Developing and enhancing societal capacity to understand, debate elements of, and take actionable steps toward a sustainable future at a scale beyond the individual are critical when addressing sustainability challenges such as climate change, resource scarcity, biodiversity loss, and zoonotic disease. Although mounting evidence exists for how to facilitate individual action to address sustainability challenges, there is less understanding of how to foster collective action in this realm. To support research and practice promoting collective action to address sustainability issues, we define the term “collective environmental literacy” by delineating four key potent aspects: scale, dynamic processes, shared resources, and synergy. Building on existing collective constructs and thought, we highlight areas where researchers, practitioners, and policymakers can support individuals and communities as they come together to identify, develop, and implement solutions to wicked problems. We close by discussing limitations of this work and future directions in studying collective environmental literacy. For socio-ecologically intertwined issues—such as climate change, land conversion, biodiversity loss, resource scarcity, and zoonotic diseases—and their associated multi-decadal timeframes, individual action is necessary, yet not sufficient, for systemic, sustained change , each person, household, or neighborhood group may understand or “see” a different part of an issue or challenge, bring a novel understanding to the table, and have a certain perspective or skill to contribute. Although some environmental literacy discussions allude to a collective lens . On the other hand, it may encapsulate environmental literacy of a group or organization united by a common identity  or cause , rather than solely or even primarily by geography. Although shifting scales can make measuring collective environmental literacy more difficult, dynamic levels may be a benefit when addressing planetary boundary issues such as climate change, biodiversity, and ocean acidification . Shared resources may also include forms of theorized capital, such as intellectual and social Putnam . Also ofFinally, given the inherent complexities related to defining, deploying, implementing, and measuring these dynamic, at-times ephemeral processes, resources, and outcomes at a collective scale, working in such a manner must be clearly advantageous to pressing sustainability issues at hand. Numerous related constructs and approaches from a range of fields emphasize the benefits of diverse collaboration to collective thought and action, including improved solutions, more effective and fair processes, and more socioculturally just outcomes Klein . These bThis synergy relies on the diversity of a group across various dimensions, bringing power, strength, and insight to a decision-making process (Bear and Woolley This paper presents one conceptualization of collective environmental literacy, with the understanding that numerous ways exist to envision its definition, formation, deployment, and measurement. Characterized by a collective effort, such literacies at scale offer a way to imagine, measure, and support the synergy that occurs when the emphasis moves from an individual to a larger whole. By expanding the scale and focusing on shared responsibility among actors at the systems level, opportunities arise for inspiring and enabling a broader contribution to a sustainable future. These evolving notions serve to invite ongoing conversation, both in research and practice, about how to enact our collective responsibility toward, as well as vision of, a thriving future.Emerging from the many discussions of shared and collaborative efforts to address socio-environmental issues, our conceptualization of collective environmental literacy is a first step toward supporting communities as they work to identify, address, and solve sustainability problems. We urge continued discussions on this topic, with the goal of understanding the concept of collective environmental literacy, how to measure it, and the implications of this work for practitioners. The conceptual roots of collective environmental literacy reach into countless fields of study and, as such, a transdisciplinary approach, which includes an eye toward practice, is necessary to fully capture and maximize the tremendous amount of knowledge, wisdom, and experience around this topic. Specifically, next steps to evolve the concept include engaging sustainability researchers and practitioners in discussions of the saliency of the presented definition of collective environmental literacy. These discussions include verifying the completeness of the definition and ensuring a thorough review of relevant research: Are parts of the definition missing or unclear? What are the “blank, blind, bald, and bright spots” in the literature Reid  p. 158? Even at this early stage of conceptualization, this work has implications for practitioners. For scientists, communicators, policymakers, land managers, and other professionals desiring to work with communities to address sustainability issues, a primary take-away message concerns the holistic nature of what is needed for effective collective action in the environmental realm. Many previous efforts have focused on conveying information and, while a lack of knowledge and awareness may be a barrier to action in some cases, the need for a more holistic lens is increasingly clear. This move beyond an individually focused, information-deficit model is essential for effective impact (Bolderdijk et al. Growing discussion of collective literacy constructs, and related areas, suggests researchers, practitioners, and policymakers working in pro-social areas recognize and value collective efforts, despite the need for clearer definitions and effective measures. This definitional and measurement work, in both research and practice, is not easy. The ever-changing, dynamic contexts in which collective environmental literacy exists make defining the concept a moving target, compounded by a need to draw upon work in countless, often distinct academic fields of study. Furthermore, the hard-to-see, inner workings of collective constructs make measurement difficult. Yet, the “power of the hive” is intriguing, as the synergism that arises from communities working in an aligned manner toward a unified vision suggests a potency and wave of motivated action essential to coalescing and leveraging individual goodwill, harnessing its power and potential toward effective sustainability solutions.


Quality improvement (QI) initiatives often reflect approaches based on anecdotal evidence, but it is unclear how initiatives can best incorporate scientific literature and methods into the QI process. Review of studies of QI initiatives that aim to systematically incorporate evidence review ) may provide a basis for further methodological development.https://osf.io/hr5bj) of EBQI, we searched the databases PubMed, CINAHL, and SCOPUS. The review addressed three central questions: How is EBQI defined? How is evidence used to inform evidence-informed QI initiatives? What is the effectiveness of EBQI?In this scoping review (registration: We identified 211 publications meeting inclusion criteria. In total, 170 publications explicitly used the term “EBQI.” Published definitions emphasized relying on evidence throughout the QI process. We reviewed a subset of 67 evaluations of QI initiatives in primary care, including both studies that used the term “EBQI” with those that described an evidence-based initiative without using EBQI terminology. The most frequently reported EBQI components included use of evidence to identify previously tested effective QI interventions; engaging stakeholders; iterative intervention development; partnering with frontline clinicians; and data-driven evaluation of the QI intervention. Effectiveness estimates were positive but varied in size in ten studies that provided data on patient health outcomes.EBQI is a promising strategy for integrating relevant prior scientific findings and methods systematically in the QI process, from the initial developmental phase of the IQ initiative through to its evaluation. Future QI researchers and practitioners can use these findings as the basis for further development of QI initiatives.The online version contains supplementary material available at 10.1007/s11606-022-07602-5. Comprehensive review and critical appraisal of relevant research, for example, is not typically emphasized or conducted.6 In practice, QI teams often use anecdotal evidence alone to shape innovations, and low-validity methods to evaluate them.7 EBQI initiatives, as a subset of all QI initiatives, aim to systematically incorporate pre-existing scientific evidence and methods into the QI process as a core focus.Evidence-based quality improvement (EBQI) is one of a growing number of strategies used to enhance quality improvement (QI) initiative impacts in clinical practice. EBQI aims to integrate scientific evidence and methods into the QI process while maintaining focus on team-based innovation and problem-solving within real-world settings. Standard healthcare QI approaches focus powerfully on the need for measurement to determine innovation effects, and teams are advised to consult subject matter experts to strengthen their work.7 Among other factors, the rapid evolution of partnership improvement initiatives between healthcare organizations and researchers, and the increasing availability of embedded healthcare researchers within healthcare organizations have made EBQI more accessible and attractive to healthcare organizations.5Given its foundation in applying best evidence and distinct focus on collaboration with the practice, EBQI is increasingly recognized as a valuable approach to structure implementation of advances in healthcare delivery.8 to our knowledge, EBQI has not been evaluated in an evidence synthesis across studies.To date, core elements of EBQI have not been well documented, leaving a critical knowledge gap about components of EBQI and how it differs from other QI approaches. In addition, evidence of the effects of employing EBQI has yet to be synthesized. We found no prior systematic reviews of EBQI, and while individual studies have shown promising results10:Review question 1: How is EBQI defined?Review question 2a: How is evidence defined in these initiatives?Review question 2b: What are the components of EBQI?Review question 2: How is evidence used to inform evidence-informed quality improvement initiatives?Review question 3: What is the effectiveness of EBQI to promote uptake of evidence-based practices?This scoping review explores the EBQI literature. We document how EBQI is defined in publications and aimed to identify key components that characterize this methodology across studies. The review catalogues definitions and characteristics of EBQI as currently used in practice. Particular emphasis was on the definition, scope, and use of evidence, i.e., the core aspect of EBQI. We also examined evidence of effectiveness of EBQI. The scoping review was guided by these review questionsOur objective was to conduct a systematic search to identify the available knowledge, provide a clear description of the methodology, and inform further development of methods for incorporating research evidence into QI initiatives.9 In addition, we conducted a consultation exercise to inform and validate findings. The project was deemed exempt by our institutional Human Subject Committee. The protocol was registered in the Open Science Framework and is publicly available.10 The reporting follows PRISMA-ScR, a PRISMA adaptation for scoping reviews.12The scoping review followed a detailed review protocol. We followed the steps outlined by Arksey and Malloy: (1) determining the research question; (2) identifying relevant studies; (3) selecting studies; (4) charting the data; and (5) collating, summarizing, and reporting the results.The literature searches are documented in the supplemental digital content . First, 19 we searched only for studies published between 2017 and 2020.Second, we used a broader search strategy aimed at identifying QI initiative evaluations that were not explicitly labeled as EBQI. We assumed that some authors may not use the term “EBQI” even when they have used an evidence-based QI strategy and describe a similar approach in the full-text publication. We applied a string of exclusion criteria to arrive at a manageable sample (see eligibility section), and given the large literature on QI interventions,We searched PubMed , CINAHL , and SCOPUS . We searched for EBQI publications without date restriction, other QI studies were limited to three years of QI publications as described below in more detail.Primary care effectiveness subsample: Among EBQI publications, we identified studies reporting effectiveness results for the evaluation of an EBQI initiative. Studies had to report on patient health, and we restricted to primary care to identify a more homogenous sample of research studies.EBQI–labeled publications: All publications using EBQI terminology were included in the data abstraction.EBQI–compatible studies: Empirical studies involving U.S. healthcare professionals, reporting on an evaluation of a QI initiative in primary care, and documenting evidence review as part of their methodology to select, design, or implement a QI intervention. Evidence review was defined as a literature review undertaken at the beginning of the project, documentation of locally generated data to determine the need for the intervention (practice-based evidence), and/or utilizing of authoritative sources such as evidence-based clinical practice guidelines. Two independent literature reviewers screened citations and full-text publications; discrepancies were resolved through discussion in the team. Reviewers first excluded all citations that did not indicate an empirical evaluation of a QI initiative. The remaining citations were screened as full-text publication, applying all eligibility criteria described in the SDC .Eligibility criteria were organized in a SPIOS  framework; full details are shown in the SDC. Briefly, we applied the following:Evidence to identify target: using evidence (data) to identify the target of the QI initiativeIterative: conducting an interactive process for selecting the QI interventionEngagement of stakeholders: reaching out within the organization to ensure a collaborative processEvidence to identify intervention: reviewing evidence  to select effective QI interventionsQI facilitation: use of facilitation of the QI processLeadership involvement: involving clinical operations leadership in the QI initiativePriority setting with leadership: setting priorities for the QI initiative together with clinical operations leadershipFrontline engagement: engaging frontline personnel early in the QI initiativeEvidence to determine success: using data to determine the success of the QI initiativeAnalytic support: using analytic support to help QI teamsData abstraction was tailored to the review questions. We used ten features in total to characterize the included studies . The information was collated in evidence tables and component tables allow a concise overview. Effectiveness outcomes were summarized in a random-effects meta-analysis.The preliminary scoping review results were presented to Dr. Lisa Rubenstein, a proponent and conceptual originator of EBQI. The formal consultation step aimed to ensure that the review addresses the right questions, identified all relevant literature, and synthesized the included material appropriately. Dr. Rubenstein was not involved in the planning of the review and assessed methods and results de novo. The consultation exercise resulted in one additional domain (priority setting with leadership) that was added to the data abstraction see .The literature searches identified 2001 citations. Of these, we obtained 496 for full-text inclusion screening. Figure We included 211 publications, detailed in the evidence tables in the SDC. In total, we identified 170 diverse publications that used the term EBQI. SDC Figure 13 or described EBQI broadly as a continuous quality improvement method.14 Rubenstein et al.15 defined EBQI as “a continuous quality improvement approach whose goal is translation of research on care delivery models into routine practice.” Figure The majority of EBQI–labeled publications did not define EBQI; only 23 of the 170 studies provided a definition or detailed description of the EBQI process. Studies highlighted different aspects of EBQI such as stakeholder engagementThe second evidence table .When we compared features across the subsets, evidence to identify the target of the quality improvement intervention was more frequently reported in EBQI–labeled studies than in EBQI–compatible studies (72% vs 43%). Across EBQI–labeled and EBQI–compatible studies, involvement of leadership in priority setting for the quality improvement target (44% vs 21%) and the provision of analytic support (36% vs 26%) were least frequently reported. EBQI studies consistently reported more EBQI features: the median number of components used within study was 7 for the EBQI–labeled sample (maximum of 10) and 5.5 for the EBQI–compatible sample. The distributions in the two sets differed statistically significantly . This gap calls into question the focus of these studies on using evidence to identify and define QI aims, a critical entry point for introducing evidence into the QI process. Most, but not all (88%) of the studies reviewed evidence to select and shape the QI intervention design, another critical entry point for applying published research, local data, and implementation science knowledge. More complete reporting on evidence use across studies would promote assessment of fidelity to the EBQI process, which is critical to evaluation of the success of the QI initiative and our ability to learn from initiatives across settings.Our review also shows that overall, there is still insufficient information regarding the effectiveness of EBQI. We only found a small number of studies using EBQI that reported on key and patient-centered outcomes, i.e., patient health, and studies addressed substantially different intervention targets, ranging from breast-feeding to depression treatment. We did not find studies that compared EBQI with other quality improvement strategies in head-to-head comparisons; hence, the effect of EBQI in the included studies was invariably confounded with the QI content. It is not known yet how EBQI compares to other quality improvement strategies, in particular quality improvement interventions that are based on anecdotal evidence. Future research should evaluate the comparative effectiveness of EBQI to provide more information on this critical aspect.19 The sampling strategy was chosen to obtain a systematic and pragmatic sample that would serve as an exemplar of EBQI–compatible studies. However, it should be noted that earlier approaches were not included, which undoubtedly left out important approaches, and EBQI–compatible approaches in other fields, such as improvements in hospitals in international settings, could have provided additional important information.Our review has several limitations. While we systematically identified all known EBQI publications, we sampled the literature for EBQI–compatible studies and restricted to those published in recent years and limited to primary care given the large QI literature.We show that EBQI is a promising and growing strategy that aims to integrate prior scientific findings and methods into QI initiatives. Commonly used EBQI features integrate evidence throughout the improvement process, from the initial developmental phase of the QI initiative through to its evaluation. Future research should clearly document EBQI processes to enable better characterization of core initiative features and should assess the comparative effectiveness and success in addressing patient-centered goals.ESM 1(DOCX 656 kb)


A new type of structural material has begun to be used in the reinforcement of deformed shield tunnels, known as filament wound profiles (FWPs). The FWPs are formed by wrapping carbon-fiber-reinforced polymer (CFRP) around steel tubes that are grouted with concrete inside. However, for practical engineering applications, the design of FWPs requires further insight into their mechanical behavior, since there is no standard method for this at present. In this study, compression and bending tests were carried out to investigate the mechanical behavior of FWPs. A reliable numerical model was established based on the test results, and the effects of the design parameters on the mechanical properties of the FWPs were analyzed qualitatively. The key design parameters of bearing capacity and stiffness were determined through numerical experiments. Based on the experimental results, a method for the calculation of bearing capacities and stiffness was proposed. It was verified that the results of the calculation formulae and the experimental results showed good agreement. Moreover, the results of the formulae were relatively conservative, and most of the errors were within 15%. Thus, this calculation method can be used to calculate the load-bearing capacity and stiffness of FWPs in practical projects. The incidence of diseases of shield tunnel linings is gradually increasing with the dual effect of the natural environment and the unexpected changes in loading conditions. Therefore, the demand for shield tunnel reinforcement is also increasing . The metBased on the idea of lightweight structural materials, FWPs have been introduced and applied to reinforce deformed shield tunnel structures in recent years . As showAs a new kind of structural reinforcement material for shield tunnels, the inspiration of FWPs comes from the concrete-filled CFRP–steel tube (CFRP–CFST) column members that are used in building structures. The mechanical behavior and failure mode of CFRP–CFST under compression , bendingIn this study, the mechanical behaviors of FWPs were investigated by component tests, to provide a foundation for the derivation of a method for calculating the mechanical properties of FWPs. Numerous numerical tests were carried out to provide data for the verification of the calculation method. With the proposed new calculation method, the mechanical properties of FWPs can be quantitatively analyzed. Moreover, the design of FWPs can be adjusted flexibly according to the reinforcement requirement of the deformed shield tunnel linings, making the usage of reinforcement materials more economical and efficient.The rest of this paper is organized as follows: The component tests of the FWPs are carried out, and the mechanical properties of FWPs are investigated and summarized. The numerical tests are carried out to analyze the influence of different design parameters on the mechanical properties of FWPs. Based on the experimental results and the numerical simulation results, the formulae are derived for calculating the ultimate load-bearing capacity and stiffness of FWPs under compression, tension, bending moment, and combined axial force and bending moment. The reliability of the formulae is verified by experimental data.Three groups of specimens were tested. They referred to intermediate products during the production of FWPs. The latter were produced as follows: Four steel tubes were integrated to a profile see a by meanThe tubes of the FWPs were composed of Q420 steel. The tensile strength of the CFRP was 4 GPa, and the elastic modulus was 235 GPa. As shown in Compression tests of the FWPs were carried out using a static loading method, and the load was applied by a 200 t universal testing machine, as shown in Four-point bending tests were carried out in a force-controlled fashion. The tested specimen beam was simply supported see c. The jaIn the bending tests, the experimental measurements concerned the strain and the deflection of the specimens. As for measuring the strains, two gauges were located each on the top and the bottom surface of the specimens. Three gauges were evenly located on the side surface, as shown in The compression test results and load–displacement curves of the members are shown in In the bending tests, there was no visible failure phenomenon of the specimens in group A until the integrated steel tubes yielded. As the displacement increased sharply, associated with the load bucking of the steel tubes at the position of the point loads see , the speThe failure mode of the specimens of groups B and C was virtually the same. Their failure process started with the damage to the bonds between the individual CFRP layers, resulting in a hissing sound. Immediately afterwards, the displacement of the tested specimens increased sharply. The failure process ended with tearing of the CFRP at the load points. This phenomenon is of great relevance in engineering practice, because it is a sign of the failure of both non-grouted FWPs and grouted FWPs. The ultimate load-bearing capacity and the stiffness under the bending test are shown in The CFRP material has one-way load-bearing characteristics, and it can only bear tensile stress, which means that the six layers of 90According to the comparison between the compression test results of group A and group B in In the bending tests, the ultimate load-bearing capacity of specimens of group B and group C was 93.0% and 127.2% higher than that of the specimens of group A, respectively see . Both thThe load was mainly borne by the steel tubes and concrete under compression, with the restriction in transverse deformation due to the CFRP. When the ultimate compressive load-bearing capacity was reached, the concrete underwent transverse deformation, and the steel tubes lost their stability and deformed outwards. The failure mode of the FWPs under compression was that the transverse deformation of the FWPs could not be limited by the CFRP, and the CFRP was torn down.In the bending tests, six layers of 90° CFRP and steel tubes contributed to the tensile stress together in the tensile area of the section, while the concrete and steel tubes bore the compressive stress together in the compression area of the section. Three layers of 0° CFRP restricted the transverse deformation of the steel tubes in the compression area of the section. When the ultimate bending moment was reached, the 0° CFRP in the compression zone at the loading point could not restrain the transverse deformation of the steel tubes and was torn down, and then the FWPs failed in the bending test. The failure mode of the FWPs under bending moment was that the CFRP was torn down in the compression zone of the FWP section because of the buckling deformation.The commercial finite element software ABAQUS6.13/Explicit was employed to simulate FWPs. The material properties are shown in research ,20. The The interactions between steel tubes and concrete cubes were simulated by the surface-to-surface contact, and the steel tubes are bound with CFRP shells.It can be seen from As shown in The load–displacement curves of FWPs with different design parameters under axial compression, axial tension, and bending are shown in In order to eliminate the influence of the dimensions on the results, the relative value index was applied for analysis. The design parameters and performance indicators were normalized and made dimensionless according to the following formula:From From From From From From It can be concluded from The ultimate tensile load-bearing capacity the Code , and theAs shown in Flat section assumption: The section of FWPs remains flat during bending, without relative slip between materials.Material stress–strain linear elasticity assumption: Concrete compression, steel compression, steel tension, and CFRP tension are all linearly elastic. The contribution of concrete in the tension zone of the section is ignored. The contribution of CFRP to pressure is neglected.The ultimate compressive strain of concrete is 0.0033.Equivalent rectangular stress distribution is used in the stress pattern of concrete in the compressive zone of the section, and the compressive strength is 0.85The derivation process adheres to the following basic assumptions:The calculation formula for The FWPs were subjected to compression bending and tension bending in the full-scale test, and the load-bearing capacity calculation formula was derived from the Code . The forThe elastic compressive stiffness (Based on the derivation process of Formula (8), the bending stiffness  and (20). After summarizing the Plane section assumption of the FWP section;The influence of local buckling of the steel tubes is not considered;The tension of the concrete is ignored;CFRP can only bear the tension in the fiber direction.The following assumptions are considered in the calculation process:As shown in It can be seen from The comparison between the The comparison between the formula of The calculation method proposed here is based on the working mechanism of the FWPs. The formula is simple and can be calculated by hand. However, the results of the calculation method are relatively conservative, and the errors are within 15% according to There have been few compression and bending tests carried out to verify the accuracy of the calculation formulae to date, but it could also be verified by new component tests and numerical simulations for the practical application of tunnel reinforcements in the future. New approaches, such as neural networks ,23, coulFrom the compression test, it can be concluded that the steel tubes and concrete bear the compressive load when the FWPs are compressed, and the 0When the FWPs bear the bending moment, the concrete cubes and the steel tubes in the compression area at the FWP section bear the compressive stress, while the steel tubes and the six layers of 90° CFRP in the tension area bear the tensile stress. The bending failure mode is that the steel tubes in the compression area of the section buckle and deform outwards at the loading point, while the 0° CFRP cannot limit the transverse deformation of the steel tubes, and the 0° CFRP is torn down.According to the sensitivity analysis of the load-bearing capacity parameters, the key parameters of compressive ultimate load-bearing capacity of FWPs are steel thickness, steel grade, and the number of 0° CFRP layers. The key parameters of ultimate tensile load-bearing capacity are steel thickness, number of 90° CFRP layers, and CFRP strength; The key sensitive parameters of ultimate bending capacity are steel thickness, steel grade, and number of 90° CFRP layers.According to the sensitivity analysis of the stiffness parameters, the key parameters of compressive stiffness are steel thickness and concrete grade. The key parameters of tensile stiffness are the steel tube thickness, the number of 90° CFRP layers, and the CFRP elastic modulus. The key parameters of bending stiffness are the thickness of the steel tubes and the number of 90° CFRP layers.According to the mechanical behavior of FWPs, the load-bearing capacity and stiffness calculation formulae for FWPs under tension, compression, bending, compression–bending, and tension–bending conditions were derived and established. The formula results are conservative and consistent with the component test results, FEA test results, and theoretical calculation results. Most of the errors are within 15%, which means the calculation method can be used for actual design.In this paper, the mechanical behavior of FWPs was clarified through component tests, and a reliable FEA model of FWPs was established. The effects of the design parameters were qualitatively summarized through parameter analysis. Based on the mechanical behaviors of FWPs and the data of FEA tests, the load-bearing capacity and stiffness calculation formula of the FWPs were established and verified. The conclusions are as follows:The formula proposed in this paper for calculating the mechanical properties of the FWPs lays the foundation for subsequent research on the design method of FWP-reinforced shield tunnels.


The MRC systems are required to give not only the correct answer but also its explanation. We use state-of-the-art PLMs to build baseline systems and adopt various unsupervised approaches to extract both answer and evidence spans without human-annotated evidence spans. The experimental results show that these models are still far from human performance, suggesting that the ExpMRC is challenging. Resources (data and baselines) are available through https://github.com/ymcui/expmrc.Achieving human-level performance on some Machine Reading Comprehension (MRC) datasets is no longer challenging with the help of powerful Pre-trained Language Models (PLMs). However, it is necessary to provide both answer prediction and its explanation to further improve the MRC system's reliability, especially for real-life applications. In this paper, we propose a new benchmark called ExpMRC for evaluating the textual explainability of the MRC systems. ExpMRC contains four subsets, including SQuAD, CMRC 2018, RACE Machine reading comprehension; Explainable artificial intelligence; Natural language processing The MRC-related study has received wide attention over the past few years. We have seen tremendous efforts to create challenging datasets However, although the state-of-the-art systems can achieve better performance than the average human on some MRC datasets with the help of pre-trained language models whether attention can be explanationsUnderstanding the intrinsic mechanism of the neural network is a challenging issue. In natural language processing field, there are several intense discussions on the relevant topics, such as +  to be annotated, containing both span-extraction and multi-choice MRC tasks in both English and Chinese. As SQuAD, CMRC 2018, C3 datasets are well-defined datasets with careful annotation procedures, we did not perform additional pre-processing. Regarding our RACE+, we follow the pre-processing steps as in RACE At this point, we have four subsets , and answers. We only need to annotate their evidence span on top of them. Before evidence annotation, the annotators are required to consider whether a question is appropriate for annotation. After removing sensitive content, we skipped some questions based on the following criteria.After the initial check, first, the annotators are asked to read the question and the correct answer (passage span or option text). Because, as the ground truth answer already exists in the original dataset, it is unnecessary to require the annotators to answer the questions again, which increases their burden when they recommend the wrong answer, and they will eventually consult the ground truth answer to find the correct evidence. Then, the annotators select (copy-and-paste) a span from the passage that can be evidence of the answer. The evidence should be a minimal passage span that can support the answer and does not always need to be a complete sentence or clause. We encourage the annotators to select the evidence that needs reasoning skills, although this is not a usual case in these datasets, especially in span-extraction MRC, where most of the questions do not need reasoning.Selecting a single contiguous span makes the task much easier for the model, or it will become a sequence labeling task. During the annotation, if a redundant span is included to form a single span, we instructed our annotator that the length of the redundant span should not exceed 30% of the valid span length. However, in most cases (over 90%), a single contiguous span is enough for our selected datasets. It could be problematic for other datasets that require long-range inference, but this does not often happen in our ExpMRC.The annotators are paid approximately $0.50 per evidence for all types of MRC data. Depending on the dataset language, the annotators are either English-majored or Chinese-majored graduate students from China.2Following previous works, we also adopt multiple evidence references for each question to maximize the inter-agreement between the annotators. During annotation, we do not reveal the annotated evidence span of the other annotators to the current annotator to increase the diversity and avoid copy-and-paste behavior. After the preliminary annotation, all evidence spans are checked one by one to ensure a high-quality dataset. Finally, the annotations are verified that the correct answer can be selected by only reading the evidence and question to ensure that the annotation is valid.3.3The statistics of the proposed ExpMRC are listed in For all subsets, we provide We also provide statistics to see what skills are needed when we find evidence text in multi-choice MRC. We can also see that the subsets of span-extraction MRC tasks exhibit more types of ‘surface matching’ (simple word matching) and ‘semantic matching’  to find evidence. While, for multi-choice MRC tasks, there are more evidences that require complex reasoning, which demonstrates that it is harder to extract evidence for these subsets.‘who, when, and where’ in RACE+ and C3, suggesting that these subsets are much more difficult, which is in line with the statistics above.The distribution of the question type in each task's development set is depicted in 4unsupervised approaches for our baseline systems, where ground truth evidence spans are not provided in the respective original training set.Given that the proposed ExpMRC is designed to evaluate the explainability in terms of the system's explanation text, we mainly focus on the 4.1predicted answer. In order to find more accurate evidence sentences, we adopt three approaches.•Most Similar Sentence: We calculate the token-level F1 score between the predicted answer span (or choice text) and each passage sentence. Then we select the sentence that has the highest F1 as the evidence prediction. In span-extraction MRC tasks, the extracted evidence is the sentence that contains the prediction span in most cases.•Most Similar Sentence with Question: Similar to the ‘Most Similar Sentence’, but we use both the question text and predicted answer span as the key to finding the most similar passage sentence.•Answer Sentence: In span-extraction MRC tasks, we can directly extract the sentence that contains the answer prediction as evidence.For non-learning baselines, we mainly use the prediction and question as the clues for finding evidence. For simplicity, we only consider extracting sentence-level evidence in these baselines, although the ground truth evidence may not always be a complete sentence. We first split the passage into several sentences using ‘.!?’ as delimiters. Then we select one of the passage sentences as the evidence prediction. As a preliminary, we should train a normal MRC system using the respective original training set that contains <passage, question, answer> to get These approaches largely rely on the accuracy of answer prediction, as an incorrect prediction will directly affect the evidence finding process.4.2•Span-Extraction MRC: The concatenation of the question Q and passage P are fed into PLM, and we use the final hidden representation with two fully-connected layers to predict the start and end positions of the answer span. The input sequence forms as in •Multi-Choice MRC: The concatenation of the passage P, question Q, and choice As no training data are provided in ExpMRC, we seek a pseudo-training approach to accomplish a machine learning baseline system. First, we generate pseudo-evidence for each sample in the respective training set, which has no evidence annotation. We use the ground truth answer and question text to find the most similar passage sentence as the pseudo-evidence to form pseudo-training data. Then we use the pseudo-training data and PLM to train a model that outputs both answer and evidence. Specifically, we add an additional task head on top of the PLM's final hidden representation, alongside its original answer prediction task, as shown in The evidence prediction is identical to the answer prediction in span-extraction MRC, where we project the final hidden representation The final training loss 55.1To evaluate how well the MRC model can generate explanations for the answers, we use the following metrics, which are divided into answer evaluation and evidence evaluation.+ and C3, we use accuracy for evaluation.For answer evaluation, we strictly follow the original evaluation script for each subset. Specifically, we use the F1-score (F1) to evaluate SQuAD and CMRC 2018. We discard Exact Match (EM) and only evaluated F1 for simplicity. Note that, as these datasets are in different languages, the evaluation details are slightly different. For RACEFor evidence evaluation, we use F1 metrics, as most of the evidence spans are quite long, and it is difficult for the machine to extract the evidence spans exactly and thus we do not adopt EM. Also, the central idea of the evidence is to provide enough information to support the answer, so it is proper to adopt F1. Note that we only evaluate the correctness of evidence in this metric, regardless of the correctness of the answer. Altogether, we also use an overall F1 metric to provide a comprehensive evaluation of the system. For each instance, we calculate the score of the answer metric and evidence metric. The overall F1 of each instance is obtained by multiplying both terms, as shown in Equation 5.2cross-validation approach that regards one of the candidates as the prediction and treats the rest of the candidates as ground truths. Final scores are obtained by averaging all possible combinations.•SQuAD, CMRC 2018: In these datasets, there are multiple references for both answer and evidence, and thus we use the cross-validation approach for both and obtain their products as instance-level human performance.•RACE+, C3: As these datasets have only one reference answer, we invite three annotators to answer a random set of 100 questions in each set to obtain the averaged human answer performance. For the evidence, we directly use the cross-validation approach for the selected random set. Similarly, the instance-level human performance is obtained by the product of the answer and evidence score.Following previous works ceiling human performance roughly. Finally, we average the scores in all instances to obtain the final overall human performance. Note that the answers and the evidences are not annotated by the same annotator, where the former is from the original dataset, and the latter is ours.Note that as the evidence spans are annotated by referring to either the answers or additional hints, the actual human performance can be lower, and thus, these results should be regarded as 66.1AdamWe use pre-trained language models as the baseline system backbones. Specifically, we use BERT-base and BERT-large-wwm 6.2The results are in Overall, the best-performing baselines are still far behind the human performance, indicating that the proposed dataset is challenging. Additionally, the gaps in multi-choice MRC subsets are larger than those in span-extraction MRC. For all subsets, adding question text for similarity calculation is more effective than only using the predicted answer. For span-extraction MRC, traditional token similarity methods seem to be more effective as the answer is already a passage span, and its evidence often lies around its context. In contrast, the pseudo-data training approach is more effective in multi-choice MRC, where the options are not composed of the passage span, which is not capable of direct mapping, and it requires similarity calculation in semantics but not only in the token-level calculation.3 development set, pseudo-data training at a large-level baseline yields better performance on both answer and evidence prediction than the others. However, its overall score of 50.7 is lower than the best-performing baseline of 50.9. After checking the prediction file, we discovered that there are more samples that have either better evidence spans for the wrong answer prediction or worse evidence spans for correct answer prediction, which decreases the overall score.Improving both answer and evidence prediction does NOT necessarily improve the overall score. For example, in the C3 using large-level PLM . This suggests that using pseudo evidence helps improve answer prediction, and we expect there will be another improvement when we use a more effective method for extracting high-quality pseudo evidence.Another interesting observation is that although pseudo-data training baselines do not yield better overall scores mostly, we see almost consistent improvements in the answer prediction accuracy, such as in C6.3To balance the ratio between the answer and evidence loss, we apply a lambda term to the evidence loss. To explore the effect of the lambda term, we select different + and C3. A possible guess is that two subtasks (answer extraction and evidence extraction) are the same in span-extraction MRC, and thus, the evidence extraction task benefits from the learning of answer extraction. However, as the evidence labels are not accurate enough, increasing the lambda term hurts the learning of evidence extraction.Overall, by increasing the lambda term, the evidence score and overall score decrease, suggesting that the pseudo-data training cannot be regarded as important as the original supervised task training (answer prediction), as the pseudo-data is not constructed by the ground truth evidence. However, in regard to the answer score, we observe that the span-extraction MRC tasks are less sensitive to the lambda term than the multi-choice MRC tasks. The optimal lambda value differs in span-extraction and multi-choice MRC tasks, where SQuAD and CMRC 2018 show a smaller value than RACE6.4In this section, we analyze the possible steps to achieve better evidence extraction performance. In addition to the ‘Most Similar Sentence with Question’ and ‘Predicted Answer Sentence’ (PA Sent.), we also provide two additional baselines for large-level PLMs. We extract the sentence that contains the ground truth answer (GA Sent.) and evidence (GE Sent.) to measure the upper bounds for those systems that only extract sentence-level evidence. The results are shown in As can be seen, the PA-GA and GA-GE gaps in span-extraction MRC are very small (approximately 3%~5%), suggesting that the current system is about to reach the ceiling performance when only using sentence-level evidence extraction. In contrast, in multi-choice MRC, we see a large gap between GA and GE, indicating that only using the answer sentence is not enough to achieve strong evidence extraction performance. The gap between GE and human performance indicates the gains from expanding sentence-level evidence to a free-form evidence span. In addition to the SQuAD task, the others yield a 5.5%~9.4% gap, which demonstrates that finding the exact evidence span in these tasks can still achieve a decent improvement.7+, C3, covering span-extraction MRC and multiple-choice MRC in both English and Chinese. ExpMRC aims to evaluate the MRC system to give not only correct predictions on the final answer but also extract correct evidence for the answer. We set up several baseline systems to thoroughly evaluate the difficulties of ExpMRC. The experimental results show that both traditional and state-of-the-art pre-trained language models still underperform human performance by a large margin on most of the subsets, indicating that more efforts should be made on designing an effective approach for evidence extraction. We hope the release of the dataset will further accelerate the research on the explainability and interpretability of MRC systems, especially for the unsupervised approaches.In this paper, we propose a comprehensive benchmark for evaluating the explainability of MRC systems. The proposed ExpMRC benchmark contains four datasets, including SQuAD, CMRC 2018, RACEYiming Cui: Conceived and designed the experiments; Performed the experiments; Analyzed and interpreted the data; Wrote the paper.Ting Liu, Shijin Wang: Analyzed and interpreted the data.Wanxiang Che: Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data.Zhigang Chen: Contributed reagents, materials, analysis tools or data.10.13039/501100012166National Key Research and Development Program of China (2018YFB1005100).This work was supported by https://github.com/ymcui/expmrc.Data associated with this study (ExpMRC datasets and baselines) have been deposited at The authors declare no conflict of interest.No additional information is available for this paper.


Gut microbes have been recognized to convert human bile acids by deconjugation, dehydroxylation, dehydrogenation, and epimerization of the cholesterol core, but the ability to re-conjugate them with amino acids as an additional conversion has been recently described. These new bile acids are known as microbially conjugated bile acids (MCBAs). The aim of this study was to evaluate the MCBAs diversity produced by the gut microbiota through a metabolomics approach. In this study, fresh fecal samples from healthy donors were evaluated to explore the re-conjugation of chenodeoxycholic and 3-oxo-chenodeoxycholic acids by the human gut microbiota. No significant differences were found between the conversion trend of both BAs incubations. The in vitro results showed a clear trend to first accumulate the epimer isoursochenodeoxycholic acid and the dehydroxylated lithocholic acid derivatives in samples incubated with chenodeoxycholic and 3-oxo-chenodeoxycholic acid. They also showed a strong trend for the production of microbially conjugated dehydroxylated bile acids instead of chenodeoxycholic backbone conjugates. Different molecules and isomers of MCBAs were identified, and the new ones, valolithocholate ester and leucolithocholate ester, were identified and confirmed by MS/MS. These results document the gut microbiota’s capability to produce esters of MCBAs on hydroxyls of the sterol backbone in addition to amides at the C24 acyl site. This study opens a new perspective to study the BAs diversity produced by the human gut microbiota. Bile acids (BAs) are terpenoids biosynthetized by the human body. BAs are produced from cholesterol in the hepatocytes, stored in the gall bladder, and released into the small intestine . SpecifiBAs carry out important functions in fat absorption thanks to their amphiphilic nature. Their role is key in the lipid metabolism. BAs form mixed micelles in the small intestine that facilitate solubilization, digestion, and the absorption of dietary lipids and fat-soluble vitamins. Micelles solubilize cholesterol in bile preventing cholesterol crystallization which may prevent gallstone formation . BAs areEnterocloster bolteae and Clostridium bolteae as the main producers of these BAs. The mechanism through which the gut microbes mediate this conjugation is still unknown, but it is thought that it could be similar to the mechanism of amino acid N-acyltransferase (BAAT) [The original set of BAs depends of the host biosynthesis. However, the final BAs pool is significantly influenced by the gut microbiota. Primary BAs are converted into the secondary bile acids by the gut microbes and, consequently , this coe (BAAT) , an enzyThe understanding of the BAs pathophysiology has been the goal of many studies in recent years which have demonstrated the relevance of the BAs and the microbiota in the development of very important diseases ,13,14. TThe aim of this study was to apply a sensitive analytical method to identify secondary BAs and new microbially conjugated bile acids ((MCBAs) by ultra-high-performance liquid chromatography coupled to mass spectrometry (UHPLC-MS/MS). Metabolomic platforms have shown to be a very adequate tool for identification and confirmation of primary and secondary BAs . This stAuthentic standards of 3α,7α-Dihydroxy-5β-cholan-24-oic Acid (chenodeoxycholic acid) and 3α-Hydroxy-11-oxo-5β-cholan-24-oic Acid (3-oxo-chenodeoxycholic acid) were purchased from Avanti Polar Lipids . Nutrient Broth (NB) was from Oxoid . l-Cysteine hydrochloride .Two healthy donors of stool samples, one male (age 44) and a female (age 30), were recruited at the Centro de Edafología y Biología Aplicada del Segura  and both gave written informed consent. The sample evaluation of two donors is adequate to describe the presence and confirmation by metabolomics of secondary and conjugated BAs, providing an appropriate number of samples to certify detection. Each volunteer provided a fresh stool sample early in the morning to perform the fermentation experiments. Samples were stored at 4 °C and further processed within one hour of donation.Institutional ethical approval was not necessary as the experiments were did not constitute an intervention study, and only fecal samples were collected, as advised by the Catholic University of Murcia  Ethical Committee. The volunteers gave written informed consent.2/H2/CO2 (85:5:10) at 37 °C. Aliquots of stool samples (10 g) were diluted 1/10 w/v in Nutrients Broth supplemented with 0.05% l-cysteine hydrochloride and homogenized by a stomacher in filter bags. Four types of samples were used: (i) BAs + fecal samples incubated; (ii) fecal samples incubated (control 1); (iii) BAs + fecal samples non-incubated; and (iv) fecal samples non-incubated (control 2). Aliquots of fecal suspensions (50 µL) were inoculated into 5 mL of fermentation medium anaerobe Wilkins Chaldean containing either 50 µm of chenodeoxycholic acid (CDCA) or 50 µm 3-oxo-chenodeoxycholic acid (3-oxo-CDCA). The chenodeoxycholic acid (CDCA) was the primary BA selected due his medium hydrophobicity and therefore his medium associate toxicity, being the study able to evaluate how the microbiota conversions modulate the initial hydrophobicity. The oxo-BA, 3-oxo-chenodeoxycholic acid (3-oxo-CDCA) was used in order to evaluate the conversion trend to produce dehydroxylateds BAs or oxo-BAs. Three replicate cultures were prepared in parallel from each fecal suspension. Two types of fecal control samples were prepared, one including incubation and one without the incubation procedure. Fecal sample controls and either CDCA and 3-oxo-CDCA (5 mL) were incubated with fecal microbiota and samples were collected after five days of incubation at 37 °C. The duration of the fecal incubation was set in order to ensure conversion procedures by the gut microbiota. Usually after 24–48 the bacteria are already in a stationary phase and it is in this phase when the secondary metabolism, which acts in this conversion, commonly occurs [g rpm. Samples were centrifuged at 3500× g for 10 min at 4 °C. The organic phase was evaporated under reduced pressure in a speed vacuum concentrator . All of these procedures were performed at CEBAS-CSIC . Extracts were then transferred to the Department of Food Analysis and Nutrition  for instrument analysis. Samples were re-dissolved in 500 µL of methanol, and filtered through a 0.22 µm PVDF filter , and they were diluted 1:2 in methanol before the UPLC-IM-QTOF-MS analysis.Preparation of fecal suspensions and subsequent fermentation experiments were performed under anoxic conditions in an anaerobic chamber  with an atmosphere consisting of Ny occurs . After tm/z range of 50–1700 at the rate of 2 spectra/s. The m/z range was autocorrected on reference masses 119.0363 and 980.0164.A metabolomics analysis was performed on a U-HPLC  coupled to a high-resolution mass spectrometer with a hyphenated quadrupole time-of-flight mass analyzer  with an Agilent Jet Stream (AJS) electrospray (ESI) source. The mass analyzer was operated in negative mode under the following conditions: gas temperature 180 °C, drying gas 12 L/min, nebulizer pressure 45 psig, sheath gas temperature 350 °C, sheath gas flow 11 L/min, capillary voltage 3500 V, nozzle voltage 250 V, fragmentor voltage 350 V, and octapole radiofrequency voltage 250 V. Data were acquired over the v/v) (B), both containing 5 mM ammonium acetate and 0.1% formic acid. The gradient started with 25% B for 2 min, increased in 1.5 min to 27% B, in 2 min to 35% B, held for 4.5 min, increased in 1 min to 43% B, held for 2 min, increased in 2 min to 58% B, held for 3 min, increased in 0.5 to 65% B, in 0.5 min to 80% B, in 1 min to 100% B, held 1 min at 100% B, and decreased to the initial conditions followed by 2 min of re-equilibration. The injection volume for all samples was 3 µL, the column oven temperature was set at 40 °C.The chromatographic analysis was mostly replicated from Reiter et al. 2021, equipped with 100 × 2.1 mm, 100 Å, 1.7 μm, Kinetex C18 column  and performed at a constant flow rate of 0.4 mL/min. Mobile phases consisted of water (A) and acetonitrile/water , compound binning and alignment (mass and RT tolerance), feature filter (absolute height), extract ion tolerance (EIC), EIC peak integration  and spectrum extraction. The pre-processing operation gave a data matrix based on 10806 entities from a full data set. The data matrix was imported to Mass Professional Profiler  for processing including log transformation and Pareto scaling [The data pre-processing was performed on all samples using Profinder software  in negative polarity mode. The pre-processing operations were set in seven configurations under the Molecular Feature Extraction (MFE) batch for small molecules. The operations included summary extraction parameters  to allow its use in the Agilent software package environment.p-value cut-off: 0.05; p-value computation: Asymptotic; Multiple Testing Correction: Benjamini-Hochberg) statistics analysis and Fold change tools were used for filtering entity candidates which were not present in the control and were detected in the samples after the incubation with BAs.ANOVA , in addition to lithocholic acid and 3-oxo-5β-cholan-24-oic acid, was the most prominent BA produced after incubation  Table 1Table 1.7 of absolute abundance, while its precursor CDCA, incubated with a concentration of 50 µM, gave a signal response of 1.39× 109. Therefore, attending the signal response differences, the results showed the relatively relevant production of the epimer. The common expected epimers ursodeoxycholic acid (UDCA), produced via 7α/β-HSDH, and isodeoxycholic acid (iDCA), produced via 3α/β-HSDH, were not observed following the analytical data provided by the referenced method [7, 1.4 × 107 and 1.73 × 107, respectively. No epimers were detected for the monohydroxylated BAs lithocholic acid and 7α-Hydroxy-5β-cholan-24-oic acid. The oxo-BAs 3-oxoCDCA, 7-oxoLCA, and 3-oxo-5β-cholan-24-oic acid were identified. The 3,7-Dioxo-5β-cholan-24-oic acid was not detected. The results showed an increase of 3-oxoCDCA and 7-oxoLCA, in case of sample incubation with CDCA, but an increment of 7-oxoLCA in the case of incubation with 3-oxoCDCA was also detected. These results can be explained due the fact that an increment of CDCA was detected in samples incubated with 3-oxoCDCA by the reversible action of 3α/β-HSDH.The iUDCA identified expressed 2.7× 10d method . LithochOnce the classical microbial conversions were evaluated, the in vitro fermentation of the secondary BA CDCA and the secondary oxo-bile acid 3-oxo-CDCA were used to investigate the conversion trends of MCBAs by the gut microbiota.The MCBAs were investigated by using an in-house database built and based in all the possible calculated conversions .The database included, in addition to BAs re-conjugated in the 24-acyl site, the mono and di esters of MCBAs on the 3 and 7 hydroxyls. According to this, a total of 226 molecules were calculated and searched.Those ions that were detected in incubated samples, undetected in control samples and matched in the MCBAs database were filtered and selected as candidates for further evaluation. No significant differences were found for both BA incubations in agreement with the classical trend of conversion. The results showed a higher accumulation of conjugated dehydroxylated BAs instead of the conjugates derived from the CDCA backbone. Eighteen MCBAs were identified after incubation with secondary BAs and only one was tentatively identified as a conjugate derived from chenodeoxycholic acid .m/z 116.0717), which in agreement with our results. Five and three conjugated molecules of valine and leucine were identified and confirmed by MS/MS, respectively. The identification of the five valine-conjugated molecules showing an equal m/z prompted us to study the occurrence of conjugates derived from hydroxyl esterifications as possible new molecules since the valine conjugate, identified as valolithocholic, can only yield three isomers of these molecules according to the previous classical conversion results. With regard to this, the valine conjugates were identified as valolithocholic acid and valolithocholate ester , prololithocholic  alanolithocholic  and arginolithocholic (arginolithocholate ester), lysocholic acid (lysocholate ester) and threonocholic acid (threonocholate ester) were detected.The precise mechanism through which gut microbes perform the different conjugations proposed in this study has yet to be described, although to describe the conjugation in the 24-acyl site, a similar mechanism to that of hBAAT within the liver involving a Cys-Asp-His triad has been suggested, with cysteine functioning as the catalytic residue for nucleophilic attack .In summary, the classical conversion is based on the production of the epimeric isoursodeoxycholic (IsoUDCA) and lithocholic acids even when the reaction starts with the oxidized BA. Leaving aside the dehydroxylation reactions, the trend is the accumulation of the epimer instead of the oxidized form. On the other hand, in the case of dehydroxylated derivatives, the accumulation of the oxidized BAs is relevant.These results were significant since the epimerization causes an alteration of the hydrophilicity of BAs . This chAccordingly, the correct performance of lipid absorption functions by BAs and their toxicity are affected by the microbial community of the host based on its ability to perform specific BA transformations. The classical conversion trend of secondary BAs may affect the final conversion into MCBAs.m/z and MS/MS fragments as well as the modifications observed in the retention times. According to the results, both the classical conversions and the new conjugation conversions change the chemical attributes by changing their hydrophobicity and therefore the BAs toxicity. BA hydrophobicity is determined by the number, position and orientation of the hydroxyl groups, as well as the amidation at the C-24 position. Regarding the magnitude of BA hydrophobicity, the order would be UDCA < CA < CDCA < DCA < LCA [Regarding the new microbially conjugated bile acids, the production of MCBAs derived from CDCA and 3-oxo-CDCA was not as relevant as the accumulation of the epimer iUCDA, which is the most relevant conversion together with the LCA production. On the other hand, the epimer isoLCA and 7β-Hydroxy-5β-cholan-24-oic acid were the BAs preferred by gut microbes to produce MCBAs. The reason why the β-hydroxylated acid backbone is used to produce MCBAs while the β-dihydroxylated is not used is unknown. In general, the mono hydroxylated sterol backbone was the only structure used for the re-conjugations . The proCA < LCA . The resThis deep study of the presence of conjugates may be of great relevance. It has been described how theabrownin alters the intestinal microbes and suppresses bile-salt hydrolase (BSH) activity. This results in the increase in levels of the ileal conjugated bile acids and the production of the inhibition of the intestinal FXR-FGF15 signaling being potential anti-hypercholesterolemia and anti-hyperlipidemia therapies . These rTherefore, the balance of epimerization, dehydroxylation and consequent re-conjugation will determine the global hydrophobicity of the BAs pool of the host and therefore the consequent reactions. The present in vitro study describes this new vision of BA conversion by the human gut microbiota in a reduced sample size, and shows the possibilities of how to explore the conversion diversity on populations affected by diseases related with changes in the pool of BAs.To summarize, the importance of BAs is a fact, and they have been related with important pathologies such as non-alcoholic fatty liver diseases, irritable bowel syndrome, steatohepatitis, colorectal cancer and type-2 diabetes ,43,44,45In conclusion, the importance of developing a greater understanding of the primary BAs and their interaction with the gut microbiota is key for unlocking the complete physiopathology of the BAs. The BAs influence has been reported to be related to relevant non-communicable diseases such as type-2 diabetes and colorectal cancer. Advancing the knowledge and understanding of these diseases is directly related with the relations of the binomial host microbes-BAs and the final pool produced. Therefore, the interaction between the gut microbes of the host and the primary BAs is a key factor in determining the final pool of BAs and their activity.This study identified leucolithocholate ester and valolithocholate ester as new microbially conjugated bile acids. This find certified the capability of the gut microbes to produces esters of MCBAs on hydroxyls of the sterol backbone in addition to amides at the C24 acyl site and therefore highlighted the presence of a new family of MCBAs produced by esterification. These new MCBAs may modify the toxicity of the original unconjugated BA, alter the farnesoid X receptor signaling, and ultimately influence i the related diseases. The newly discovered microbially conjugated bile acids open a new study perspective in the BAs field and their influence on health.


Agitated behaviors is a common neuropsychiatric symptom (NPS) in dementia, defined as inappropriate verbal, vocal, or motor activity that is not thought to be caused by an unmet need. It is frequently reported as a major problem, that impairs the quality of life for the elderly themselves and for caregivers. There has been increasing interest in the use of sedative antidepressants to treat NPS due to concerns over the safety and efficacy of antipsychotics in this setting.We aim to review clinical evidence of alternatives to antipsychoticst to manage agitation in dementia.We conduct a non-systematic review of recent evidence on dementia and agitation, using PubMed/Medline database.Although non-pharmacological interventions are the first-line treatment for agitation, it is a legitimate target for therapeutic intervention and according to previous guidelines, antipsychotic are among the most used drugs, albeit restricted because of side-effects. A substitution strategy to avoid antipsychotic prescription was highly considered, however there is limited evidence to support the use of antidepressants as a safe and effective alternative for agitation in dementia. Studies compare Mirtazapine, Selective serotonin reuptake inhibitors (SSRIs) and Trazodone and a reduced benefit in mortality is observed. However, citalopram was more effective were more likely outpatients for moderately agitation and Mirtazapine reveals being potentially harmful, in different studies.Moving forward, a greater understanding of NPS neurobiology, will help to clarify the efficacy of Antedepressants for the treatment of agitation in dementia. Benefits an also the patient and caregiver preference should be kept in mind.No significant relationships.


Exogenous BAs can serve as emulsifiers and when supplemented in broiler chicken diets, they can facilitate the absorption of fat and fat-soluble nutrients. As far as we know, no research compared the impacts of BAs on broiler chickens fed with animal fat and vegetable oil. Therefore, the current research aimed to explore the impacts of fat type and BAs on growth performance, nutrient digestibility, lipid metabolism, and breast muscle fatty acids composition in broiler chickens. The results showed that the positive impacts of BAs were obvious for broiler chickens fed diets with lard compared with soybean oil.p < 0.05). The level of saturated fatty acids, monounsaturated fatty acids (MUFAs), and the n-6 to n-3 polyunsaturated fatty acids ratio in breast muscle were also increased (p < 0.05) when feeding lard versus soybean oil. Dietary supplementation with BAs elevated average daily gain and reduced the ratio of feed to gain at d 0–21 and 0–42, significantly (p < 0.05). The digestibility of EE in diets and the percentage of breast muscle on d 42 were also increased by BAs (p < 0.05). Serum total cholesterol content as well as the percentage of abdominal fat on d 42, and ALT activity on d 21 were decreased when BAs were fed (p < 0.05). The concentration of total fatty acids, saturated fatty acids, and MUFAs of breast muscle were decreased by BAs. These results indicate that BAs can increase growth performance and nutrient digestibility, elevate carcass characteristics, and improve lipid metabolism, and their effects on nutrient digestibility and carcass characteristics were more pronounced in broiler chickens fed diets with lard.The current study aimed to explore the effects of fat type and exogenous bile acids (BAs) on growth performance, nutrient digestibility, lipid metabolism, and breast muscle fatty acids composition in broiler chickens. A total of 432 one-day-old Arbor Acres male broilers were stochastically distributed to a 2 × 2 factorial design comprised of two fat types (soybean oil and lard) and two levels of BAs (0 and 80 mg/kg) included in diets, totaling 4 treatments of 6 replicate pens with 18 chicks per replicate pen. Compared with treatments with soybean oil, dietary inclusion of lard increased the digestibility of ether extract (EE) in diets and the percentage of breast muscle on d 42, and increased the level of serum triglycerides and decreased serum alanine aminotransferase (ALT) activity on d 21 ( The energy value of fats is at least twice those of protein and carbohydrates ,2. They In general, BAs are a series of compounds composed of a hydrophobic face, a concave hydrophilic face, and a lateral chain . They arThe dietary sources of fats and oils mainly include vegetable oils and animal fats that are individually abundant with UFAs and saturated fatty acids (SFAs) . It has The current study was performed in the FengNing Research Unit of China Agricultural University  and all animal process was authorized by the Institutional Animal Care and Use Committee of China Agricultural University . Shandong Longchang Animal Health Care Co. Ltd.  provided us with the experimental porcine BAs; the total BA level was over 95.0%. Their composition was tested by high-performance liquid chromatography: HDCA (70.87%), CDCA (19.95%), and HCA (7.53%). These porcine BAs were processed from porcine bile through a series of physicochemical means.A total of 432  one-day-old male Arbor Acres broilers were bought from Arbor Acres Poultry Breeding Company . They were stochastically distributed into a 2 × 2 factorial design composed of 2 fats (soybean oil and lard) and 2 BAs levels (0 and 80 mg/kg) included in diet, totaling 4 treatments with 6 replicate pens of 18 broiler chickens. Experimental treatments were listed as follows: SO (diets included with soybean oil), LO (diets included with lard), SB (diets included with soybean oil supplemented with 80 mg/kg BAs), and LB (diets included with lard supplemented with 80 mg/kg BAs).Broiler chickens received water and feed ab libitum, and lights were turned off for an hour every day. During the first three days, room temperature started at 35 °C and was lowered 3 °C every week to finally achieve 24 °C. The relative humidity was 45–55%. At the end of the first and second week, broiler chickens were vaccinated against Newcastle disease. Inactivated infectious bursa disease vaccine was inoculated to all chickens when the second and fourth weeks finished.Nutrients formulated in experimental diets satisfied even surpassed the suggested values suggested by the NRC  Table 1Table 1. Weight of body and weight of feed intake were noted on d 21 and d 42. Average daily gain (ADG), average daily feed intake (ADFI), and the ratio of feed to gain (F:G) at d 0–21, d 21–42, and d 0–42 were computed with the above corresponding values, following the formulas: ADG = (Average finish weight—average start weight)/Age (days); ADFI = Total feed consumption per chick/Age (days); F:G = ADFI/ADG.feed × Nutrient feces)/(Cr feces × Nutrient feed).Diets were added with chromic oxide during d 35 to d 42 at a level of 3.0 g/kg feed, serving as the marker to measure the digestibility of DM, CP, EE, and gross energy (GE). About 100 g of feces from every replicate was collected on d 40, 41, and 42. The feces were pooled within a replicate and dried at 65 °C, then DM, CP, EE, and GE were analyzed according to the methods that are the same as that used for the analysis of diets. The GE and chromium in diets and feces were measured with 6400-Automatic Isoperibol Calorimeter  and atomic absorption spectrophotometer , respectively. Calculation formula of digestibility: digestibility (%) = 100% − 100% × , triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), and the activity of aminotransferase, i.e., alanine aminotransferase (ALT) and aspartate aminotransferase (AST). These parameters were tested by commercial kits  with an Automatic Biochemical Analyzer .About 20 g of breast muscle from each repeat collected on day 42 were lyophilized in a lyophilizer for 60 h and the lyophilized muscle samples were smashed in the pulverizer for fatty acid analysis. Fatty acid profiles of breast muscle were analyzed with gas chromatography  and followed instructions reported by Sukhija and Palmquist . The prep < 0.05), then a comparison of the means was conducted using Tukey’s multiple range test. Statistical significance was based on a p-value less than 0.05.Data of this study were analyzed as a 2 × 2 (fat type × BAs) factorial design of treatments by two-way ANOVA with the GLM procedure of SAS 9.2 . This model was comprised of the impacts of fat type and BAs as well as the interaction of fat type and BAs. If the interaction between fat type and BAs tested differently, significantly (p > 0.05). The supplementation with BAs elevated ADG and reduced F:G at d 22–42 and d 0–42 (p < 0.05). The interaction between fat type and BAs was not observed .The breast muscle percentage of broiler chickens was increased by diets with lard in comparison with diets with soybean oil . An interaction between fats and BAs was not found in nutrient digestibility (p > 0.05).Diets included with lard increased EE digestibility in broiler chickens compared to diets with soybean oil . On d 42, BAs lowered the content of serum TC and HDL-C (p < 0.05).Compared with diets included with lard, diets with soybean oil decreased serum TG content and increased the activity of ALT in broiler chickens on d 21 . The level of MUFAs, SFAs, and total fatty acids were comparable in soybean oil groups with or without BAs, whereas BAs decreased their level when feeding broilers with diets that included lard (p < 0.05).Compared with diets with lard, soybean oil diets elevated the concentration of polyunsaturated fatty acids (PUFAs), n-6 PUFAs, n-3 PUFAs, and P/S, and decreased the n-6 to n-3 PUFAs ratio of breast (BAs are synthesized through an enzyme-catalyzed reaction from cholesterol in liver perivenous hepatocytes in vivo . Upon foBesides the positive effect of BAs on lipids digestion, the degree of unsaturation of dietary fats also affects the intestinal digestion of lipids. Vegetable oil containing high concentrations of UFAs is easily digested and better absorbed than animal fat . HoweverThe carcass characteristic is one of the essential indexes for the economic efficiency of broiler chickens. Previous studies reported that exogenous BAs could improve carcass characteristics through lowering valueless abdominal fat accumulation and elevating muscle production such as leg and breast ,18. ThisDe novo fatty acids synthesis mainly occurs in the liver of broiler chickens, and triglycerides are transported from the liver to peripheral tissues through LDL and from peripheral tissues to the liver through HDL ,32. In tBAs, acting as signal molecules, can improve not only lipid metabolism but also glucose utilization and inflammation through FXR and G-protein-coupled bile acid receptors. Furthermore, bile acid receptors have become a popular potential treatment for liver diseases such as nonalcoholic fatty liver disease, liver inflammation, and fibrosis, and are beneficial for liver health . Liver-rThe nutritional value and characteristic flavors of meat are related to their fatty acid content. It has been reported that UFAs can serve as essential precursors to produce fatty aromas and characteristic flavors of chicken meat through oxidative decomposition and the Maillard reaction . AdditioDietary supplementation with BAs increased growth performance and nutrient digestibility, improved carcass characteristics, as well as reduced lipid deposition. Moreover, the effects of BAs were more obvious for broiler chickens fed diets with lard than for those with soybean oil. Thus, BAs work better with dietary fats with a higher degree of saturation.


This study aimed to assess the methodological and reporting quality of the guidelines and consensus on calcium and vitamin D supplementation in healthy children, and the consistency of these recommendations.A systematic search of relevant guideline websites and databases, including PubMed, Embase, CNKI, WangFang, and SinoMed, was undertaken from inception to April 7, 2021, by two independent reviewers who assessed the eligible guidelines using the validated Appraisal of Guidelines for Research and Evaluation Instrument II (AGREE II) and the Reporting Items for Practice Guidelines in Healthcare (RIGHT) tools. Overall, the between-reviewer agreement was evaluated using an intra-class correlation coefficient.A total of 24 guidelines and consensuses from 2002 to 2022 were identified from China, the United States, Canada, France, Australia, New Zealand, Europe, and other countries and regions. These were of mixed quality, and scored poorly in the rigor of development, editorial independence, and applicability of the domains of AGREE II. Among the seven domains of the RIGHT checklist, domain one (basic information) had the highest reporting rate (69.3%), whereas domain five  had the lowest reporting rate (11.5%). The overall quality of the included guidelines and consensuses was low. Only 12 guidelines were recommended, with modifications. The recommended calcium intake for children of different ages varies greatly . Among the included guidelines and consensuses, a vitamin D (VD) prevention dose of 400 IU/day in infants was generally considered safe, and 25-hydroxyvitamin-D [25(OH)D] levels of <20 ng/mL (50 nmol/L) or 20–30 ng/mL (50–75 nmol/L) indicated VD deficiency or insufficiency. However, the recommended amount of VD for children of different age groups and risk strata differed considerably . The choice of VD2 or VD3 supplements and sunlight exposure also differed across the guidelines and consensuses.There is considerable variability in calcium and VD guidelines and consensus development methods in calcium and VD supplementation for healthy children. Therefore, efforts are necessary to strengthen the methodological rigor of guideline development and utilize the best available evidence to underpin recommendations. Calcium, the most abundant mineral element in the human body, is pivotal for good bone health and can enhance muscle function and immunity. Vitamin D (VD) plays a critical role in regulating the balance between calcium metabolism and bone formation in the human body. Currently, calcium or VD deficiency is one of the biggest global public health problems, and studies from both developed and developing countries have shown that calcium and vitamin D deficiency is highly prevalent in children –3. CurreAt present, several guidelines are accessible on calcium and VD supplementation for healthy children worldwide. However, the recommendations differ in terms of the necessity of routine calcium and VD supplementation in healthy children, the dosage and upper limit of supplementation, and the source of supplementation, which complicates the clinical decision-making and limiting the choices available to patients and their families for these issues. Clinical practice guidelines are based on systematic reviews of evidence that balance the benefits and harms of different interventions and provide patients with recommendations on the best health practices . High-quIn this study, we aimed to evaluate the characteristics, methodological and reporting quality, and related recommendations of clinical practice guidelines and consensuses on calcium and VD supplementation in healthy children.This study was performed in accordance with the guidelines from the preferred reporting items for systematic reviews and meta-analyses (PRISMA).1 GIN,2 NICE,3 SIGN,4 IPGRP,5 WHO,6 AAP,7 ASN,8 and FENS9 were systematically searched. The search strategy combined the keywords  with various expanded keywords (“guideline” or “consensus” or “recommendation”) from inception to April 7, 2021 . A supplementary search was also performed in the references of the included studies. The details of the search strategy are shown in PubMed, Embase, CNKI, WangFang Data, and SinoMed databases, and the official websites of AHRQ,The inclusion criteria were as follows: (1) papers that included guidelines or consensus on calcium or VD supplementation  for healthy children  and reference nutrient intake (RNI); while relevant statements of “non-healthy children”, such as premature infants, low birth weight infants, overweight/obese children, nutritional rickets, and the use of drugs affecting vitamin D metabolism, were not included in the consideration of this study); (2) papers in which the guideline developers were professionals or had academic associations in healthcare; and (3) papers in which the language was limited to English and Chinese.The exclusion criteria were as follows: (1) papers in which the target population was preterm infants; (2) papers in which the specific recommended dose was not mentioned; (3) papers with an unavailable full text; (4) papers that used older versions of the included guidelines; and (5) papers that included guidelines reviews, translations, interpretations, or other non-original guidelines.According to the inclusion and exclusion criteria, two reviewers (H.L.Z. and Z.P.X.) independently extracted the characteristics of the included guidelines and consensuses based on a standardized and pre-designed form. The extracted items included the first author, publication year, country or region, developing organization, guideline development methods, assessment methods of evidence quality, and recommendation formation methods. Any disagreement was discussed or resolved by consulting a third reviewer (Z.S.D.).10 and relevant examples, only when two reviewers have high consistency (ICC > 0.85), the formal appraisal was conducted.Before the formal AGREE II and RIGHT evaluations, two reviewers (H.L.Z. and Z.X.) systematically learned the AGREE II online tutorial trainingIntra-class correlation coefficients (ICC) were used to assess the consistency of the reviewers’ understanding of each item. Then, the guidelines and consensuses were evaluated independently by the two reviewers in line with the AGREE II and RIGHT statements, and any disagreement was resolved by discussion with a third reviewer (Z.P.X.).Appraisal of Guidelines for Research and Evaluation Instrument II  was usedThe RIGHT checklist provided reviewers with clear, explicit descriptions of guideline development processes and procedures and the evidence used to formulate each recommendation. It consists of 22 key items organized within seven domains. Each item was scored as fully reported (1 point), partially reported (0.5 points), not reported (0 points), or not applicable (0 points). The reporting rate was defined as the ratio of the obtained score to the maximum possible score.We comprehensively summarized the recommendations of calcium and VD supplementation guidelines or consensuses in healthy children and compared their similarities and differences. We discussed the recommended intake and supplementation of calcium and VD for healthy children of all ages; the appropriate level of 25-hydroxyvitamin-D (25(OH)D), VD2, or VD3 supplements; and sunlight exposure suggestions.Microsoft Excel 2019 was used to sort out the scaled scores of AGREE II and RIGHT in each domain. Descriptive statistics, including median and interquartile range (IQR) (or mean and standard deviation [SD]) and percentage analyses, were performed for the standardized scores of each domain. The consistency between the two reviewers was measured by calculating the ICC with a 95% confidence interval (CI) using IBM SPSS 25.0. ICC scores of >0.75 indicated acceptable consistency .The search initially yielded 7,874 records, and 24 guidelines and consensuses were finally included, 12 guidelines were evidence-based, four were non-evidence-based, and eight were consensus, all of which were developed by local or international medical societies. One guideline  was globOverall, the ICC scores were > 0.80 in each domain, suggesting good agreement between the reviewers. Only 12 (50%) guidelines and consensuses were “recommended with modification,” and the rest were “not recommended.” The quality of the domains was heterogeneous. With respect to the overall domain scores across all guidelines or consensuses, the first domain (scope and purpose) scored the highest with a median score of 83.3%, and the third domain (rigor of development) scored the lowest with a median score of 18.8%. The sixth domain  and fifth domain (applicability) scored < 30%. Regarding the clarity of presentation, 88% (21/24) of the recommendations were specific and unambiguous, 79% (19/24) presented different options for management of the condition or health issues clearly, and 71% (17/24) had easily identifiable key recommendations. In contrast, the weakest area of the analyzed guidelines was rigor development. Only one fifth of the guidelines and consensus were externally reviewed by experts before publication , and even fewer guidelines provided a procedure for updating the guidelines . A comprehensive evaluation was conducted in combination with various domains, and the overall quality of the included guidelines and consensuses was low. The ICC and AGREE II scores of each domain are summarized in The ICC scores for all domains were > 0.80, demonstrating considerable consistency between the reviewers. The mean overall reporting rate was 42.3 ± 14.3%, ranging from 24.3 to 69.7%. Among the seven domains, basic information received the highest reporting rate (69.3%), whereas review and quality assurance received the lowest reporting rate 11.5%). A comprehensive evaluation of various domains revealed that only seven guidelines had an overall score of over 50% .5%. A co, 27, 28.The overall quality of the included guidelines and consensus was low, and the comprehensive methodological quality and reporting quality of evidence-based guidelines are higher than those of non-evidence-based guidelines and consensus. Only seven guidelines were recommended with modifications, and had an overall reporting rate of over 50%. The AGREE II score and RIGHT reporting rate summary analysis results are shown in A total of three calcium supplementation guidelines and consensuses , 21, 30,The daily intake recommendations for calcium or VD vary considerably according to the guidelines and consensuses referenced. Regarding the preventive calcium dose, two guidelines  recommended calcium supplementations for children ranging from 400 to 1,150 mg per day.Regarding preventive VD dose, most guidelines  recommended daily intake ranging from 400 to 600 IU/day. A total of five guidelines and consensuses recommended an upper limit dose ranging from 1,000 to 4,000 IU per day. An additional file shows this in more detail in Regarding the choice between VD2 and VD3 supplements, three guidelines and consensuses were considered both to be equivalent , 14, 15,Seventeen guidelines and consensuses 71%, 17/24) recommended obtaining VD from sunlight to maintain bone health. Meanwhile, 20 guidelines and consensuses  recommended serum concentration levels of 25(OH)D greater than 50 or 75 nmol/L , and used words, such as “optimal,” “sufficient/sufficiency,” “adequate,” “at least,” and “obtain and maintain.” An additional file shows this in more detail in  recommenvia its active hormonal form, 1,25-dihydroxycholecalciferol , working together with the parathyroid hormone to maintain calcium homeostasis  The guidelines and consensuses should include the participation of multidisciplinary teams, such as methodologists and health economists. (2) Patient values and dietary preferences in the developmental stage must be considered. (3) A comprehensive literature search strategy with clear inclusion and exclusion criteria should be reported in detail. Quality evaluation, classification of evidence, and the development process or method of forming recommendations should also be described. The quality of the evidence supporting the recommendation  and the strength of the recommendation  should be described so that users or readers of the guideline can accurately understand and apply the guideline. When developing recommendations, it is necessary to consider not only the effectiveness, but also safety using supporting data. (4) Adequate declaration and management of conflicts of interest should be carried out. (5) Lastly, the quality evaluation tool of guidelines should include guideline register protocols to increase the transparency of the guideline development process.Similarly, the RIGHT evaluation results suggest that the overall reporting quality of the guidelines and consensuses was low. The domain with the highest reporting rate was basic information, and that with the lowest reporting rates were evidence, review, and quality assurance. The following issues still need to be addressed: (1) The year of publication should be indicated in the title or subtitle of the guidelines for a clearer understanding of users. (2) The target population and guideline setting should be reported clearly and accurately, so that the guidelines can be better promoted and applied. All contributors who participate in the guidelines development and their roles should be described. (3) It is recommended that the key issues of the guidelines be provided in the population, intervention, comparisons, and outcomes format. (4) The description and specifications of the review and quality control procedures should be addressed. (5) Conflicts of interest and their management strategies should be fully reported to improve the credibility of the guidelines. (6) Finally, relevant reports on the accessibility of the guidelines, limitations, and suggestions for future research should be increased.The guidelines and consensuses of different countries or regions differ greatly in recommendations regarding the necessity, dosage, and upper limit dose of calcium supplementation and VD in healthy children. The possible reasons underlying these differences are as follows: (1) Guidelines and consensuses regarding the definition of VD deficiency remain controversial, and test methods for serum 25(OH)D levels have not been standardized; (2) regions with different latitudes and altitudes differ in sunlight intensity, and there are differences in the basic VD status of healthy children, resulting in inconsistent recommended serum 25(OH)D thresholds , 25; (3)The adequacy of vitamin D in the body can be estimated by measuring the serum 25(OH)D concentration. Most guidelines and consensus recommend that the serum 25(OH)D concentration should be higher than 20 ng/mL (50 nmol/L). Studies , 43 haveTo the best of our knowledge, this is the first review of the recommendations on calcium and VD supplementation in healthy children, based on the AGREE II and RIGHT evaluations. Previously, researchers have evaluated the quality of the guidelines on VD supplementation in children with VD deficiency , 47. HowSome limitations indicated are as follows: (1) As calcium or VD supplementation in healthy children is quite common in various countries, this study did not include some non-English guidelines, resulting in a language selection bias. (2) Some items of the AGREE II or RIGHT evaluations lacked clear criteria for judgment or were determined to be inapplicable. Therefore, we could not rule out the subjectivity of certain item evaluations, and the scoring scale needs to be further optimized and refined. (3) There may be contradictions in that the guideline qualities were low, but are widely used in clinical practice. This is because the AGREE II instrument can only be used to evaluate the guideline formation process rather than the actual validity of the guideline recommendations. To address the conflicting question of methodological quality and clinical validity, other evaluation tools should also be combined, such as AGREE-REX .Recommendations on calcium and VD in healthy children showed substantial variation in a set of 24 guidelines and consensuses across countries worldwide. Further research is needed to explore the reasons for these differences, providing scientific basis for the formulation of public health strategies for children. A team of clinicians, nutritionists, methodologists, health economists, etc., will develop localized recommendations based on the characteristics of the region. The methodological quality and reporting quality of the existing guidelines and consensuses in healthy children must be improved. Guideline developers need to strengthen the standardization of the guidelines to improve their quality and formulate trustworthy recommendations.The original contributions presented in this study are included in the article/PZ and SZ conceived and designed the study. LH and PZ conducted the data screening and extraction. LH and XZ appraisers with experience in quality assessment of guidelines, scored each guideline using the AGREE II instrument and RIGHT statement and collected and analyzed the data. LH wrote the first draft of the manuscript. PZ, SZ, ST, and JH critically revised the manuscript in response to feedback. All authors have read and approved the final manuscript.