of safety. The conclusion generated has the form of a tree in the sense that it consists of an overall conclusion about the superiority of the treatment at the root level which points to several children representing the (interim) conclusions for specific comparison criteria. Take the following example of an automatically generated conclusion comparing two types of insulin, the Neutral Protamine Hagedorn insulin (NPH) and insulin glargine (IGlar) as treatments for Type 2 Diabetes Mellitus (T2DM): Atomic Arguments while the arguments generated by our method and aggregating the results across clinical trials are called Aggregated Arguments.The overall conclusion (pointed with ↦) claims the superiority of IGlar with respect to NPH insulin when efficiency and safety are weighted equally. As a justification of this overall conclusion, we have the (interim) conclusions/arguments claiming superiority of IGlar with respect to NPH insulin in terms of safety and efficacy, respectively (pointed with ⇒). As a child of the (interim) conclusion claiming the superiority of IGlar compared to NPH insulin with respect to efficacy, we have an argument claiming superiority of IGlar compared to NPH insulin in terms of higher effectiveness in reducing HbA1c. As a child of the (interim) conclusion regarding the superiority of IGlar compared to NPH insulin regarding safety, we have an (interim) conclusion that IGlar is superior to NPH insulin regarding the reduction of nocturnal hypoglycemia. Finally, the children of the last two (interim) conclusions point to claims in specific publications backing up the claim of superiority with respect to higher effectiveness in reducing HbA1c as well as reducing cases of nocturnal hypoglycemia. Each node in the argumentation tree thus represents an (intermediate) conclusion that is justified by the nodes below, until reaching the claims of specific publications. The specific conclusions derived from claims of specific publications are called The method relies on a knowledge base in which all relevant trials have been semantically described in the Resource Description Framework (RDF) following the C-TrO Ontology . We noteIn the following, we first describe the C-TrO ontology and how it is used in our approach to semantically capture the results from clinical trials in a knowledge base. We further describe the procedure for automatically generating the Dynamic Interactive Argumentation Tree (DIAeT) representing the hierarchical conclusion on the basis of the given knowledge base. We present the relevant definitions and other important concepts needed to expose our approach before describing the method formally. We also hint at requirements that NLP methods that automatically extract evidence from publications need to fulfill.In order to provide a proof-of-concept for our method, we have manually populated an RDF knowledge base following the structure of the C-TrO ontology . ExistinC-TrO has been developed as a general schema to represent the design and results of clinical studies, and it is independent of a particular data source. We used Protégé  to populWhile we have modeled the evidence manually for this work, the option of applying NLP methods to extract the evidence from publications automatically is appealing. However, there are a number of requirements to be fulfilled by such NLP methods to be applicable in our context. Such methods should be able to generate a machine-readable representation of a publication that comprises the study design, population characteristics, in particular the condition, inclusion and exclusion criteria, age of participants, duration of a study, and most importantly the arms of the study with the corresponding treatment information including dosage information, frequency of application, etc. Further, the central outcomes including values and units need to be extracted for every endpoint, primary and secondary, comparing the different arms. Corresponding semantic medical vocabularies such as the Medical Subject Headings (MeSH) or the International Classification of Diseases (ICD) should be used to normalize treatments, conditions, etc.Arguments Structured arguments consist of a set of premises and a conclusion or claim in which the premises are statements that support the conclusion. In our approach, arguments represent a valid conclusion about the superiority of a therapy/intervention that can be reached on the basis of the clinical trial evidence available in a given knowledge base. The arguments can be nested in the sense that each argument consists of a set of premises and a conclusion where each premise itself can be an argument. In this context, we define an argument as a 5-tuple  where: C is a conclusion about the superiority of therapy t compared to other therapies {t1,...,tn},d is a dimension  along which therapy t is compared to the alternative therapies,p1,...,pm} is a set of premises from which the conclusion follows. A premise pi can be an argument or a set of facts from a knowledge base.{t′}. We distinguish between two types of arguments: Atomic Arguments (AtAs) and Aggregated Arguments (AgAs).For demonstrative purposes, in the remainder of this article we only consider a singleton set for the competing therapies, i.e., {Atomic Arguments (AtA) represent a single result from a published clinical trial that warrants a superiority conclusion with respect to a specific dimension d. An example of an atomic argument is in the annotated statement taken from a published clinical trial (PMID 12734781  since the weights are normalized.Note that the weights are non-negative values and Confidence acceptance threshold As in the general case the evidence can not be assumed to be homogeneous with studies having contradictory findings, our method introduces a confidence threshold τ that needs to be reached or surpassed by the confidence of an aggregation argument to be accepted. The interpretation of the threshold corresponds to the relative share of clinical studies that need to agree on a certain result (e.g. superiority of therapy A compared to B for a specific outcome).If a user wants to consider only results for which no contradictory evidence exists, then the threshold has to be set to 1. In the general case, a user can set the threshold to a value corresponding to the inconsistency he/she is willing to accept regarding the conclusion. The default value for the threshold is 0.5 (or 50%), indicating that at least half of clinical trials need to agree on a certain outcome. A user can set the threshold higher to impose a stricter requirement on the homogeneity of the evidence.The DIAeT is a tree where the nodes represent arguments and the edges connect arguments with sub-arguments. The atomic arguments correspond to the leaf nodes and the aggregated arguments to the inner nodes. The children of a node are sub-arguments (or sub-conclusions) that occur in the premises of the given argument node.The construction of the DIAeT is driven by a given dimension tree and follows a recursive procedure. Each node recursively calls the procedure that generates sub-arguments that support the conclusion at the node in question. The procedure starts at the general conclusion located at the root node of the argument tree and stops at the leaf nodes that correspond to atomic arguments.⊔,⊔′,⌈,{⊣⌋⊔∫⌈) for a leaf dimension noded for each publication p that compares treatments t and t′ with respect to dimension d, where factsd represents the evidential facts in publication p that justifies the claim of superiority of t over t′ w.r.t. d.The end of the recursion coincides with the generation of as many atomic arguments = or aggregated arguments (else). In both cases t over treatment t′ with respect to dimension di.accepted if its degree of confidence ⟦AgA⟧ is not less than the user-defined (or default) acceptance threshold τ. Thus, if the degree of confidence ⟦AgA⟧≥τ for t, then the conclusion (C) will state that treatment t is superior to treatment t′ w.r.t. dimension di. Afterwards, the generated arguments are verbalized by domain-specific templates. The procedure to construct a DIAeT is summarized in Algorithm 1.An aggregated argument is IOP reduction and conjunctival hyperemia have weights of 1 because they are leaf nodes and therefore there are no other dimensions with which they could be compared. Next, both efficacy and safety have weights of 0.5 meaning that both dimensions are equally important in this example.Figure d4 and d5). For IOP reduction (d4), there are 11 out of the 11 clinical trials that state that latanoprost is more effective in reducing IOP than timolol, such that conjunctival hyperemia (d5), only in one of the six clinical trials that report this adverse effect, it was found that fewer patients suffered conjunctival hyperemia when applying latanoprost, such that d4 and d5 respectively) are 1. Finally, Efficacy: “the evidence shows that latanoprost is superior to timolol”, as Safety: “the evidence does not show that latanoprost is superior to timolol”, as Overall conclusion: “latanoprost is superior to timolol”, as Figure Our approach allows to modify the weights of the dimensions and/or exclude certain evidence points. For example, studies that are biased or where the methodology applied is unclear, can be excluded by adjusting the parameters. One could also explore other scenarios (or “what-if” simulation) by filtering different criteria, such as publication year, duration of the study, and number or age of the participants in the clinical trials.safety and a lower weight of 0.3 to efficacy. The new weights would generate different degrees of confidence. For example, the degree of confidence for Overall conclusion: “it can not be concluded that latanoprost is superior to timolol”, as In the previous example, we could for instance explore other scenarios by assigning a higher weight of 0.7 to safety has a significantly higher weight than efficacy , the overall conclusion changes to “Itcannotbe concluded that latanoprost is superior to timolol”. Otherwise, the conclusion indicates that “Overall, the evidence showed that latanoprost is superior to timolol”, including the case when one study is excluded.Further, if one excludes a study that compares the two drug treatments but that does not mention any result about conjunctival hyperemia , then the degree of confidence of The user can also explore the conclusions generated according to different acceptance thresholds. For example, Table Figure Figure The DIAeT approach has been implemented as a web tool as a proof of concept to support its evaluation with end users. Figure Figure conjunctival hyperemia where there are five atomic arguments attacking a single supportive evidence (study CT_7). Supportive arguments in this example are those that state that latanoprost causes less conjunctival hyperemia cases than timolol, while attacking arguments are those that imply a contradiction to the supportive arguments by stating that either latanoprost causes more conjunctival hyperemia cases, or that there are equal number of cases caused by both drugs . The evidence used to generate the DIAeT is displayed in the clinical evidence table. In this table, the user can find more information about the clinical trials, such as duration, number of patients, sources of possible biases, etc. , weights, confidence threshold, and exclude/include clinical studies , and then re-generate the conclusions. For example, specific studies can be excluded from the considered evidence if the user deems that the study does not meet certain criteria. All the studies that are considered by the system as supporting evidence are ticked in the evidence table. The user can then decide to untick them if he wants to explore what happens by not including them. Figure Although the final decision on the best treatment is made by medical expert users, the method implemented as a tool would help them in the exploration of the information by, for example, narrowing the search space or helping her to understand under which conditions and assumptions it can be assumed that a certain treatment is superior to other treatments. If the medical experts find some interesting, unexpected or contradictory conclusions, they can directly check possible explanations for these conclusions in the published clinical trials.In this section, we first describe the results of two use cases designed to evaluate whether our method is able to produce similar conclusions to the ones of published systematic reviews. Next, we describe a survey conducted to assess the possible benefits and the use of our method as a web tool.As a proof of concept of our method, we present two use cases. One use case is on glaucoma and another on Type 2 Diabetes Mellitus (T2DM). The aim is to analyse whether our method is able to generate similar conclusions compared to the ones reached in the existing published systematic reviews selected for these two diseases.We first formalized the evidence of each of the trials considered in the respective systematic reviews for glaucoma and T2DM , 20 as defficacy and safety, which are common aspects of interest in clinical trials. The sub-dimensions of these dimensions were specified according to the main endpoints  analyzed for each disease when applying the medical treatments studied in the respective systematic reviews. Although our approach allows any number of dimensions, we only include one endpoint and one adverse effect as sub-dimensions for simplifying the use cases. Equal weights were assigned to efficacy and safety . Table We then defined the dimension trees for each disease. Both dimension trees contain dimensions for ty i.e., 0% each. efficacy and safety used in both use cases to establish superiority of a treatment over other treatments are the following : EfficaNote that these criteria can be changed or augmented to include more complex cases. For example, the efficacy criterion could include combined therapies that involve the application of more than one drug treatment to the same interventional arm at different time points and duration. However, because the use cases presented here refer to single-drug treatments, we use a simple efficacy criterion that involves a single treatment.Given the initial configuration, the respective DIAeTs were generated without applying any filter to the evidence retrieved from the knowledge base.glaucoma, the conclusions obtained with the DIAeT tool for efficacy, safety, and overall superiority when comparing latanoprost to timolol are: is superior to timolol in terms of efficacy .”“The evidence in 11 clinical studies shows that latanoprost does not show that latanoprost is superior to timolol in terms of safety .”“The evidence in 11 clinical studies is superior to timolol ”.“Taking into account the evidence from 11 clinical studies comparing latanoprost to timolol, it can be concluded that latanoprost For “Latanoprost showed better IOP lowering effects than timolol with an additional 4–7% reduction. The differences were all statistically significant except for the result from a single 12 months study.”“Latanoprost caused hyperaemia and iris pigmentation in more patients than timolol. The risk for hyperaemia was over twice that seen with timolol .is superior to timolol for reducing intraocular pressure.”“Latanoprost The conclusions reached in the systematic review by Zhang et al.  with resoverall, latanoprost is superior to timolol despite the different side effects that it might provoke. This conclusion is in line with the ones obtained by our tool that states that in general latanoprost is superior to timolol, and in particular in terms of efficacy considering IOP reduction. However, in terms of safety, considering hyperaemia, latanoprost is not superior to timolol.Zhang et al. conclude that, T2DM, the conclusions on efficacy, safety and overall superiority generated by our tool when comparing Glargine Insulin (IGlar) to NPH Insulin are: does not show that Glargine Insulin is superior to NPH Insulin in terms of efficacy (weight of HbA1c: 1).”“The evidence in 9 clinical studies is superior to NPH Insulin in terms of safety .”“The evidence in 9 clinical studies shows that Glargine Insulin is superior to NPH Insulin .”“Taking into account the evidence from 9 clinical studies comparing Glargine Insulin to NPH Insulin, it can be concluded that Glargine Insulin For is superior to NPH insulin despite IGlar not being superior to NPH Insulin in terms of efficacy.Therefore, the evidence shows that overall IGlar “The study demonstrated a difference in HbA1c reduction in favor of twice daily NPH insulin...”“The analysis of individual endpoints demonstrated comparable reduction of HbA1c in each arm, but with concomitantly lower rate of symptomatic and nocturnal hypoglycemia in IGlar group.”“In conclusion, for the majority of examined efficacy and safety outcomes, IGlar use in T2DM patients was superior or at least non-inferior to the alternative insulin treatment options.” .In the systematic review conducted by Rys et al. , the conThese conclusions coincide with the ones generated by our tool in that overall IGlar is superior to NPH insulin, in particular with respect to safety and in reducing the risk of nocturnal hypoglycemia, but not superior in efficacy in terms of the reduction of HbA1c levels.The presented use cases include only some relevant dimensions for each disease. However, other important dimensions could be defined. For example, for T2DM the dimension long-term harm can be added, which may include conditions such as myocardial infarction, stroke, or kidney failure. Although these use cases contain few dimensions , they demonstrate that the method can automatically generate similar conclusions for these endpoints as the conclusions reached in manually produced systematic reviews. Moreover, a main benefit of our approach is that it supports exploring the consequences of different preferences and weights interactively and reasoning under different assumptions.To evaluate the use and acceptance of the DIAeT tool, we conducted an on-line survey in which 17 medical experts (13 men and 4 women) from different hospitals in Germany took part. The participants were between 25 and 54 years old, most of them in the range of 35-44 years. They had different medical specializations and at least one year of experience in their fields , pediatrics (2), general medicine (2), emergency medicine (2), cardiology (2), oral surgery (1), otorhinolaryngology (2), and neurology (1), internal medicine (1)).The survey consists of three sections, and most of the responses are based on a 5-points Likert-scale  where 1:The results for the first section are shown in Table Table In the third section, we use the System Usability Scale (SUS) , which iThe responses and obtained scores are presented in Table Overall, the results of the conducted survey suggest that our method implemented as a web tool can be useful for medical practitioners to support the exploration and summarization of clinical evidence.knowing to doing gap) by the aggregation of contradictory or incomplete clinical evidence - according to the criteria and preferences of the expert users - that leads to the generation of textual and justified conclusions. Further, it could help to facilitate the selection of evidence and the calibration of parameters that allows a more effective production of systematic reviews.The creation of systematic reviews is a long-term process requiring substantial personnel and efforts , and keeThe DIAeT approach presented in this article is argument-based and similar to the practical aspect of Toulmin’s model of argumentation . ToulminThe abstract framework of Hunter and Williams  is also Regarding the semantic technology aspect, the DIAeT method requires clinical trial information formalized in a knowledge base following a suitable ontology and the integration of semantic vocabularies. While this may seem to be a bottleneck for the large-scale implementation of the proposed approach, there are currently signs that this will indeed not be a limiting factor. For one, it is possible to develop intuitive interfaces that guide authors of clinical trial publications, voluntaries or crowd-sourcing participants to describe the main results of a clinical trial with respect to a given ontology. In a recent study , we haveThe method is generic since the core elements to build the argument tree, such as dimension tree and superiority criteria, can be adapted to other health conditions or diseases. For this purpose, it would be necessary that the knowledge base contains the information relative to these conditions. If the method was used in a context other than clinical trials, a knowledge base with the appropriate information would be needed.Although recent text mining and NLP solutions have progressed in the extraction of the core ‘evidence tables’ from clinical trial publications , a limitIn this article, we have presented a method that facilitates the synthesis of clinical evidence via an argument-based approach that automatically generates a tree-shaped conclusion on the basis of clinical trials semantically captured in a knowledge base. Our approach allows users to explore the impact of filtering the evidence as well as of setting weights for different comparison dimensions interactively and dynamically on the generated conclusion, thus supporting to carry out sensitivity analyses.The method has been implemented as a web tool that can be adapted to different indications or therapeutic areas. The web tool allows users to systematically explore the implications of excluding certain points of evidence, or indicating relative preferences of endpoints via weight setting. Our argument-based approach has been shown to be able to generate conclusions that are comparable to those of the manually produced systematic reviews. It has also shown to be generic in the sense that it can be applied to different health conditions, as shown in the use cases presented in two different diseases.Our evaluation with medical experts has revealed that the tool is easy to understand and use and that it has the potential to support experts in assessing the current evidence as a complement or extension to existing guidelines, helping them to reach better decisions. The method can also support the automation of systematic reviews, as explored by the International Collaboration for the Automation of Systematic Reviews (ICASR).In future work, we intend to develop the methodology further to support the development of continually updated (“living”) systematic reviews. We will also develop information extraction methods that can automatically extract relevant evidence from published trials.


Given the ecological importance of top predators, societies are turning to non-lethal methods for coexistence. Coexistence is challenging when livestock graze within wild predator habitats. We report a randomized, controlled experiment to evaluate low-stress livestock handling (L-SLH), a form of range riding, to deter grizzly (brown) bears, gray wolves, cougars, black bears, and coyotes in Southwestern Alberta. The treatment condition was supervision by two newly hired and trained range riders and an experienced L-SLH-practicing range rider. This treatment was compared against a baseline pseudo-control condition of the experienced range rider working alone. Cattle experienced zero injuries or deaths in either condition. We infer that inexperienced range riders trained and supervised by an experienced rider did not raise or lower the risk to cattle. Also, predators did not shift to the cattle herds protected by fewer range riders. We found a correlation suggesting grizzly bears avoided herds visited more frequently by range riders practicing L-SLH. More research is required to compare different forms of range riding. However, pending experimental evaluation of other designs, we recommend use of L-SLH. We discuss the cobenefits of this husbandry method. Human-ie.g., BearSafe program; e.g., relocations, aversive conditioning and targeted trapping and killing; In the United States, agriculture and related industries contribute 1.1 trillion US dollars to the national gross domestic product (GDP), and the highest value livestock sector is cattle production . In Canae.g., wolves in Michigan, USA  which has been developed among a relatively small group of livestock owners in the North American West  Hibbard. We alsoi.e., the distance at which the animal will respond to the handler’s presence, and uses this contact to gently move the animal according to the livestock’s instinctual responses. As ungulates generally prefer to move as a herd, handlers push individual animals towards the herd, and allow the herd to move together at a calm, yet steady pace. These techniques apparently improve livestock stress, health and yield , black bears (Ursus americanus), wolves (Canis lupus), cougars (Puma concolor) and coyotes  from the associated cattle. This predicts that the cattle guarded by a single range rider in our study (pseudo-control) would be more vulnerable than the cattle guarded by several range riders (treatment). The comparison in this study is therefore between the presence of a single rider acting as a baseline (which we define as a pseudo-control), relative to the increased human presence of multiple new riders. Alternatively, a second mechanism might be that herd stress levels predict vulnerability to predation because L-SLH would encourage and reinforce herding behaviors that reduce the risks posed by LCs. This alternative hypothesis predicts that the number of range riders is irrelevant and both pseudo-control and treatment would be effective. Also, the experience level of the range riders might affect the stress and hence vulnerability of the cattle. Accordingly, our experiment was designed to reveal if, counter-intuitively, LCs approached herds with a greater number of less experienced range riders more often, because cattle would be more stressed than cattle exposed to a single experienced range rider. Finally, a frequent unsubstantiated claim about non-lethal methods of predator control is that predators will shift to less-protected neighbors. Our design can detect this effect if herds frequently visited by multiple range riders (treatment) were visited less often by LCs than those supervised by a single range rider (pseudo-control).Here we present the first experimentally evaluation of any form of range riding and define a few of the parameters that are important to L-SLH as a non-lethal cattle protection method. We hypothesize that range riders might deter predators from cattle by two primary mechanisms: First, the presence of more humans might deter large carnivores such as grizzly bears (2) of Alberta provincial lease land in the Pekisko Heritage Rangelands area, which is part of the foothills of the southern Canadian Rocky Mountains south of the Banff-Jasper-Yoho National Park complex and north of the Waterton Glacier International Peace Park (We conducted this study on the Spruce Ranching Co-op (hereafter the Co-op), a grazing area used by 38 permitted cattle owners who collectively bring about 2,000 cow-calf pairs and 500 pregnant heifers in June of each year . The Co-ace Park . The Co-ace Park . Despitei.e., a baseline condition, which we defined as the presence of the ranch manager. We use a pseudo-control instead of a placebo-control because a placebo-control requires the treatment to be compared against the lack of treatment, which in this case amounts to no human supervision. However, in this study a true control situation cannot be created because livestock owners are unwilling to leave their livestock unattended due to known risk of LC attacks on cattle. At least four individual cattle had been injured or killed by LCs in each of the past three years prior to our study. Provincial statistics on cattle predation in our study region, which is comprised of rugged public lands where human supervision is scarce, reveal that 476 animals were confirmed attacked by carnivores between 2015–2019 , a California based non-profit. During our study, he visited every herd  at the same rate he has always done without consideration of the treatment (two range riders) schedule; (2) When the ranch manager required extra help in pseudo-control fields , he hired additional help, as he would normally do. The ranch manager therefore saw each herd on average every 9 days depending on the herd and changing conditions related to weather, his own schedule, and availability of hired helpers. Therefore, we compare the pseudo-control of ranch manager to the treatment of ranch manager with two recently trained range riders. We could only indirectly infer whether range riders are more effective than no protection.The ranch manager represents a pseudo-control because: (1) The ranch manager continued the same practices he has employed for the past 20 years. The ranch manager is highly trained in L-SLH as he has practiced these behaviors on this ranch for two decades. He began learning these methods by attending clinics with Whit Hibbard (see introduction), and now travels throughout the US and Canada discussing L-SLH with interested ranchers through workshops presented by The Working Circle (We hired two range riders (referred to as Rider A and Rider B). Protocols for this study did not require IRB approval as no data about range riders was collected. The ranch manager trained both range riders. Rider A has run their own ranch in the past and had attended L-SLH clinics with Whit Hibbard. Rider A was also familiar with the landscape but had never spent full seasons working with cattle on the Co-op before a short two-month pilot season in 2019. During the 2019 pilot season, the ranch manager trained Rider A for a week, during which time Rider A shadowed the ranch manager and spent supervised time moving cattle and learned to travel efficiently across the Co-op. Rider A also received a few days of training over the past two decades when the ranch manager hired them. Rider B had worked on the Co-op in the past, with about two decades of experience on their own land and on the Co-op. Therefore, Rider B already had some knowledge of how to travel safely and efficiently across the Co-op. However, Rider B had never been trained formally in L-SLH methods.During our study, Riders A and B received a week of training from the ranch manager, during which time they shadowed the ranch manager and helped move and manage cattle. This implies some potential “blurring” of treatment and pseudo-control as the idiosyncrasies of the ranch manager’s methods might have been transmitted to the two inexperienced riders. However, the ranch manager visited all herds including the treatment herds so his presence and behavior were a background baseline to the entire experiment and every herd (therefore a pseudo-control) and we were investigating the effect of the supplemental riders on half of the herds. Riders were responsible for the same herds, numbering up to 5 herds at a time. Riders worked together as a pair in areas where bears had recently (within the past 2 weeks) been seen, or that were heavily wooded where bears are difficult to detect. Riders worked alone when they deemed there to be no safety advantage from working in pairs. In other words, in fields with more open space. Riders therefore worked in pairs 38% of the time. All treatment herds received visits from riders working alone and in pairs. Rider A helped train Rider B who was less well versed in L-SLH. Rider pairs or single riders saw each treatment herds every 1–3 days.L-SLH practices included keeping track of cattle behaviors during range riders’ visits and encouraging cattle to bunch together when they appeared to be spread too widely across a pasture. Range riders moved cattle as described on e.g., warning shots, bear bangers and cracker shells). When possible, the ranch manager moved cattle to a new field further from recent LC presence.When range riders found dead cattle, they contacted Alberta Fish and Game (AFG) to determine the cause of death. When AFG conservation officers implicated an LC in the death, range riders spent more time with the herd, ensuring that predators did not return. If LCs were spotted, range riders or conservation officers used aversive methods  cells within each grazed pasture and selected three cells at random. Within each of these three cells, we placed cameras in locations deemed likely to be visited by LCs . We moved cameras from pasture to pasture in response to herd movements. Each pasture overlapped an average of 17 grid cells. Therefore, a selection of three grid cells only covered about 17% of each field. However, we augmented this coverage by also conducting predator surveys within pastures; these covered the entire field and included each of the three grid cells with a camera (see section on indirect sign surveys).We used 34 unbaited trail cameras to detect LC presence around herds. We monitored each herd with three cameras. To place cameras, we used ArcGIS 10.7 to create a grid of 40-acre . We define Individual LC visits as visits to a camera by a single individual of a species. A new visit by an individual of the same species began when the LC was recorded on a camera 1+ hours after the last recorded photo of an LC of that species. Our criterion of one hour between photos served as an index of frequency to estimate LC presence near subject herds. Because we were not concerned with actual abundance but rather presence of LCs around cattle, we did not identify specific individuals within each LC species of interest. Therefore, we did not determine whether individual LC’s were returning. We simply analyzed the presence of LCs.We recorded all individual LC visits and numbers of visits by camera-days (The lead author (NXL) was present the majority of the study period . NXL completed weekly surveys of LC presence focused on detecting wolf, bear, cougar and coyote activity in pastures with subject herds. These surveys included visits to each of the three trail cameras where NXL conducted systematic 100m transects along the closest animal trail to the camera. Along these transects NXL looked for scat, tracks and other signs. During each visit to a pasture, NXL also examined roads, vehicle trails, creek crossings and barbed wire fence-lines for LC signs. NXL recorded these data as presence or absence of LC by species. We examined tracks and scats whenever possible and identified them using . Therefoi.e., from possible misidentification and non-detection of sign, the LC survey data included only NXL’s observations and not those of range riders and the ranch manager. This approach also maintained the blinding of range riders to our response variable, carnivore presence. NXL blinded the second author (AT) to treatment condition during analyses. Furthermore, we cross-referenced camera photos with sign data. Not all indirect sign was captured in photos. Other aspects of indirect sign increased our confidence in species identification, such as location or type of sign.To reduce possible uncertainty in LC survey data, W = 0.94, p = 0.40), coyotes , and pooled LC , we used paired test adjusted by Hills and Armitage  and cougar  records were not normally distributed, therefore for these species we use a non-parametric Wilcoxon sum rank test to evaluate the treatment effect and order effects on wolf and cougar data  sequence results in differing LC presence relative to pseudo-control to treatment (PC-T) sequence . Data from photos were recorded as number of individual visits per camera trap day, and data from indirect sign surveys were recorded as the presence or absence of predators per sign survey. These two variables were standardized individually and then summed to determine the total presence of each LC species per day . Also, wArmitage  to analygar data . We use sequence . FurtherWe also used Spearman’s rank tests to estimate correlation between the LC presence near herds and the frequency of range rider presence. These correlations do not provide as strong inference as the above tests of treatment effects because the daily schedule of visits by range riders was not under our control. Nevertheless, our two estimates of the change in frequency of range rider visits between phases might reveal if human supervision was associated with changes in LC presence near herds. We defined the dose effect for each herd separately, in two ways: (a) the change in the number of days in which at least one range rider was present in a herd (hereafter range rider days), and (b) the change in the number of range riders summed across each phase in a herd (hereafter dose effect). For both range rider days and dose effect, we calculated the numbers in phase 2 and subtracted the numbers in phase 1 for this within-subject analysis. We correlated both (a) and (b) to the change in presence of bears, wolves, coyotes, and pooled LCs within herds as phase 2 presence − phase 1 presence. To do so, we summed LC presence across days in each phase for each herd separately. We did not analyze cougars separately because of small sample size.2) of public grazing land between July 1 and October 31, 2020 .Treated herds experienced on average 2.75 times more human presence than pseudo-control herds (average 15.5 combined visits by range riders per herd vs pseudo-control) did not predict pooled LC presence near herds in a within-subjects analysis that met the assumptions of normality and equal variance (t-test t(3) =  − 1.53, p = 0.89). Therefore, we find no support for the first hypothesis that the number of range riders had an effect. Likewise, because treatments differed from pseudo-control in the experience of the added range riders, we find no support for an effect of experience or inexperience of range riders. Furthermore, the lack of treatment effect undermines the suggestion that LCs generally were deterred from one type of range riding to the other.The treatment conditions (treatment t(3) =  − 0.21, p = 0.85) and coyote (t(3) =  − 0.35, p = 0.75) presence did not differ across treatment condition . Therefore, species-specific presence data conform to that for pooled LC showing no treatment effect (Bear (ondition . Cougar t effect .t(3) =  − 0.22, p = 0.84). We observed no difference across phases for wolves , bears  =  − 0.50, p = 0.65), coyotes (t(3) =  − 0.37, p = 0.74) and cougars .Period effects might confound comparisons by altering conditions across all replicates in unison. Pooled LC presence did not significantly differ across phases . Using a spearman’s rank correlation we found that grizzly bear presence was weakly negatively correlated with days of range rider presence , but not with dose effect, which accounted for the number of riders present summed across days in each herd . There was no effect of range rider days or dosage on black bears, wolves or coyotes, nor on pooled LC. Therefore, we infer range riders were effective in protecting cattle, given losses in prior years and other Alberta ranches (see Methods). These data support the hypothesis that L-SLH reduced vulnerability but is not definitive given our pseudo-control and lack of control over the dose of range rider presence in each herd.To account for the frequency of range rider presence on change in LC presence we examined the change in ‘dosage’ of range riders within a herd regardless of phase or treatment condition. We include the washout period   on every herd, and no livestock losses occurred during any treatment condition, we can conclude that L-SLH does not increase the risk of attack by LCs on cattle. We cannot rule out that a single experienced range rider practicing L-SLH every 9 days was as effective as one such experienced range rider supplemented by 1-2 inexperienced range riders, all practicing L-SLH and visiting herds every 3 days.We find no support for the hypothesis that the risk to cattle from wolves, coyotes, black bears and cougars is affected by the single variables of number of range riders and their experience in practicing L-SLH. However, grizzly bears appeared to avoid herds exposed to regular range rider presence. Further, because L-SLH was being practiced at different dosages  apparently killed a calf in the week preceding when we would switch that herd from pseudo-control to treatment. During the wash-out, all eight herds experienced the lowest frequency of range rider supervision because only the ranch manager visited each herd. Furthermore, the dead calf’s herd experienced an average amount of grizzly bear presence in phase 1 , it had a lower-than-average number of days with range riders  during this phase. This suggests that the lack of human presence provided an opportunity for attack but did not attract grizzlies. While this single attack does not change the statistical significance of the treatment effect, it does suggest that the addition of two newly trained range riders is more effective at reducing risk to cattle than the ranch manager working alone because it increased the number of days riders could be in the herd. Therefore, it is likely that there is a dose effect of L-SLH range riders, but more research is needed to confirm and evaluate how much time should be spent with a herd.Though the effect was not significant, wolves were observed slightly more frequently during phase 2 and near treatment herds during phase 1 of the study . The incThe second possibility for increased wolf activity in treatment herds in phase 1 is the novelty of new range riders. We presume the intelligence of wolves leads them to investigate novelties such as range riders . Carnivoi.e., ‘traditional’) livestock handling and/or a true control. This would help to determine whether other forms of human presence deter, attract or have no effect on predator attacks on livestock. True controls might involve a saddled, riderless horse with the cattle herd or visits by humans who do no herding at all. However, we demonstrate in this experiment, how difficult it is to implement a true control, as many livestock owners are unwilling to leave their herds unattended; (2) L-SLH methods should be studied to examine the number of newly trained range riders that are optimal for predator deterrence and cost effectiveness. The results of this study suggest that fewer riders may be just as effective on the predators being deterred, but that some predators, such as grizzly bears, may require a minimum amount of range riders practicing L-SLH. Further, studies comparing numbers of newly trained riders would produce evidence regarding what level of training must be attained for effective predator deterrence, particularly as there are few L-SLH-veteran range riders working today. Therefore, given a lack of further research on range riding, and a lack of consensus on the efficacy of other forms of range riding, L-SLH should be prioritized as the only form of range riding, to our knowledge, to have been experimentally tested.We observe that when properly executed L-SLH protects cattle with fewer riders. Furthermore, it is a method that is quickly taught. Our recommendations are that (1) L-SLH be tested in a randomized controlled experiment against non-L-SLH , L-SLH also presents itself as a non-lethal predator control method which is effective for both target and adjacent properties without harming the carnivores  or treatment-pseudo-control (T-PC).Click here for additional data file.10.7717/peerj.14788/supp-2Supplemental Information 2LC presence columns are based on number of days with at least one grizzly bear, black bear, wolf and coyote presence by phase is also included.Click here for additional data file.10.7717/peerj.14788/supp-3Supplemental Information 3Click here for additional data file.


Nutrition is critical to prevent some chronic diseases. Nutrition literacy refers to ability to gain, understand and evaluate nutrition facts to choose appropriate foods. Nutrition literacy has recently drawn the attention of professionals with respect to health promotion. The purpose of this study was to investigate nutrition literacy and potentially related demographic factors among workers of a steel company in Chaharmahal and Bakhtiari province, southwest Iran.In this descriptive-analytical study in 141 workers of Taraz Steel company in 2021, participants were selected by convenience sampling and a self-report nutrition literacy scale nativized to Iranians was used to collect data. Data were analyzed by SPSS 22 using Mann-Whitney U test, Kruskal-Wallis test and Spearman's correlation coefficient.P = 0.020). Also, people with adequate monthly salary attained a higher mean score on determination of food groups (P = 0.021) and higher overall nutrition literacy (P = 0.003) compared to other people. No relationship was observed between nutrition literacy and body mass index as well.About 75% of workers had adequate nutrition literacy and around 24% inadequate nutrition literacy. The highest percentage of mean score was obtained for determination of food groups (85.4%) and the lowest for calculation of food units (47%). The mean score of nutrition literacy was significantly higher in people with higher education (Most workers have adequate nutrition literacy but their scores on calculation of food units are relatively low. It is essential for policymakers to collect information on the level of nutrition literacy in different populations, especially Iranian workers, to reduce the prevalence of nutrition-related chronic diseases. One per five deaths worldwide occurs due to unhealthy nutrition . BesidesIt has been found that individuals, subpopulations and communities with higher nutrition literacy are more able to understand the nutrition facts and consequently to follow a healthy diet . These pSome studies have shown that nutrition literacy interventions may assist people of low SES in improving their nutrition , 14. In Investigating the status of and gaining knowledge about nutritional literacy is critical to adopt effective educational interventions to improve the nutritional behavior and patterns of individuals, subpopulations and communities. A previous study in Iran showed that various inappropriate eating habits including high consumption of unhealthy foods, lack of eating breakfast, and low consumption of fruits, vegetables, dairy products, and whole grains are common inappropriate nutritional habits among Iranian adults .According to the available evidence, few studies have so far been done to investigate nutritional literacy in the Iranian adults, especially the workers.Because workers usually have a low SES and have comparably less time to think about their health and improve their nutritional health and nutritional behaviors due to busy schedules, appropriate educational interventions must be designed, evaluated and implemented to improve their nutritional literacy status through gathering of relevant information. The aim of this study was to investigate nutrition literacy and its relationship to demographic variables among workers of a steel company in Chaharmahal and Bakhtiari province, southwest Iran.n = 141) were enrolled in the study by census sampling method. Inclusion criteria were being literate and volunteering to participate in the study, and the exclusion criteria were lack of complete filling out of the questionnaires and withdrawing from study.A cross-sectional, descriptive study was conducted in workers of Taraz Steel company, Iran between January, 2021 and March, 2021. First, the study protocol was approved by the Vice Chancellor for Research and Technology of Shahid Sadoughi University of Medical Sciences (Ethics code: IR.SSU.SPH.REC.1399.187), and then the necessary coordinations were made to administer the questionnaires. To this end, the studied factory was visited in person. Due to the limited size of the study population, all workers  Demographic characteristics checklist  and (2) The main scale (consisting of 35 items) to measure nutrition literacy . The 35 Ability to read and understand nutrition (six items); in this section, first a short text was provided to the respondent and he/she was asked to answer the items related to the text. Understanding food groups (10 items); in this section, 10 images related to foods were provided to participants to assign them to the relevant food group. Determination of food groups (three items); in this section, the respondent answers the items related to the daily requirement of the body to each food unit . Calculation of food units (six items); this section is aimed to evaluate ability to calculate body mass index (BMI) as well as ability to calculate the amount of calories and other information on a food label. Answers to the items are scored either 1 (correct) and 0 (incorrect/I don't know), with minimum and maximum attainable scores on the whole scale being 0 and 35, respectively. The cut-off point of the scale is 24; i.e., a score <24 indicates inadequate nutrition literacy and a score of 24 or higher does adequate nutrition literacy , 19.P < 0.05 was considered significance level.Data were coded and then analyzed using SPSS version 22. First the normality of data distribution was first analyzed by the Kolmogorov-Smirnov test. Then Mann-Whitney U test was run to examine inter-group variance, Kruskal-Wallis test to do comparisons among three or more groups, and Spearman's correlation coefficient to examine the correlations between variables. The mean age of our participants was 35.06 ± 5.85 years. Also their average work experience was 9.91 ± 6.09 years, their average family size 3.25 ± 1.57 individuals, and their average working h per day 9.91 ± 6.09 h. Other demographic information is shown in n = 106) of them had adequate nutrition literacy and about 25% (n = 35) inadequate nutrition literacy. The mean score of nutrition literacy was higher in individuals with postgraduate education than in other individuals . Around 75% (P = 0.021) and higher overall nutrition literacy (P = 0.003) compared to others. The mean score of ability to calculate food units and read food labels (P = 0.036) and total nutrition literacy (P = 0.043) was higher in workers without shift work than in those with shift work. The mean score on determination of food groups was higher in workers without a history of disease (P = 0.003). Other demographic variables  did not show a significant relationship to nutrition literacy and its dimensions (P > 0.05). The determination of food groups (85.4%) and the calculation of food units (47%) had the highest and lowest percentages of mean scores, respectively . Also family size had an inverse, significant correlation with the ability to read and understand nutrition facts (r = −0.163) and determination of food groups (r = −0.184). Working h per day showed an inverse, significant correlation with determination of food groups (r = −0.165), ability to calculate food units and read food labels (r = −0.252), and total nutrition literacy (r = −0.186). There was no significant correlation between nutrition literacy scores and its dimensions and BMI (P > 0.05)  .To the best of our knowledge, the present study is first to investigate the nutrition literacy of Iranian workers. In this study, the participants' mean score of nutrition literacy was 27.10 ± 3.74 (maximum attainable score: 35) and most (77.43%) of them had satisfactory nutrition literacy. In agreement with the present study, the results of a study in Iran on 110 primary school teachers showed that 77.3% of them had adequate nutrition literacy . A studyToday, people can easily access information about nutrition and healthy eating habits through searching the Internet. Acceptable nutrition literacy represents the capability to understand nutrition information and food groups, read food labels, and identify appropriate food units, and ultimately to make informed decisions and/or support others in choosing the right food , 23. In High nutrition literacy is believed to help people choose healthier foods and consume fewer calories . ResearcIn this study, over half of the workers had adequate nutrition literacy and nutrition literacy was directly correlated with education level and monthly salary. It is essential to determine nutrition literacy in different demographic groups to identify people with low nutrition literacy so that effective educational interventions can be designed for them to improve their food-related behaviors and subsequently nutrition literacy. Improved nutrition literacy also assists in improving nutritional health in the long term. Taken together, policymakers in Iran should constantly take into account the nutrition literacy of different populations to improve their lifestyle and reduce the incidence of some chronic diseases in them.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by Ethics code (IR.SSU.SPH.REC.1399.187) by the Vice Chancellor for Research and Technology of Shahid Sadoughi University of Medical Sciences. The patients/participants provided their written informed consent to participate in this study.MM and PY study conception and design. FM acquisition and analysis of data. SK literature review. PY and ZR drafting and edition of manuscript and acquisition and analysis of data. All authors read and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Bile acid malabsorption (BAM) represents a common cause of chronic diarrhea whose prevalence is under-investigated. We reviewed the evidence available regarding the pathophysiology and clinical management of bile acid diarrhea (BAD). BAD results from dysregulation of the enterohepatic recirculation of bile acids. It has been estimated that 25–33% of patients with functional diarrhea and irritable bowel syndrome with diarrhea have BAM. Currently, the selenium homotaurocholic acid test is the gold standard for BAD diagnosis and severity assessment. However, it is an expensive method and not widely available. The validation of the utility in the clinical practice of several other serum markers, such as 7α-hydroxy-4-cholesten-3-one (C4) and the fibroblast growth factor 19 (FGF19) is ongoing. The first-line treatment of patients with BAD is bile acid sequestrants. Patients that are refractory to first-line therapy should undergo further diagnostics to confirm the diagnosis and to treat the underlying cause of BAD. An early and correct diagnosis of BAD would improve patient’s quality of life, avoiding additional diagnostic tests that burden health care systems. Considering the limited availability and tolerability of specific medications for BAD treatment, future research is awaited to identify other therapeutic approaches, such as gut microbiota modulating therapies. Bile acid malabsorption (BAM) is a cause of chronic diarrhea first recognized by Alan Hofmann in 1967 and called cholegenic diarrhea or cholerheic enteropathy ,3,4. In Identification of papers on BAD for this narrative review, was carried out with a literature search up to 10 September 2021 with MEDLINE via PubMed, Ovid Embase, and Scopus using the following medical subject heading (MESH) terms ‘bile acids’ OR ‘bile acids malabsorption’ OR ‘bile acids diarrhea’ OR ‘SeHCAT’ was performed by four authors. Articles more relevant for the topic of this clinical review were selected without language or time restriction; references of selected articles and systematic reviews were also evaluated, when of interest. Pre-clinical, in vivo, and in vitro studies were included only in the pathophysiology section. Disagreements on the relevance of studies selected for inclusion in the review were resolved by a third independent reviewer.BAs are amphipathic molecules synthesized in the liver in a multi-enzymatic process . BAs areBA active reuptake in the terminal ileum requires the apical Na+ dependent bile salt transporter (ABST) and the intestinal BA binding protein (I-BABP), which transports BAs into enterocytes, and the basolateral heterodimeric organic solute transporter (OSTα/β), which in turn secretes BAs into the splanchnic circulation to theF portal vein . In the Besides, BAs can activate receptor G protein-coupled receptor  in the intestine the cell surface. TGR5 is an important hormonal regulator in the human body expressed in gallbladder, brown adipose tissue, skeletal muscle, enteroendocrine cells, sinusoidal endothelial cells, bile duct epithelial cells and Kupffer cells, but not in hepatocytes ,31. LCA Firmicutes, primarily in Ruminococcaceae spp. and Clostridium cluster XIVa and a reduction in the relative abundance of Bacteroides [Escherichia coli and a decrease in Clostridium leptum and Bifidobacterium, all influencing BAs pool [Clostridia bacteria, especially C. scindens [Clostridia-rich microbiota is able to enhance total BAs excretion, which is mirrored by high levels of fecal BAs and serum 7α-hydroxy-4-cholesten-3-one (C4) [Lachnospiraceae family, Ruminococcaceae family, Bifidobacterium longum, Prevotella copri, Akkermansia muciniphila and two members of the Bacteroides genus [Clostridia and the role of metabolomic as potential biomarkers responsible for BAD occurrence and target for therapy [BAM associated diarrhea (BAD) results from increased colonic motility and water secretion . These ateroides ,47. AnotBAs pool . In linescindens . Indeed,one (C4) . Anotherone (C4)  showed tes genus . This imes genus . Converses genus . However therapy . Klothoβ (KLB) interacts biochemically with FGFR4, allowing FGF19 to trigger intracellular signaling resulting in downregulation of cytochrome P450 7A1 (CYP7A1) activity and suppression of BA synthesis [Klothoβ gene and accelerated colonic transit in IBS-D [Besides, mutations and dysfunctions of constituents involved in the regulation of BAs enterohepatic circulation have been studied as possible mechanisms responsible for idiopathic BAM. In particular, FGF19, produced by the ileal enterocyte, binds Fibroblast growth factor receptor 4 (FGFR4) expressed on the hepatocyte cell membrane. A functional gene ynthesis . As mattynthesis . Besidesynthesis  explorinynthesis . Interesynthesis . On the ynthesis  identifiin IBS-D . Other ain IBS-D . FinallyThe classification of BAM is based on the causes that lead to malabsorption and diarrhea and includes four categories . Type 1 The prevalence of BAM varies in relation to the type and etiology. Type 1 BAM is secondary to ileal disfunction and it was found in 86% of patients with chronic diarrhea and CD, ileal resection or radiation enteropathy . In CD pType 2 BAM is also known as “idiopathic” BAM and manifests clinically as functional diarrhea or IBS-D, since most of these patients have no defect in bile acid absorption. The putative mechanism of this condition is due to an hepatic overproduction of bile acids and an impaired feedback by FGF19 . In a stIn a systematic review by Wedlake et al.  almost oIdiopathic BAM was also found to be associated with post-infective diarrhea. In a study by Niaz et al. , 55% of Type 3 BAM is related to gastrointestinal disorders not associated with ileal dysfunction, such as post-cholecystectomy diarrhea. Borghede et al.  reportedPatients with BAM complain an increased frequency of watery chronic diarrhea (80%) and fecal urgency (85%), associated with abdominal discomfort, which can include abdominal pain, bloating and fecal incontinence . Accordi75SeHCAT is the test with the highest diagnostic accuracy for BAM . SeHCAT Homotaurocholic acid, a synthetic conjugated bile acid, is labeled with the 75 selenium (Se) isotope mimicking the action of an endogenous BA. This radiotracer is absorbed through the intestine, excreted by the liver and reabsorbed in the terminal ileum (enterohepatic circulation) . The patvs primary fecal BAs) [This test is the first option to diagnose BAD in countries where 75SeHCAT is not available . It requcal BAs) .C4 is a serum biomarker that represents a direct measure of hepatic BA synthesis . It is aFGF19 is a hormone released by ileal enterocytes after stimulation of nuclear farnesoid X receptors (FXR), usually induced by BAs reabsorption , and it BAST empirical trial is not recommended to diagnose BAM, despite its use is justified in the absence of other diagnostic tests . Howeverp ≤ 0.01) [p = 0.001), while there was no amelioration of bowel frequency, urgency, flatulence, belching, borborygmi and stool consistency [Low-fat diet with less than 20% of daily energy intake provided from fat, associated with BASTs, is effective in improving gastrointestinal symptoms of BAD such as abdominal pain, nocturnal defecation, urgency, flatulence, stool consistency and frequency ,111. A psistency . TherefoCholestyramine, colestipol and colesevelam are BASTs available either in powder or tablet formulations. These molecules are positively charged non-digestible resins which bind BAs in the intestinal lumen forming an insoluble complex that is eliminated in stools . BASTs avs hydroxypropyl cellulose in patients with chronic watery diarrhea and SeHCAT 7-day retention ≤ 20% [p = 0.048). In another randomized trial assessing cholestyramine efficacy in BAD, patients with 75SeHCAT retention of 10% or 20% reported response rates of 40% and 53.8%, respectively [Cholestyramine is the most widely used BAST . A randoon ≤ 20% . The choectively . Howeverectively . Side efectively  and coulectively . Moreoveectively . Rarely,ectively , cholestectively ,120 due Colesevelam, is a water-insoluble polymer with a binding affinity to BAs 4–6 times stronger than cholestyramine. Moreover, it is related to higher patient compliance due to lower incidence of side effects  and fewer clinical interactions . In a siThe activation of the FXR pathway by agonist drugs such as the obeticholic acid (OCA)  is able to induce the transcription of FGF19 and the inhibition of CYP7A1,which is the first and rate-limiting enzyme in bile acid synthesis . FXR agoRuminococcaceae [Clostridia bacteria  which correlated with the levels of fecal BAs and serum C4 in IBS-D patients [Considering the ability of BAs to modulate bowel functions and their tight correlation with gut microbiota, an additional interest has been paid to the evaluation of gut microbiota in BAM in order to employ microbial modulating therapies in these patients ,89. Fecaoccaceae  and the patients . HoweverBAM is an under investigated cause of chronic diarrhea. In patients with persistent symptoms of watery diarrhea, ileal disease or following gastrointestinal surgery, bile acid diarrhea should be suspected and investigated. Difficulties in early diagnosis due to limited availability of diagnostic test, in particular 75SeHCAT, have been widely reported. Considering the limited availability of specific medications for the treatment of this condition and the poor tolerability and compliance of patients for these drugs, future research is awaited to identify other therapeutic approaches, such as gut microbiota modulating therapies.


Physical literacy has quickly gained global attention as a holistic approach to combat physical inactivity and obesity. However, research silos may limit the growth and application of the physical literacy paradigm for effective physical activity promotion. The purpose of this study was to measure the underlying network structure of scholars publishing on physical literacy  through co-authorship analysis.Data collection resulted in 1,070 documents related to physical literacy retrieved. A total of 198 articles met inclusion criteria and were included in the full network, with authors operationalized as actors in the network. A total of 75 empirical studies were included in the sub-network for critical appraisal and further analysis. Social network analysis was then conducted at the macro- and component-level, using quantification and visualization techniques.Results revealed a collaborative, yet fragmented physical literacy network with sub-groups representing substantive and geographically diverse scholars. The majority of scholarship lacked empirical evidence, suggesting a research-practice gap.Recommendations for advancing physical literacy research and practice include strategic collaborations that transcend geographic and disciplinary boundaries, cooperative efforts across scholars and practitioners, and productive discourse through professional avenues to progress knowledge generation, dispersion, and application. Physical inactivity is considered one of the most significant public health issues of the twenty-first century based on its prevalence, global reach, and health effect Blair, . The WorFrom an ecological perspective, individual , interpersonal , and environmental  factors often impede physical activity engagement among underserved populations  can be employed to characterize and quantify the social structure and interaction among scholars contributing to the physical literacy idea space Freeman, . BroadlyScholars within the physical literacy scientific community have identified an absence of empirical research to support the operationalizing, theorizing, and measuring of physical literacy ?RQ2: What is the social network structure of the global sub-network of authors publishing empirical research on physical literacy .Social network studies seeking to evaluate the global network structure of a community of people require data on the presence—or absence—of social interactions among the members of the population studied  used as a guide  published in peer-reviewed journals; (2) written in English language; and (3) utilized the phrase “physical literacy” in the title or abstract. Technical reports, book chapters, abstracts, conference presentations, and community resources were excluded. Full-text digital copies for 11 articles could not be retrieved via any available sources  and were also excludedData collection resulted in a total of 1,070 records retrieved. A backward search of reference lists from the eligible records resulted in retrieving an additional 38 records. Preliminary screening identified 365 duplicate records, once removed a total of 743 records were screened for inclusion and exclusion criteria. Upon screening, 545 records were excluded and 198 articles included in the full network see 2. Among The structure of relational webs is a central concept within global social networks  in this sub-network. The average number of authors per publication was 3.43. A total of 490 pairs of authors collaborated at least twice, 352 pairs three times, 296 pairs four times, 228 pairs five times, 120 pairs six times, 18 pairs seven times, 16 pairs eight times, six pairs 12 times, four pairs 13 times, and two pairs at least 14 times which was the maximum frequency of co-authorship.As indicated in As presented in Group 2 was composed of two researchers from Canada and one from Australia (associated with Group 5 in the full network). To frame the physical literacy construct, these authors synthesized the many definitions of physical literacy found in the literature. Research from Group 2 reflected an integration of health and education, with keywords including physical activity promotion, free play, sport, and youth development. Similar to the measurement contribution of Group 1, members of Group 2 were responsible for the development of the Physical Literacy Assessment for Youth (PLAY) tools. Members of Group 2 were also part of the Physical Literacy Research Group, responsible for the special issue on physical literacy in the Journal of Teaching in Physical Education.Group 3 included three researchers from the UK, one from Canada, and one from Australia (associated with Group 4 in the full network). Research from Group 3 seemed to focus on clarifying the definitions, foundations, and measures of physical literacy to inform policy and practice. This was illustrated by the authors' engagement with prominent groups working to promote and develop physical literacy, contribution of multiple systematic reviews of physical literacy literature, and use of keywords such as definition, policy, practice, and international. Further, members of Group 2 developed a new definition of physical literacy sensitive and appropriate to the Australian context, that can also contribute to productive scholarly debate and conceptual development of the physical literacy construct.The density of the network structure is based upon the degree of interconnectedness among all possible social ties within the social network Scott, . The denConsidering the “six degrees of separation”  and 28 components in the empirical sub-network (excluding isolates). For Newman's modularity, a relatively high value within a co-authorship network component indicates a network consists of authors that are more likely to publish papers together while a low value indicates authors are less likely to work together. The results show that scholars within the physical literacy co-authorship network were more likely to collaborate, having relatively high values of Newman's modularity for the full network (0.695) and empirical sub-network (0.630).Through SNA of the physical literacy scientific community, the network structure can reveal existing research silos and potential unifying pipelines to prompt cooperative efforts around a scientific paradigm necessary for physical literacy to be systematically leveraged for global application Crane, . To advaWhile Young et al.  identifiAs a whole, the co-authorship network tended to be geographically bound  and researchers from universities across Canada —Group 1—were identified as the most co-authored scholars  and most influential in disseminating information through the network. This finding suggests this particular collaboration may be uniquely positioned to serve as a scientific bridge within the physical literacy scholarly community. Within this cluster, Tremblay and Longmuir—the lead developers of the CAPL—were identified as the most well-connected scholars. However, the comparable closeness centrality within the full network and empirical sub-network suggests no singular leading actor in the physical literacy idea space, confirming the diversity of perspectives present.Of the 198 articles in the full network, <40% were classified as empirical studies. These results suggest a research-practice gap, aligning with Giblin et al.'s  findingsSince 2018, 47 empirical studies have been published—of which 14 came from BMC Public Health's special issue on the CAPL, contributing to Group 1's influence within the empirical sub-network. Further, seven studies came from the Journal of Teaching in Physical Education's special issue on physical literacy, contributing to Group 2's influence within the empirical sub-network. These findings demonstrate increasing interest in physical literacy evidence and intervention in the past several years. Physical literacy special issues in academic journals may foster exponential growth of the physical literacy idea space through scholars' cooperative efforts to advance physical literacy scholarship. However, these special issues may also perpetuate bias as the literature remains constrained to dominant fields , viewpoints , and measures , limiting scholars' exposure to alternative ideas necessary to re-examine and improve the physical literacy paradigm (Quatman and Chelladurai, Despite the surge in physical literacy scholarship, confusion around its conceptualization remains (Shearer et al., In reviewing consensus statements and frameworks from the countries represented in the empirical sub-network, there were subtle differences in the conceptualization of physical literacy. Canada's Physical Literacy Consensus Statement  identifiInconsistencies throughout the body of empirical literature were highlighted further in a second systematic review by Edwards et al.  from GroMuch of the available research thus far has focused on the physical education, public health, or sport/exercise science sectors within the youngest generations (Roetert et al., However, the current study demonstrates physical literacy scholarship is a fragmented network which might impede or slow down the advancement of physical literacy strategies to address physical inactivity and obesity Crane, . While tAligning with Whitehead's  holisticAn approach to building connections within the fragmented physical literacy network could be engaging in productive discourse and coordinating efforts through professional associations, conferences, workshops, meetings, as well as academic and practitioner journals. The study identified several professional avenues—such as the International Physical Literacy Association—that provide an opportunity for scholars and practitioners across disciplines to collaboratively advance physical literacy. Through innovative collaboration, the physical literacy scientific community can facilitate continued growth and application of a cumulative body of knowledge to mitigate physical inactivity among underserved populations through the promotion of physical literacy.physical literacy for a more complete picture of physical literacy scholarship. The systematic search and selection process was also limited to six major online research databases. Broadening the search to multidisciplinary databases, such as SCOPUS or Web of Science, might capture additional literature in other disciplines. Further, the current study's focus on empirical scholarship does not account for all actors engaged in the physical literacy idea space. Future research should consider examining the social network of physical literacy scholars engaged in non-empirical work that contributes to the advancement of the paradigm.While the current study extends our understanding of the physical literacy idea space, the results should be interpreted with several limitations in mind. Physical literacy literature retrieved was limited to the English language due to the authors' language barriers, which may result in bias toward the Anglo-Saxon research lens. Future scholars should consider inclusion of literature written in other languages and translated variations of the term The authors only used co-authorship to capture the individual and collaborative work of the physical literacy scientific community (Hazlett et al., The current study examined the social network of physical literacy scholars to advance the evolution, growth, research, and application of this paradigm for physical activity promotion. Study findings revealed a highly collaborative yet fragmented physical literacy network, with opportunity for greater social interactions among the scholars working in the physical literacy idea space. Of the 198 articles included in the full network, only 75 articles were classified as empirical studies. This gap between research and practice must be addressed for the physical literacy paradigm to effectively inform physical activity interventions for the goal of promoting healthy development of the whole person. Through SNA, diverse collaborative groups were identified, with implications for cooperative efforts to build a cumulative and coherent body of knowledge that enables physical literacy to be globally operationalized and leveraged for physical activity promotion. Ultimately, the physical literacy paradigm can provide a unifying framework for public health, recreation, sport, and education agencies to effectively promote physical activity among underserved populations in greatest need.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.SB, MP, and CZ collected the data and supported manuscript development. LL-H and AK analyzed the data and drafted the manuscript. LS and CQ-Y provided critical revisions of the manuscript. All authors made substantial contributions in drafting or revising the manuscript. All authors gave final approval of the version submitted.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.