As sustainable development practitioners have worked to “ensure healthy lives and promote well-being for all” and “conserve life on land and below water”, what progress has been made with win–win interventions that reduce human infectious disease burdens while advancing conservation goals? Using a systematic literature review, we identified 46 proposed solutions, which we then investigated individually using targeted literature reviews. The proposed solutions addressed diverse conservation threats and human infectious diseases, and thus, the proposed interventions varied in scale, costs, and impacts. Some potential solutions had medium-quality to high-quality evidence for previous success in achieving proposed impacts in one or both sectors. However, there were notable evidence gaps within and among solutions, highlighting opportunities for further research and adaptive implementation. Stakeholders seeking win–win interventions can explore this Review and an online database to find and tailor a relevant solution or brainstorm new solutions. Ecosystem degradation can exacerbate infectious diseases that have long plagued humankind or cause novel pathogens to spillover from animals to humans.Of course, no single win–win intervention will work in all contexts or solve all problems within complex socioecological systems.Unfortunately, the information needed to identify, implement, and evaluate win–win interventions that prevent or control human infectious diseases tends to be scarce, inconsistent, and unconsolidated.To facilitate timely, evidence-based decision making, we review existing evidence regarding win–win solutions that aim to simultaneously reduce human infectious disease burden and advance conservation goals. We use the terms intervention and solution interchangeably because there are growing policy initiatives for enacting nature-based solutions.The 46 potential solutions addressed diverse threats, collectively covering all continents (except Antarctica), most major pathogen groups (except fungi), and most conservation threat classes defined by the International Union for Conservation of Nature .Most solutions addressed pathogens with environmentally mediated transmission, such as vector-borne diseases and zoonotic diseases transmitted from animals to people , mirroriOnly a few potential solutions addressed diseases without environmentally mediated transmission, such as HIV/AIDS and pneumonia. For example, people with poor health due to HIV/AIDS or other diseases are more likely to use easier and more destructive fishing practices in communities near Lake Victoria in Africa, so treatment and prevention programmes might support both human health and aquatic conservation.In addition to addressing diverse health threats, the potential solutions also addressed all IUCN conservation threats related to anthropogenic activities . SolutioWe did not include a collective case study in which climate change was the primary conservation threat and global emission reduction was the solution  because The conservation and health threats targeted by potential solutions spanned from subnational extents within single countries to multiple countries within a continent to global applicability . For exaThere were 27 potential solutions that involved implementing classic conservation interventions that have health benefits . For example, health system strengthening or family planning and reproductive health programmes—including population, health, and environment programmes in many countriesFinally, 13 potential solutions acted through interventions that were not specific to public health or conservation, but affected both sectors . Many of these were policies regarding the food–energy–water nexus,Examples of each lever type are illustrated in The diversity among potential solutions is promising because “there is no one-size-fits-all approach for One Health implementation”.To evaluate potential trade-offs caused by a given intervention, we suggest considering three viability criteria : (1) harContext dependency was common among the 46 potential solutions. For example, introducing invasive predators that consume larval mosquitoes to control malaria has often negatively impacted ecosystems ,Convention on International Trade in Endangered Species), and there is increasing, but not universal, public support for bans or restrictions on luxury commercial wildlife trade in Asia due to the 21st century coronavirus outbreaks.Similarly to most solutions, those that address pathogen spillover from wildlife to humans had data gaps regarding trade-offs. For example, wildlife trade is a conservation threat and pathway for spillover from wildlife.Two criteria can be used to determine whether solutions are immediately achievable . Impactful solutions have the potential to meet stakeholders’ quantitative goals  and effective solutions can successfully achieve the desired outcomes. For example, building nest boxes to increase local predatory bird populations is proposed to control the rodent species that are reservoirs for hantaviruses.We categorised existing evidence quality for each potential solution using a modified Bridge Collaborative rubricThere were seven solutions that already had medium to high evidence quality for conservation and human health success . For exaThere were 17 potential solutions that had low overall evidence quality due to low evidence diversity, applicability, or consistency that was difficult to explain for one or both outcomes. For example, two observational studiesIn addition to goals , stakeholders also have resource constraints. Resources determine which solutions can be implemented at the necessary scales and intensities to achieve the desired outcomes  and how big the impact will be for a given resource budget . Various stakeholders might evaluate these four criteria differently because of differing goals, priorities, and resources.We note that resource costs and affordability are distinct; cost is the resource price tag whereas affordability is the ability to pay. For human infectious diseases, public health intervention cost-effectiveness is usually quantified in disability-adjusted life-years (DALYs) averted per US, Canadian, or Australian dollar but DALYs and cost were rarely reported for the 46 potential solutions. This omission highlights an important area for future research because for most stakeholders, and perhaps especially those interested in human health outcomes, cost-effectiveness and affordability will be the most important considerations when choosing a solution.For some of the proposed solutions, the potential conservation and health impacts would likely be too small for most stakeholders to justify the cost. For example, invasive python control in Florida reduces predation pressures on native vertebrates and might reduce human exposure to the vector-borne Everglades virus.Quantifying the net value associated with all positive impacts in all sectors for a given intervention is difficult. However, identifying these potential impacts explicitly can help stakeholders to compare multisector interventions.Data-limited solutions that appear safe and feasible could be ideal for immediate research and adaptive implementation. However, strict adaptive implementation requires that multiple interventions are implemented simultaneously and compared, and approaches are subsequently modified according to what works best.10The growing Planetary Health field emphasises the links between human wellbeing and ecosystem integrity, but there has been scarce guidance for how to leverage these relationships to implement viable win–win solutions that specifically reduce human infectious disease burden. Here, we identified 46 such potential solutions. We found that proposed solutions address diverse, context-dependent, and dynamic threats with cross-sector interventions that are equally diverse. Numerous solutions had the potential to be safe and feasible under predictable contexts and some were supported by medium and high quality evidence of success. Some solutions had the potential for large human health or conservation impacts, such as forest conservation projects and health system strengthening initiatives. Others had small effects but might still be highly valued by local stakeholders. Synergies such as these might be pivotal for achieving the soon-to-be-revised Sustainable Development Goals.101Although promising, all the proposed solutions had some evidence gaps and, collectively, they did not cover all possible health and conservation threats. Evidence regarding conservation and health impacts (quantitative outcomes) and intervention cost-effectiveness and affordability were especially scarce, highlighting priorities for future research. Currently, these data gaps within and among solutions complicate decision making. More evidence will accumulate when stakeholders invest in research, adaptive implementation, monitoring, and evaluation for existing approaches. New solutions will also be created, filling in existing gaps or addressing new problems. Until then, the viability criteria described here can be used to compare and update the evidence database for potential solutions, differentiating the solutions that do not work from those that successfully and cost-effectively advance health and conservation.To find and synthesise evidence among proposed solutions, we used a subject-wide evidence synthesis, a two-phase approach for identifying and assessing a broad suite of interventions supported by heterogeneous evidence . In the first phase, we performed a systematic literature review of peer-reviewed papers and book chapters, which we used to identify solutions that have been proposed to reduce human infectious disease burdens and advance conservation goals . In the To create a list of proposed win–win solutions (phase 1), we systematically reviewed publications in Thomson Reuters Web of Science and PubMed (n=12 270 papers), including records published between database inception and March 14, 2018. We performed the search using 167 English terms regarding conservation, ecology, infectious disease, and human populations , who used keyword searches to find additional peer-reviewed publications and grey literature. These rapid reviews were not systematic because they did not examine all published literature—a task that would not be possible for 46 interventions. Instead, investigators specifically sought publications relevant to 20 information categories, determined a priori, and summarised all information in a standardised format . A singlAfter finishing the collective case study summary, each investigator used a list of qualitative variables defined a priori to categorise information consistently for comparison across case studies. Variables included geographical location, conservation threat, infectious disease threat, mechanism or lever type, evidence for conservation and human infectious disease outcomes, and 11 criteria that we identified as indicative of viable solutions (harmless, contained, consistent, feasible, acceptable, impactful, effective, affordable, scalable, sustainable, and cost-effective; database.The 46 evidence summaries are publicly available in a searchable We declare no competing interests.


Gastric cancer (GC) is a common lethal malignancy worldwide. Gastroscopy is an effective screening technique for decreasing mortality. However, there are still limited useful non-invasive markers for early detection of GC. Bile acids are important molecules for the modulation of energy metabolism. With an in-depth targeted method for accurate quantitation of 80 bile acids (BAs), we aimed to find potential biomarkers for the early screening of GC. A cohort with 280 participants was enrolled, including 113 GC, 22 benign gastric lesions (BGL) and 145 healthy controls. Potential markers were identified using a random forest machine algorithm in the discovery cohort (n=180), then validated in an internal validation cohort (n=78) and a group with 22 BGL. The results represented significant alterations in the circulating BA pool between GC and the controls. BAs also exhibited significant correlations with various clinical traits. Then, we developed a diagnostic panel that comprised six BAs or ratios for GC detection. The panel showed high accuracy for the diagnosis of GC with AUC of 1 (95%CI: 1.00-1.00) and 0.98 (95%CI: 0.93-1.00) in the discovery and validation cohort, respectively. This 6-BAs panel was also able to identify early GC with AUC of 1 (95%CI: 0.999-1.00) and 0.94 (95%CI: 0.83-1.00) in the discovery and validation cohort, respectively. Meanwhile, this panel achieved a good differential diagnosis between GC and BGL and the AUC was 0.873 (95%CI: 0.812-0.934). The alternations of serum bile acids are characteristic metabolic features of GC. Bile acids could be promising biomarkers for the early diagnosis of GC. Gastric cancer (GC) is a highly aggressive and fatal malignancy with high mortality and accounts for the second leading cause of cancer-related deaths worldwide , 2. PathGC development has been associated with both genetic and environmental factors. In addition, metabolites are the end products of a complex interplay between intrinsic metabolism, environmental exposure and genetic predisposition . OccurreOn the other hand, bile reflux has been shown to be an independent risk factor for precancerous gastric lesions and GC . Bile acPrevious studies have shown that metabolites in blood or urine have the potential to be GC biomarkers , 19. SinSerum samples were collected from the GC patients, BGL patients and healthy participants (Con) at the First Affiliated Hospital of Dalian Medical University from May 2020 to October 2021. The GC patients were pathologically diagnosed by biopsy and divided into sub-groups based on the AJCC staging system, 8th edition , as shown in After injection of 2.5 μL of redissolved BA extraction, a total of 63 BAs Table S5The targeted BA annotation was based on the BA standards , 26. We The BAs with missing values of more than 50% were excluded, and then we employed the K-nearest algorithm to impute the missing values . The molAs shown in After screening out the BAs with excess missing values or unstable detection, we obtained a total of 49 BAs. We then added biologically significant ratios and total concentrations of sub-classes to then BAs. By calculating the BAs (ratios or sub-classes) with significant differences between the GC and Con groups, a heat-map of 34 features was drawn , including HCA, TLCA, NorCA, DCA-3G, TLCA-3S and HDCA/LCA were obtained Table 2.The discovery set was used to construct the diagnostic panel. The OPLS-DA score plot showed an obvious separation between the GC group and the Con group . TLCA was the strongest activator of TGR5 among all the BAs and promoted the occurrence of liver cancer by activating the TGR5 . RemodelThe metabolism of BAs is mainly influenced by the catalysis of liver and intestinal microbiota. However, different diseases have been found to have specific features of BAs metabolism , 47. TheWe used an in-depth metabolomics approach which provided high-quality and information-rich BAs data in patients with GC. Differential BAs, including many low-abundant BAs, were annotated based on the BA standards. Due to limited detection methods, data on the low-abundance BAs remain scanty. Recent data has shown that some of these BAs are closely related to human health. Besides, BAs play a key role in regulating gastric mucosal homeostasis, which mediates stomach upset. Thus, the newly reported BAs could serve as screening markers. In addition, these molecules provide a new tool in understanding the pathophysiology of GC.Although our study had an important outcome, there is a need to confirm the diagnostic value of those candidates in a multi-center large sample cohort. In addition, the molecular mechanism of BA metabolism disorder on the occurrence and development of GC needs further evaluation in cell assays.Taken together, our data demonstrated that the BAs metabolism disorder is involved in GC development. Our diagnostic model using 6 BAs or ratio provided promising diagnostic efficiency for GC, which could perform early screening of high-risk populations and promote early diagnosis of GC.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Ethics Committee of First Affiliated Hospital of Dalian Medical University. The patients/participants provided their written informed consent to participate in this study.CP: data curation, formal analysis, software, methodology, writing - original draft, and writing - review and editing. DD: data curation, formal analysis, investigation, methodology, project administration, writing - original draft, and writing - review and editing. TW: data curation, formal analysis, investigation, and methodology. ZW: methodology, formal analysis, resources, and validation. BZ: data curation and formal analysis. QY: data curation and formal analysis. GL: conceptualization, resources, validation, and supervision. YL: conceptualization, resources, project administration, validation, and supervision. PY: conceptualization, resources, validation, supervision, funding acquisition, project administration, writing - review and editing. All authors contributed to the article and approved the submitted version.This research was funded by The Key Research And Development Project Of Liaoning Province (No. 2018225054) and The National Natural Science Foundation of China (No. 81873156).ZW and PY are co-founders of iPhenome Yun Pu Kang Biotechnology Inc. ZW is an employee of iPhenome Yun Pu Kang Biotechnology Inc.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Dempster–Shafer evidence theory is widely used in modeling and reasoning uncertain information in real applications. Recently, a new perspective of modeling uncertain information with the negation of evidence was proposed and has attracted a lot of attention. Both the basic probability assignment (BPA) and the negation of BPA in the evidence theory framework can model and reason uncertain information. However, how to address the uncertainty in the negation information modeled as the negation of BPA is still an open issue. Inspired by the uncertainty measures in Dempster–Shafer evidence theory, a method of measuring the uncertainty in the negation evidence is proposed. The belief entropy named Deng entropy, which has attracted a lot of attention among researchers, is adopted and improved for measuring the uncertainty of negation evidence. The proposed measure is defined based on the negation function of BPA and can quantify the uncertainty of the negation evidence. In addition, an improved method of multi-source information fusion considering uncertainty quantification in the negation evidence with the new measure is proposed. Experimental results on a numerical example and a fault diagnosis problem verify the rationality and effectiveness of the proposed method in measuring and fusing uncertain information. Uncertain information exists widely in practical applications ,2. One oShannon entropy is a well-known theory for uncertainty measure in the probabilistic framework, which has attracted much attention in real applications ,33,34. HThe negation of BPA is used for modeling the uncertain information in the frame of Dempster–Shafer evidence theory ,43,44. HThe rest of this work is organized as follows. N mutually exclusive and exhaustive events, and Define that elements ,4:(1)2Ω=m, also named the basic belief assignment (BBA) or basic probability assignment (BPA), is defined as a mapping function from the power set of FOD A is defined as a focal element.A mass function atisfies ,4:(2)m∅=ℜ is a subset of the power set A body of evidence (BOE) means the focal sets and the associated belief value that can be denoted as follows:k can be regarded as a normalization factor defined as [Two independent mass functions fined as ,4:(4)mk=∑The negation information represents a kind of uncertain information in probability framework . In Dempn is the number of focal elements in the BOE. It is obvious that if the belief value is one for only one focal element, there is no uncertain information in this case and it is a certain event.In the BOE, rived as :(6)m¯Edm=−A is the focal element of BOE, A, and m; n is the number of focal elements in the BOE.Base on the belief entropy of belief functions in Equation , an imprEquation :(9)m¯(A)The belief entropy of negation evidence addresses the uncertainty measure of the negation of BPA. Two numerical examples are given to explain how to calculate the belief entropy of negation evidence.Example 1: Assume the FOD is {a, b, c}. The mass functions are Example 2: Assume the FOD is {a, b}. The mass functions are A new method of multi-source information fusion using the improved belief entropy of negation evidence is proposed in this section, as shown in Step 1Modeling uncertain information with the original BPA in Dempster–Shafer evidence theory.In real applications, due to the diversity styles of information, many methods for generation of BPAs are proposed ,45. CurrStep 2Calculating the negation of BPAs and using the proposed belief entropy of negation evidence for the uncertainty measure in the negation evidence.ith BOE 11), the Similarly, the belief entropy of negation evidence of For the third step, with Equation , the weiFor the fourth step, the mass function of each proposition after modification in Finally, for the fifth step, there are five original pieces of evidence; thus, with Dempster’s rule of combination and Equation , the modA is the recognized target, which is consistent with other methods in [A. By considering the uncertainty of negation evidence, the proposed method contributes to a higher belief degree on the expected target than the methods in [A than the proposed method. However, it should be noted that both Yuan et al.’s method in [The multi-source information fusion results with the proposed method and other methods in the experiment are presented in thods in ,46,47,48thods in ,48 have ethod in  use the Rotor unbalance}, Rotor misalignment} and Pedestal looseness}. The vibration signals are collected from three vibration acceleration sensors which are placed in different installation positions. The acceleration vibration frequency amplitudes at the frequencies of Freq1, Freq2 and Freq3 are taken as the fault feature variables. The data for fault diagnosis modeled as BPAs are provided in In this section, the proposed method is applied to an application in fault diagnosis of a motor rotor. The practical data in  is adoptApply the proposed method for multi-source information fusion in fault diagnosis.Step 1 Modeling uncertain information with BPA in Dempster–Shafer evidence theory.In this paper, BPAs of sensor reports are directly adopted from , as reprStep 2 Using the proposed belief entropy of negation evidence for uncertainty measure of the negation of BPAs.Freq1 is calculated as follows:In the proposed method, the uncertainty of sensor reports is measured based on the belief entropy of negation evidence. With Equations  and 11)11), the Freq2 and Freq3 can be calculated with the proposed method. The measuring results with the proposed method are listed in Step 3 Construct the weight factor of each BOE based on the uncertainty measure result.Similarly, the belief entropy of negation evidence of sensor reports under With Equation , for theThe weight of different sensor reports under Step 4 Evidence modification based on the weight factor with the belief entropy of negation evidence.With Equation , the modStep 5 Evidence fusion with Dempster’s rule of combination.The modified mass function for Equation . The resWith Equation , for theThe fusion results for According to the fusion results in A few reasons contribute to the effectiveness of the proposed conflict evidence fusion method. Firstly, the sensor data is preprocessed properly before applying the combination rules, which is a very important step in combining conflict evidence. Secondly, the new method is based on an improved belief entropy of negation evidence. The new measure can measure the negation uncertainty information in the Dempster–Shafer evidence theory framework, which contributes to a more accurate experiment result. Finally, the advantages in Dempster’s combination rule, such as satisfying the commutativity and associativity, guarantee the rationality of the fusion result.A new method of measuring uncertainty in the negation evidence and its application in multi-source information fusion is proposed in this work. The contribution of the work can be summarized as follows. (1) An improved belief entropy is proposed to measure the uncertainty of negation evidence. Currently, all the measures in the framework of Dempster–Shafer evidence theory are designed for the original evidence, and there is no uncertainty measure for the negation evidence ,41. The It should be noted that there are limitations in the work. First, many new measures in Dempster–Shafer evidence theory framework are not taken into consideration in addressing the uncertain degree of negation evidence. Second, how to measure the uncertainty among dependent bodies of evidence is ignored in the proposed method. Third, other improved combination rules can be taken into consideration for evidence fusion. Last but not least, only two data sets are adopted to illustrate and verify the effectiveness of the proposed method. The method limitation is not clear for many other data sets and cases in artificial intelligence.According to the aforementioned limitations, possible future research work is as follows. On the one hand, there is still no uncertainty measure that is accepted by all researchers in the evidence theory. A general uncertainty measure for negation evidence needs further study. On the other hand, although uncertainty measure-based weighted BPA has been widely used in multi-source information fusion, it cannot address the issue of dependent evidence fusion. How to address conflict and dependent evidence considering the uncertainty measure is a promising topic in multi-source information fusion.In this paper, in Dempster–Shafer evidence theory framework, the belief entropy of negation evidence is proposed based on the belief entropy for the negation of BPAs. The measure for negation evidence is a new perspective on uncertain information modeling and measuring. Based on the belief entropy of negation evidence, a novel method considering BPA uncertainty degree in the negation information of multi-source information fusion is proposed. An experiment on artificial data and an application on fault diagnosis are designed to demonstrate the availability and effectiveness of the proposed measure and information fusion method. Both experimental results indicate that the belief entropy of negation evidence is effective in uncertainty measuring of negation evidence, and it contributes to an accurate evidence fusion result.


Acupuncture clinical practice guidelines are authoritative medical recommendations developed by evaluating and integrating acupuncture-related evidence. However, their synthesis and dissemination are not integrated, and clinical practitioners require more credible effective evidence. The study aim was to systematically review problems disseminating acupuncture clinical practice guidelines to clinical practitioners, to facilitate evidence dissemination. This systematic review included searches of PubMed, EBSCO, Web of Science, and four major Chinese electronic databases  from inception to October 26, 2021. Two independent reviewers screened the literature, extracted information, and evaluated the quality of included studies. A systematic review was subsequently performed. Eleven studies were reviewed: nine (81.8%) cross-sectional surveys and two (18.2%) systematic reviews. The evaluated clinical practice guidelines differed across studies; seven studies (63.6%) evaluated guidelines for a specific disease, one (9.1%) evaluated guidelines for acupuncture therapies , one (9.1%) evaluated US acupuncture guidelines and recommendations, and two (18.2%) did not describe the guideline content. The included studies used different evaluation indicators. Guideline dissemination problems included lack of guideline standardization, unclear target population, mismatch between guidelines and application environment, lack of reliable health economics evaluation, poor quality content of the recommendations, lack of linkage between recommendations and evidence, and disassociation of recommendations from clinical practice et al. The development and publishing of credible acupuncture clinical practice guidelines is urgently needed to improve the usability of guidelines and standardize and disseminate tools for analysing information to clinical practitioners and to help the domestic and international acupuncture community to apply evidence to practice. Recommendations for promoting the dissemination of acupuncture clinical practice guidelines are to define clinical events suitable for the target population, to develop recommendations relevant to clinical practice, to improve the evidence evaluation index system, and to further standardize the method and process of formulating guidelines. Acupuncture-moxibustion is a method of preventing and treating various diseases –4. NumerClinical practitioners need effective ways to obtain more credible evidence to ensure that patients receive effective diagnosis, treatment, and follow-up. These measures should be decided by a consensus between practitioners and patients and should be tailored to each patient's specific needs. However, links in the evidence chain, which includes production, synthesis, dissemination, and implementation, are not currently integrated . There rStudies on problems with the dissemination of acupuncture-moxibustion clinical practice guidelines to clinical practitioners have increased; however, such studies use inconsistent methods, tools, participants, and outcomes . This syThe current systematic review is part results of a systematic review, and the systematic review registration [CRD42021279104] was completed on October 17, 2021.This systematic review included searches of Chinese and English articles in PubMed, EBSCO, Web of Science, and four major Chinese electronic databases  from inception to October 26, 2021 . AdditioInclusion criteria were as follows: studies using various methods/tools for quality assessment of dissemination and application of clinical practice guidelines for acupuncture-moxibustion in clinical practice.Exclusion criteria were as follows: literature in languages other than English and Chinese; duplicate publications; publications for which the data could not be obtained, such as conference abstracts; clinical practice guidelines; literature related to the interpretation of guidelines, consensus, standards, procedures, and norms; studies on acupuncture-moxibustion methodology in addition to acupuncture-moxibustion guidelines; and studies on acupuncture-moxibustion service processes.Two researchers independently screened the literature and cross-checked the data. In the event of disagreement, a third researcher was invited to adjudicate. The literature screening was carried out by first reading each source's title and abstract. After excluding obviously irrelevant sources, the full text was read to determine the final inclusion. Literature management and duplication removal were performed using NoteExpress 3.4.0.8878 software.The literature was independently extracted and cross-checked by 2 researchers. Disagreements were resolved by discussion, and a consensus was reached through a third researcher. For sources with incomplete information, the authors of the source were contacted if possible. Data were extracted using a predeveloped data extraction form. Before performing the formal extraction, the researchers involved received training and participated in a practice extraction exercise. The extracted data mainly included baseline characteristics: authors, year of publication/update, country or region, study design, study population, study institution, and publication journal. The guideline evaluation examined evaluation subjects, evaluation/methodological tools, evaluators, problems identified, and recommendations made.Because no specific checklist has been developed to assess the quality of articles evaluating acupuncture-moxibustion guidelines, we referred to the Joanna Briggs Institute (JBI) checklist for evaluating cross-sectional studies  to evaluA systematic review was performed to assess the problems in dissemination of acupuncture-moxibustion clinical practice guidelines among clinical practitioners.An initial review of 4,044 relevant sources was conducted. After removing duplicates, 3,087 studies were identified. After screening the titles and abstracts, 100 studies were retained. After browsing the full-text articles, we further excluded 89 records. A final total of 11 studies , 16–24 wThe basic characteristics of the included studies are shown in AMSTAR II: Appraisal of Guidelines for Research and Evaluation II.Because of the different evaluation indicators used in the included studies, we evaluated 10 aspects of the clinical guidelines and problems in dissemination to practitioners identified in the included studies: clinical events defined by the guidelines, target population, application setting, health economics evaluation, content of recommended protocols, association of recommended protocols with evidence, association of recommended protocols with clinical practice, acupuncture-related practice norms, promotion methods and efforts, and methods and theories of guideline writing.Clinical events defined by the guidelines. A total of three studies , 17, 19 Target population of the guideline. Five studies , 19, 20 Application environment of the guidelines—three studies , 18, 19 Health economics evaluation in the guidelines—four publications referred to the lack of guideline health economics evaluation supported by reliable data, such as cost-effectiveness ratios of recommended interventions , 22, 24.Content of the recommended programs in the guidelines—nine –22, 24 pLinking recommendations to evidence—four studies identified problems with the association between recommendations and evidence , 16, 19;Discrepancies between recommendations and clinical reality—four studies , 19, 20 Code of practice related to acupuncture—three , 20, 24 Modalities and intensity of promotion of the guidelines—five studies , 22, 23 Methodology and theory for the preparation of the guideline. One study concluded that current guideline development methods were not applicable to acupuncture and that guideline developers lacked an appropriate understanding of the methods and content of acupuncture guideline development , such asA total of 11 studies were included in this systematic review and evaluation of the quality of evidence for the dissemination of acupuncture clinical practice guidelines to clinical practitioners. The studies reported problems with the Clinical Practice Guidelines for Evidence-Based Acupuncture: Insomnia ; 35 EvidOwing to the inclusion of 5 studies published after 2019, when the 2019 acupuncture group standard “Acupuncture and Moxibustion Clinical Practice Guidelines Formulation and Evaluation Standards” (CAAM-2019 [001]) was issued by the Chinese Society of Acupuncture and Moxibustion , the preIt is recommended that acupuncture clinical practice guidelines more precisely define clinical events suitable for the target population , 27. CliIt is recommended that acupuncture clinical practice guidelines are relevant to clinical practice . It is iThere is a need to improve the evidence evaluation index system of acupuncture clinical practice guidelines. The selection of efficacy evaluation indicators and targeted data analysis should be combined with clinical needs to ensure the measurability of the recommendations. It is recommended that a detailed guideline update plan be developed and that targeted requirements are introduced into the guideline development process to promote greater clarity in the development process, greater methodological rigor in research, stronger associations, and more scientific evidence in the included studies. The clinical characteristics of the evidence should be based on real-world clinical problems that are of substantial interest or that need to be resolved. High-quality clinical trials appropriate to the practice of acupuncture and moxibustion, as well as multidisciplinary and interdisciplinary collaborative studies, would facilitate the development of guidelines that meet real clinical needs. It is also important to explore the methods of nonclinical trial findings, such as those found in ancient literature and the experiences of famous doctors, in evidence synthesis and other guideline aspects.Guideline methodology recommendations are to further standardize the method and process of guideline formulation . Close mThe limitations of this study were that all included studies were from China (no relevant literature was published outside China) and that the research institutions and researchers were limited to the Chinese Academy of Traditional Chinese Medicine and domestic traditional Chinese medicine universities. This may have led to publication bias and results bias. Additionally, all the included studies were reviews or cross-sectional surveys; there was a lack of studies using high-quality experimental designs.There is an urgent need to improve the credibility, usability, and standardization of acupuncture clinical practice guidelines, to standardize and disseminate tools for analysing information to clinical practitioners, and to develop and publish credible guidelines to help the domestic and international acupuncture community to apply evidence. Recommendations for promoting the dissemination of acupuncture clinical practice guidelines are to define clinical events suitable for the target population, to be relevant to clinical reality, to improve the evidence evaluation index system, and to further standardize the method and process of acupuncture clinical practice guideline development. Future systematic reviews are needed that include new studies.


Patients diagnosed with ischemia without obstructive coronary artery disease (INOCA) comprise the group of patients with primary microvascular angina (MVA). The pathophysiology underlying ischemia and angina is multifaceted. Differences in vascular tone, collateralization, environmental and psychosocial factors, pain thresholds, and cardiac innervation seem to contribute to clinical manifestations. There is evidence suggesting potential interactions between the clinical manifestations of MVA and non-cardiac conditions such as abnormal function of the central autonomic network (CAN) in the central nervous system (CNS), pain modulation pathways, and psychological, psychiatric, and social conditions. A few unconventional non-pharmacological and pharmacological techniques targeting these psychosocial conditions and modulating the CNS pathways have been proposed to improve symptoms and quality of life. Most of these unconventional approaches have shown encouraging results. However, these results are overall characterized by low levels of evidence both in observational studies and interventional trials. Awareness of the importance of microvascular dysfunction and MVA is gradually growing in the scientific community. Nonetheless, therapeutic success remains frustratingly low in clinical practice so far. This should promote basic and clinical research in this relevant cardiovascular field investigating, both pharmacological and non-pharmacological interventions. Standardization of definitions, clear pathophysiological-directed inclusion criteria, crossover design, adequate sample size, and mid-term follow-up through multicenter randomized trials are mandatory for future study in this field. Evidence suggests a potential role of the central nervous system and psychosocial conditions in the clinical manifestations of microvascular angina.A few unconventional non-pharmacological approaches have shown preliminary and encouraging results.The results of the available observational and interventional trials have multiple drawbacks and a low level of evidence.Standardization of definitions, pathophysiological-directed inclusion criteria, adequate sample size, and mid-term follow-up are mandatory for future research.For decades, physicians have considered obstructive coronary artery disease (CAD) as an equivalent to ischemia and angina. However, the pathophysiology underlying ischemia and angina is more complex and multifaceted. Anatomical and functional alterations of both epicardial vessels and microcirculation, left ventricular mass and fibrosis, and non-cardiac components contribute to the clinical manifestations.Large prospective registries such as the Women's Ischemic Syndrome Evaluation (WISE) database and other seminal studies showed that angina in the absence of obstructive CAD affects up to 60% of patients undergoing diagnostic coronary angiography for the assessment of stable angina, a larger number of patients than previously thought , 2. SubjCoronary microvascular dysfunction can result from a combination of structural and functional alterations of the coronary microcirculation . The relHowever, the pathophysiology of MVA is even more complex. Actually, the relationship between ischemia and angina is not straightforward in both CAD and microvascular dysfunction . The so-Since those concepts have been recently introduced in cardiovascular medicine, we also provided a brief overview of the most relevant pathophysiological and clinical literature for each topic of the review to introduce the reader.The objectives of the review were to examine and gather evidence from observational and interventional studies on the role of the central nervous system and psychosocial factors in primary microvascular angina, formerly known as cardiac syndrome X.Atypical clinical manifestations are more common in patients with MVA than in those with obstructive CAD . MoreoveIn most of the reported studies, there is a robust female preponderance among subjects with MVA. The large multicenter WISE study showed that nearly 50–70% of women and 30–50% of men were diagnosed with INOCA, respectively . A few nChronic psychosocial stress (CPS) is a fundamental component of life, but its definition is complex. Many definitions of stress exist, making the study of the impact of CPS on cardiovascular disease challenging. CPS disrupts both health and wellbeing. These are multidimensional, intertwined entities that include both objective and subjective elements, as well as physical, mental, social, and economic dimensions . CPS canA further complication to measure the magnitude of association between CPS, the above-mentioned heterogeneous stressors, and CVD is the fact that chronic stress also promotes CVD risk factors. Moreover, as classical cardiovascular risk factors, these stressors tend to cluster , 16. ThiLast but not least, an increasing wealth of data shows that psychological health can positively or negatively affect cardiovascular health, but cardiovascular diseases can mutually affect the former .Mental stress-induced myocardial ischemia (MSIMI) is a plain manifestation linking CPS with CVD. It has been associated with future MACEs . NotablyThe intertwined relationship between the heart, body, and mind has been defined as the mind-heart-body (MHB) connection . Within Stress activates the HPA axis. This results in the release of pituitary adrenocorticotropic hormone (ACTH), which induces the adrenal cortex to produce glucocorticoids that contribute to increased adiposity, hypertension, and insulin resistance . SympathSeveral methods can be used to measure stress. Psychometric questionnaires are the most widely implemented tools in this research field, but recently, functional imaging of the central nervous system has gained interest , 34.No specific measurements of the overall level of perceived stress as well as specific functional cerebral imaging of CPS in MVA are present in the literature. Most studies in MVA investigated quality of life (QoL) as well as the distinct components of the psychosocial dimension that can result in CPS.Psychological and psychiatric risk factors seem to be a higher burden for women with INOCA and MVA than for men . As mentDiagnostic and Statistical Manual of Mental Disorders (DSM) for panic disorder , Beck Depression Inventory (BDI), and Health-Related Quality of Life (HRQoL) . The results of these studies suggest that patients with MVA have a higher prevalence of CPS, psychiatric disorders, and lower quality of life –40. Anxidisorder , 45.Interestingly, anxiety has also been associated with a conspicuous increased risk of epicardial coronary artery spasm  , but theAltogether, these results showed an association between psychiatric disorder and angina in MVA. However, their relative importance in the pathogenesis of MVA and the reciprocal influence between psychiatric comorbidities and clinical manifestation of MVA remain to be further elucidated .Psychosocial stress is highly correlated with socioeconomic, behavioral, dietary, and environmental risk factors as well as the decreased access to healthcare system . Gender Angina pain triggered by ischemia is frequently associated with dyspnea, fatigue, discomfort, and possibly fear. Pain represents a major concern for HRQoL in individuals with MVA. Patients with MVA showed poorer scores on various HRQoL scales compared to both patients with obstructive CAD and normal control , 48. MVAPatients with MVA often experience refractory angina, leading to repeated outpatient visits, hospitalizations, and unnecessary and potentially harmful diagnostic procedures that may contribute to poor HRQoL . In the Individuals diagnosed with MVA have been reported to have frequent absences from work and work limitations .The substantial economic burden and healthcare expenditures in patients with INOCA and MVA are similar to those in patients with obstructive CAD in the United States and Europe , 57.Pain represents a single component of the large spectrum of the subject's negative experiences triggered by myocardial ischemia. Dyspnea, fatigue, dyspepsia, discomfort fear, and a sense of imminent death may rarely convoy angina.The heterogeneity and somewhat refractoriness of the above-mentioned symptoms reflect the complex genesis and processing of cardiac pain and the associated symptoms . SensoryThe vagus nerve appears to have a minor role in afferent pain transmission. There are extensive connections among cardiac sympathetic plexuses, sympathetic ganglion chains, and the spinal cord . The ascStudies investigating the projections of cardiac pathways to the brain showed that the thalamus plays a central role in gating the afferent pain signals , 60. DifMultiple features of the role of the central nervous system and the autonomic system have been explored in subjects with MVA. Autonomic cardiac control imbalance has been investigated in small studies. Non-invasive surrogates for cardiac autonomic function such as sympathetic skin response and heart rate variability assessed by frequency domain R-R interval variation have been reported to be impaired in subjects with MVA , 65. MorSince 1980s, there have been studies suggesting an abnormal increase in the perception of cardiac pain in patients with MVA, even during typically painless intracardiac stimuli –69. ThisUsing a randomized, double-blind design, Pasceri et al. found that enhanced cardiac pain perception was confined to the ventricular myocardium . ConsistConversely, the study by Frøbert et al. found that the central nervous system response to multiple visceral and somatosensory nociceptive stimuli is altered in patients with MVA, thus advocating the hypothesis of a generalized pain disorder . MoreoveSPECT cerebral nuclear perfusion imaging showed a high incidence of hypoperfusion lesions in the cortical parietal lobes coincident with myocardial defects .Most likely, the complex process of pain transmission and modulation may be abnormal at multiple levels. Presumably, different components of the pain matrix may have variable relative contributions in different subjects and within the same subject at different times .Notably, pain processing may not represent the sole abnormality in the CNS functional network. Convincing evidence exists that psychosocial stress perturbs the CAN, which in turn modulates autonomic response to external stressors . RecentlIn patients with chronic coronary syndrome (CCS) and obstructive CAD, current medical management and revascularization result in symptom control in about 80% of patients . While o3).The management of refractory angina is particularly challenging with conventional pharmacological therapies. Therefore, a repertoire of unconventional pharmacological and non-pharmacological interventions has been investigated. These studies suggest that non-pharmacological psychoeducational interventions may improve quality of life and reduce health care demands to some extent, even without change in the ischemic threshold, presumably by modifying the complex pathways of pain transmission and modulation in the cortical and subcortical CNS . HoweverIn the last decade, cardiac rehabilitation has gained a role of primary importance in coronary heart disease and chronic heart failure management.Cardiovascular rehabilitation has been shown to counteract deconditioning and reduce angina in MVA , 96. LikSimilarly, non-blinded, randomized evidence in females reinforced the role of support groups in MVA management. Support groups may enhance social participation, problem discussion, and may improve different items of the SF-36 questionnaire at 12 months .Altogether, these data suggest that non-pharmacological interventions consisting of social and psychological support may reduce health care demands and improve quality of life in MVA at least at short- and mid-term follow-up .Cognitive-behavioral therapy (CBT) consists of a program of education, relaxation exercises, coping skills training, and stress management interventions . CBT is The practice of meditation dates back a few thousand years and is mostly associated with Eastern philosophies and religions, although it is also present in the Middle Eastern and Western religions.Meditation is increasingly practiced, and modern approaches concentrate principally on focused attention and mindfulness .Cunningham et al. showed that transcendental meditation may improve exercise capacity without changes in ST-segment depression or reduction of angina frequency in postmenopausal women with MVA .via scientific trials is still a challenge. Two small non-randomized studies used the Qi-regulating, chest-relaxing, and blood-activating therapies of the TCM integrated with Western Medicine for the treatment of MVA, suggesting a potential benefit on symptoms, exercise capacity, and systemic inflammation assessed by sensitive C-reactive protein (CRP)  is a millennial traditional that views the human body as a complex dynamical system and focuses on the balance of the human body within itself and its environment. Such concepts require investigations that go beyond conventional reductionism. Therefore, prove effectiveness of TCM in (CRP) .Although the methodological limitation of these small pilot studies must be recognized, these results argue for the potential usefulness of integrated psycho-physiological interventions that involve cortical, autonomic, neuroendocrine, and cardiovascular systems . IndepenTricyclic antidepressants (TA) have a balanced reuptake inhibition of the serotonin and noradrenaline neurotransmitter activities that results in an analgesic effect . Two shoSpinal cord stimulation (SCS) is a neuromodulation technique used in various chronic pain syndromes. SCS for modulation of cardiac pain requires surgical positioning of a multipolar electrode in the epidural space between the C7 and T4 vertebrae where the myocardial afferent sympathetic fibers synapse in the dorsal horns. During SCS, the electrode is connected to a programmable pulse generator that allows the subject to self-administer a customized stimulation, which usually requires fixed daily stimulations and stimulations on demand whenever angina occurs . SCS actEvidence from small observational studies showed that SCS may be an effective and safe treatment for refractory angina in MVA both at short- and long-term follow-up . SCS is Transcutaneous electrical nerve stimulation (TENS) is a non-invasive, self-administered technique to relieve pain. TENS consists of pulsed electrical impulses delivered across the intact skin to selectively activate large-diameter non-noxious afferent fibers to antagonize nociceptive afferent transmission. Pain relief with TENS is rapid in onset and offset. Clinical experience suggests potential beneficial effect for acute pain management, although data are conflicting and evidence in MVA is limited. Two small non-randomized, non-blinded studies including MVA provided preliminary data on both short- and long-term beneficial effects of TENS in reducing physical limitation, angina frequency, and possibly the perfusion reserve assessed by dipyridamole positron emission tomography , 87 Tab. NotablyThe left stellate (cardiothoracic) ganglion is an accessible station of convergence for afferent cardiac pain. Temporary and permanent sympathectomy by stellate ganglion blockade and resection, respectively, have been attempted for channelopaties and structural arrhythmias management. Anecdotal experience in patients with refractory angina has been reported, but no suitable evidence exists for the management of MVA.Most of the studies included in this review are characterized by low sample size, present cross-sectional design, and rarely a crossover design. Therefore, a potential for bias exists. This challenges the attempt to establish causal associations.Most randomized interventional trials have short follow-up, and the few trials characterized by mid- and long-term follow-up are non-randomized.Most studies required a positive EST to detect ischemia. However, the EST is known to yield a lower diagnostic accuracy compared with diagnostic imaging tests and large studies found that a positive exercise stress test was neither sensitive nor specific for MVA , 109. ThFinally, medical community is still slowly gaining awareness that MVA without CAD represents a separate condition when compared to MVA with non-obstructive CAD, with different prognostic and potentially therapeutic implications . The latThere is evidence suggesting potential interactions between clinical manifestations of MVA and non-cardiac conditions such as abnormal function of the CAN, abnormal pain modulation pathways, and psychological, mental, and social conditions. A few non-pharmacological techniques targeting these psychosocial conditions and modulating the CNS pathways have been proposed to improve symptoms and quality of life. Most of these unconventional approaches have shown encouraging results. However, the results of the available observational and interventional trials have been limited by variable patient selection, the lack of a standardized diagnosis, inadequate small sample size, and insufficient follow-up.Although there is a slow increase in awareness of the importance of microvascular dysfunction and MVA by the cardiovascular community, therapeutic success remains frustratingly low for both patients and physicians. Altogether, those considerations should promote basic and clinical research in this relevant cardiovascular field. Standardization of definitions, clear pathophysiological-directed inclusion criteria, crossover design, adequate sample size, and mid-term follow-up through multicenter randomized trials are mandatory for future research in this field.MC contributed substantially to the conception and design of the work, the acquisition, analysis and interpretation of data, to the draft and revision of the work, and provided approval for the publication of the content. GH, MMC, and AY contributed substantially to the acquisition, analysis and interpretation of data, to the draft and revision of the work, and provided approval for the publication of the content. IS and CG contributed substantially to the analysis of data, to revision of the work, and provided approval for publication of the content. AG contributed substantially to the conception and design of the work, the interpretation of data, to the draft and revision of the work, and provided approval for publication of the content. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Stress is present in several management activities of beef and dairy cattle, leading to health and productive losses to the herd. Therefore, strategies are warranted to reduce any losses related to these stressful situations, and bovine appeasing substance (BAS) is arising as a potential technology in livestock production settings. Several peer-reviewed publications have evaluated BAS in different production settings, such as weaning, feedlot entry, castration, transport to the slaughterhouse, and pre-weaning dairy cattle. Altogether, performance, health, and carcass traits have been positively impacted by BAS administration, demonstrating the efficacy of this technology for ruminants.The present review demonstrates the main attributes of stress-related responses in ruminants, and the potential interaction with the immune system of the host is also presented, demonstrating that alternatives that reduce the response to stressful situations are warranted to maintain adequate health and performance of the herd. In this scenario, pheromones and their modes of action are presented, opening space to a recent technology being used for ruminants: bovine appeasing substance (BAS). This substance has been used in different species, such as swine, with positive behavioral, health, and performance results. So, its utilization in ruminants has been reported to improve performance and inflammatory-mediated responses, promoting the productivity and welfare of the livestock industry. Routine handling and management strategies often employed in the rearing of beef and dairy cattle may trigger stress-induced inflammatory responses, which have detrimental impacts on cattle health and performance , as wellDuring their productive lives, ruminants are often exposed to various amounts and types of stressors that will likely elicit a stress response, but may not involve a pathogen itself . In turnFrom a classical standpoint, stress is defined as the reaction of an animal to factors that potentially influence its homeostasis, and animals that cannot deal with these factors are termed as stressed . Stress The cortex and medulla are the two regions of the adrenal gland, with the former synthesizing and releasing three hormone types, including the glucocorticoid called cortisol. Cortisol is well-recognized as the “stress hormone”, presenting important activities, including the (i) breakdown of body tissues, such as glycogen, muscle, and fat, to provide energy to the host during an immune challenge; (ii) production of acute-phase proteins (APPs) by the liver; (iii) regulation of a stress response; (iv) stimulating the synthesis and release of catecholamines; and (v) prevention of autoimmune disorders . Hence, The immune system is divided into a non-specific and specific immunity called innate and acquired branches, respectively. The latter is primarily responsible for adapting and building a specific immune response for each challenge the body encounters, ultimately leading to the production of antibodies and the development of immunological memory . On the (a)Febrile response: Key defense mechanism that controls replication and growth of pathogens, leading to its death by preventing the formation of bacterial coats. The eicosanoid prostaglandin-E2 (PGE2), produced from 20 carbon omega-6-derived fatty acids , is the primary inducer of the febrile response. Nonetheless, it is noteworthy that the fatty acid profile of the diet might modulate such response. In other words, feeding a diet with feedstuffs containing greater concentrations of omega-6 fatty acids  will lead to a greater pro-inflammatory state and, therefore, the occurrence of a febrile response, whereas an anti-inflammatory response is observed by feeding diets containing a greater amount of omega-3 fatty acids  . In. InB. inehaviors .One of the mechanisms by which BAS improves performance might be related to a less heightened neuroendocrine stress response. According to the aforementioned inflammatory cascade, BAS-administered beef steers had a reduced mean hair cortisol 14 days post-weaning compared with the non-treated group  80] as  as 80] aIn particular, feedlot arrival and entry are simply the tip of the iceberg when we take into consideration all the stressors that an animal might be exposed to. For example, the animal might be managed in the working chute while still in the farm of origin, handled by humans, vaccinated, ear-tagged, castrated (if applied), loaded in a commercial truck, transported, restricted from feed and water, experienced environmental changes, unloaded in a novel environment, novel management, processing, commingled with a different group of animals from a different source/origin, and received novel sources of feed and water, among others. Under a production setting, these stressful situations might occur over a 24–48 h period, stimulating a neuroendocrine stress response at feedlot entry. Moreover, it is not surprising that BRD incidence is elevated in the beginning of the feedlot period (14–21 days), as the immune system is suppressed and BRD pathogens are able to establish the disease ,81. TherB. indicus bulls in the first 15 days of the feedlot, whereas no benefits were observed in the whole 45 days of the experiment . Based on this rationale, Fonseca et al. (2021) designed a trial in which BAS was administered (1) pre-transport to a commercial feedlot (at loading); (2) post-transport, during the initial processing management at the commercial feedlot (at feedlot entry); (3) pre- and post-transport; and (4) no BAS administration . AdminisThese results highlight, once more, how BAS might be able to improve the overall performance and carcass characteristics of beef cattle during finishing, a period where several stressors are observed and have been recognized to negatively impact the health and productivity of the herd . Based oOn the other hand, BAS administration at feedlot entry yielded immediate benefits during the adaptation phase (19 days), but failed to promote long-term effects on performance over 108 days. One might argue that the lack of long-term effects is due to the fact that most of the stressful situations had occurred at feedlot entry, triggering an APR, and likely overriding the benefits of BAS in finishing animals ,89. LastCastration is a widely adopted management practice performed in feedlot cattle that eliminates aggressive behavior in male animals due to the removal of endogenous testosterone production, while also improving backfat thickness and meat characteristics ,91. On tThe castration process itself also causes physical, physiological, and psychological stress in animals, resulting in inflammatory reactions and subsequent performance loss that might last until slaughter . One altn = 390; initial BW = 274 ± 21.0 kg). On day 0 of the study, individual calf BW was recorded and animals were assigned to receive BAS  or placebo . Immediately after treatment administration, all calves were castrated using a burdizzo by trained feedlot personnel. During the feedlot entry period (days 0 to 30), all animals were offered a 60:40 roughage:concentrate diet based on grass hay, whereas, during the finishing period (days 31 to 258), a high-concentrate diet was offered. On day 30 of the study, BAS-administered animals were heavier and had a greater ADG than CON cohorts  carcasses. These stressors and the resulting neuroendocrine stress response ultimately alter meat quality and customer acceptance of this edible product, particularly due to an increase in meat pH and changes in meat tenderness and color . The pH B. indicus breeds are more temperamental than B. taurus [B. indicus animals would have a heightened stress and APR response, resulting in a greater occurrence of DFD carcasses. Hence, technologies that alleviate neuroendocrine stress responses and improve carcass quality are warranted. In order to assess the efficacy of BAS in preventing a postmortem increase in meat pH, Cappellozza et al. [It is important to mention that other factors also predispose carcasses to DFD, such as sex, breed, nutrition, animal category, temperament, and age. In different countries, DFD occurrence has been reported to be in the range of 2.0–13.5% ,106. Con. taurus , it is ra et al.  applied The dairy production system is characterized by intensive management situations, including daily milking, weaning, changes in nutritional management, prepartum DMI reduction, late lactation dry-off, vaccination program, reproductive management, novel environment depending on the season and days on milk, as well as commingling with different animals on different days and stages of lactation that alter social hierarchy of the herd ,109,110.In one of the first studies in dairy cattle, weekly BAS administration to lactating dairy cows at the moment of turn out to pasture resulted in greater milk production (+1.65 kg/day) and a reduction in somatic cell counts (13.0%), supporting the statement that BAS reduced the stress-related response of the animals due to an environmental change . In agreStress inevitably occurs in daily management situations faced by beef and dairy animals throughout their productive lives, leading to performance and health losses that can significantly impact the overall productivity of the herd. Therefore, alternatives that reduce these losses and improve animal welfare are warranted and should be further evaluated. Such an alternative might be the pheromones, chemical signals produced by the animals that might positively benefit another animal, either by promoting a specific trait  or signaling a dangerous situation. More specifically, the identification, isolation, and synthesis of synthetic analogues might be able to translate these natural endogenously produced substances into a commercial application, including bovine appeasing substance (BAS). Recently, BAS has been evaluated in different commercial settings of beef and dairy cattle, with significant improvements for the performance and health of the herd, following an encounter with a stressful situation, such as pre-weaning, weaning, feedlot entry, castration, and slaughter. Additional research efforts should be considered and are encouraged to further elucidate potential underlying modes of action by which BAS benefits the performance and health of the beef and dairy cattle herd, as well as novel situations in which this technology might improve the health, performance, and welfare of the herd.


Running-related injuries are prevalent among distance runners. Changing step rate is a commonly used running retraining strategy in the management and prevention of running-related injuries.The aims of this review were to synthesise the evidence relating to the effects of changing running step rate on injury, performance and biomechanics.Systematic review and meta-analysis.MEDLINE, EMBASE, CINAHL, and SPORTDiscus.n = 2), performance (n = 5), and biomechanics (n = 36). Regarding injury, very limited evidence indicated that increasing running step rate is associated with improvements in pain (4 weeks: standard mean difference (SMD), 95% CI 2.68, 1.52 to 3.83; 12 weeks: 3.62, 2.24 to 4.99) and function ; 12 weeks: 3.42, 4.75 to 2.09) in recreational runners with patellofemoral pain. Regarding performance, very limited evidence indicated that increasing step rate increases perceived exertion  and awkwardness  and effort ; and very limited evidence that an increase in preferred step rate is associated with increased metabolic energy consumption . Regarding biomechanics, increasing running step rate was associated with strong evidence of reduced peak knee flexion angle ; moderate evidence of reduced step length , peak hip adduction , and peak knee extensor moment ; moderate evidence of reduced foot strike angle ; limited evidence of reduced braking impulse , peak hip flexion , and peak patellofemoral joint stress ; and limited evidence of reduced negative hip  and knee work . Decreasing running step rate was associated with moderate evidence of increased step length ; limited evidence of increased contact time , braking impulse , and negative knee work ; and limited evidence of reduced negative ankle work  and negative hip work .Thirty-seven studies were included that related to injury , and reducing step rate results in an increase (or no change), to kinetic, kinematic, and loading rate variables at the ankle, knee and hip. At present there is insufficient evidence to conclusively determine the effects of altering running step rate on injury and performance. As most studies included in this review investigated the immediate effects of changing running step rate, the longer-term effects remain largely unknown.CRD42020167657. Key PointsIncreasing running step rate reduces step length, peak knee flexion angle, peak hip adduction, peak knee extensor moment and foot strike angleThere is insufficient evidence to determine the effects of changing running step rate on injury or performanceIncreasing running step rate will broadly reduce kinematic and kinetic variables at the ankle, knee and hipRunning participation provides many health and social benefits . Yet, itMany factors are proposed to contribute to running-related injuries including training load, biomechanical factors, and lifestyle and emotional stressors . As runnRunning retraining (changing running technique) can be used to reduce, or shift tissue loads . Common Understanding how changing running step rate affects biomechanics will provide a mechanistic insight into how this retraining strategy could be utilised in managing both injury and performance. A systematic review published in 2012  summarisTherefore, the primary aim of this systematic review and meta-analysis was to synthesise the evidence relating to the effects of altering running step rate on injury and performance. As changing running step rate can affect biomechanics, and therefore tissue loads, a secondary aim of this review was to synthesise the evidence relating to the effects of altering running step rate on spatiotemporal, kinetic, kinematic, muscle function, and impact-related parameters.This systematic review and meta-analysis is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The protocol was prospectively registered on the PROSPERO International Prospective Register for Systematic Reviews website in July 2020 (Registration number: CRD42020167657). The review adhered to the protocol without amendments or deviations.Using guidelines provided by the Cochrane Collaboration, a comprehensive search strategy was devised and applied to the following electronic databases with no date restrictions; (i) CINAHL via EBSCO, (ii) EMBASE via OVID, (iii) MEDLINE via OVID and (iv) SPORTDiscus. The first search was performed in April 2020 and repeated in May 2021. The search strategy was deliberately simplified to ensure inclusion of all relevant papers, with all terms searched as free text and keywords (where applicable). Concept 1 covered ‘step rate’ (step frequency OR stride frequency OR step rate OR stride rate OR cadence OR step length OR stride length) AND Concept 2 covered ‘running’ (run* OR jog*). All potential references were imported into Endnote X7  and duplicates were removed. Two reviewers (LMA and JFM) reviewed all titles returned by the database searches and retrieved suitable abstracts. Where abstracts suggested that papers were potentially suitable, the full-text versions were screened and included in the review if they met the selection criteria. A third reviewer was consulted in case of disagreements (DRB). All studies that met the inclusion criteria had their reference list hand searched. In addition, citation tracking of included studies was performed using Google Scholar.Studies comparing preferred  running step rate to an increase or decrease in step rate, while running were considered for inclusion. A change in running step rate was defined as runners being instructed to alter their preferred step rate by taking more or fewer steps, while running at the same speed. Studies were excluded if step length was manipulated without a corresponding change in step rate, or if participants ran at a set step rate without reporting their preferred step rate, as it was not possible to determine if preferred step rate was altered. Studies were also excluded if other running retraining strategies (e.g. changing foot strike) were used in addition to changing step rate. Case reports and non-English studies were excluded, along with studies with fewer than 10 participants in the cohort or each group . The lat2) and participant-reported measures of effort (e.g. rate of perceived exertion (RPE)). Biomechanical variables included kinetic, kinematic, and spatiotemporal measures.Injury, performance and biomechanical variables were included in this review. Injury variables included participant-reported measures of pain and/or function. Performance variables were those relating to both physiological measures of performance (e.g. VOTwo independent reviewers (JFM and DRB) rated the quality of included studies using the Downs and Black Quality Index . Any intAll study data were extracted from included studies by the primary author (LMA) and double-checked by a second author (JFM). If sufficient data were not reported in the published article or related supplementary material, corresponding authors were contacted via email to request further data. If additional data were not provided, the best available data from the published article were still included in the review.Means and standard deviations were used to calculate the standardised mean difference (SMD) with 95% confidence intervals (CI) for variables of interest. Data were pooled where possible. Meta-analysis was performed using the Cochrane Collaboration Review Manager 5.4 software. A random-effects model was used for the meta-analyses due to differences between the study design, interventions, participants, and research settings.Levels of evidence were determined using a modified version of the van Tulder criteria : (i) strI2 of 50% or less. I2 values greater than 50% were classified as inconsistent , with level of evidence downgraded one level if pooled results were significant. Calculated SMD magnitudes were classified as small (≤ 0.59), medium (0.60–1.19), or large (≥ 1.20) [Definition of consistent findings  was based on an (≥ 1.20) .The initial search identified 4602 titles. Following removal of duplicate publications, titles of 2320 publications were evaluated. The full text of 54 articles were retrieved, and 37 studies were identified for inclusion see Fig. . Thirty-Characteristics of the 37 included studies are given in Table 10% increase in step rate on pain and function in recreational runners with patellofemoral pain , providFive studies , 50, 53 rate of perceived exertion (RPE) with a 10% increase in step rate, but no differences were reported with a 5% increase in step rate, or with 5% or 10% reductions in step rate ; and veate (1MQ ).VO2 consumption when running at 3.13 m/s and 3.58 m/s with a 15% decrease in step rate [VO2 consumption when: running at 4.02 m/s with a 15% decrease in step rate [15% increase in step rate [4% and 8% increase or decrease in step rate [metabolic energy consumption with an 8% decrease, 15% decrease and 15% increase in step rate, while no difference was observed with an 8% increase in step rate [Three studies were identified evaluating physiological measures of running performance , 42, 53.tep rate . No dataIn the main manuscript, only the pooled results from two or more studies are presented for biomechanical variables. All SMDs and CI, including those from single studies are shown in Tables Twenty-two studies , 42, 45 Nine studies , 54, 57 Step length: In recreational runners, compared to running with a preferred step rate: moderate evidence indicated a shorter step length with a 10% increase in step rate (2HQ [I2 = 52%); and moderate evidence indicated a longer step length with a 10% reduction in step rate (1HQ [I2 = 70%).ate ; and limited evidence indicated an increase in contact time with a 10% reduction in step rate (1HQ [I2 = 0%).ate .rce  and vertical instantaneous loading rate (1HQ [I2 = 0%).ate .lse ; and limited evidence of no difference in negative ankle work (2 MQ [I2 = 0%). Increasing step rate by 5% was associated with moderate evidence of no difference in rearfoot peak pressure  and rearfoot contact time .ion  and no difference in peak tibial acceleration (1HQ [I2 = 0%). Reducing step rate by 5% was associated with moderate evidence of no difference in rearfoot peak pressure (2HQ [I2 = 0%), rearfoot max force , and rearfoot contact time (2HQ [I2 = 0%).In recreational runners, rk ; and limited evidence of no difference in average plantar/dorsiflexion at initial contact (1HQ [I2 = 0%). Increasing step rate by 5% was associated with limited evidence of reduced foot strike angle (1HQ [I2 = 0%).gle ; and limited evidence of reduced peak patellofemoral joint stress (2HQ [I2 = 0%) and reduced negative knee work (2 MQ [I2 = 0%). In recreational runners, reducing step rate by 10% was associated with limited evidence of reduced negative knee work (2 MQ [I2 = 0%).ent ; and moderate evidence of no difference in average knee flexion at initial contact (1HQ [I2 = 0%). Increasing step rate by 5% was associated with limited evidence of no difference in average knee flexion at initial contact (2 MQ [I2 = 0%).gle . Reducing step rate by 5% was associated with limited evidence of no difference in average knee flexion at initial contact (2 MQ [I2 = 0%).In recreational runners, ct . In recreational runners, reducing step rate by 10% was associated with limited evidence of increased negative hip work (2 MQ [I2 = 0%).rk ; and limited evidence of reduced peak hip flexion during stance phase (1HQ [I2 = 0%), no difference in average hip flexion at initial contact (1HQ [I2 = 0%) and no difference in peak hip internal rotation during stance phase (1HQ [I2 = 0%).ase .se  in kinetic, kinematic, and loading rate variables at the ankle, knee, and hip. In contrast, reducing running step rate generally resulted in an increase (or no change) in kinetic, kinematic, and loading rate variables.Despite coaches and clinicians commonly increasing running step rate in the management of running injuries , only tw2 [2). Of note, very limited evidence from a recent cross-sectional study found that changing a runner’s preferred step rate results in an increase in metabolic energy consumption, proposed to result from large increases in positive ankle power when decreasing step rate, and large increases in positive hip power when increasing step rate [This review found insufficient evidence to determine the effect of changing running step rate on performance. Five studies focussed on surrogate measures of performance inclusive of VO2 , 53, RPE2 , metabol2 , awkward2 , and eff2 . Althougtep rate , 51. TheThe findings from this review provide some biomechanical rationale for increasing running step rate to reduce numerous kinetic, kinematic, and loading rate variables at the ankle, knee and hip, while also resulting in changes to spatiotemporal measures.As expected, pooled data provide moderate evidence that increasing and decreasing running step rate by 10% results in a shorter and longer step length, respectively. Additionally, limited evidence indicated an increase in contact time when step rate is reduced by 10%. However, limited evidence indicated that a 10% increase in step rate provides no effect on contact time. Single studies  provide very limited evidence that contact time decreased with a 15% and 30% increase in step rate, but this was not observed with smaller increases in step rate (5% and 8%). While shorter contact time is associated with faster running speeds, the effect on performance is not known , 60. FurThe relationship between vertical ground reaction forces and running-related injury has been extensively researched, with vertical loading rate reported to have the most consistent association with injury –64. PoolAt the foot and ankle, limited evidence indicated a reduction in negative ankle work with a reduced step rate, and moderate evidence identified a reduction in foot strike angle with an increase in step rate. This latter finding is likely to be of interest to coaches and runners as reducing foot strike angle, or converting to a non-rearfoot strike pattern, are other commonly used running retraining strategies . The finThe biomechanical effects observed at the knee with an increase in step rate provide rationale for potential clinical benefits of running-related knee injuries, such as patellofemoral pain. An increase in running step rate was associated with strong evidence of a reduction in peak knee flexion angle , 47, 49,At the hip, moderate evidence indicated a reduction in peak hip adduction during stance phase with a 10% increase in step rate. As greater peak hip adduction during running has previously been associated with common running injuries inclusive of patellofemoral pain, ITB friction syndrome and gluteal tendinopathy , it coulAt the trunk and pelvis, no data were able to be pooled and most findings indicate that changing running step rate does not change biomechanical variables. The exceptions were very limited evidence from single studies indicating reduced pelvic tilt immediately, and reduced contralateral pelvic drop at 4 weeks and 12 weeks post, an increase in running step rate by 10% .Our review found that many biomechanical variables can be altered by instructing a runner to increase or decrease their preferred step rate, but it is difficult to determine if the biomechanical variations occur to achieve the goal of a change in step rate or are a result of a change. Therefore, the biomechanical findings of this review reflect what occurs in clinical practice, whether a mechanism or outcome, when runners are instructed to change their step rate.Insufficient evidence exists to determine the effects of increasing running step rate on injury and performance. Therefore, the rationale for its use largely relies on the knowledge that numerous biomechanical variables can be changed with each step, as found in this review. At present, there is no evidence to guide clinicians in identifying runners most likely to benefit from an increase in running step rate. Clinicians will therefore need to determine its appropriateness based on each runner’s clinical presentation, short- and long-term running goals, and a runner’s desire to change their running gait.It is also noteworthy that the studies included in this systematic review predominantly included recreational runners, and consideration must therefore be given to the potential differences in response among elite athletes.If an increase in running step rate is adopted by an injured runner, any reduction in biomechanical load at the site of injury could help to reduce pain, and potentially maintain running load. Increasing step rate may only be required in the short-term, allowing for a continuation of running while the injury is rehabilitated. The runner may then be able to return to their preferred step rate once the injury is resolved. A long-term change in a runner’s preferred step rate may be warranted where a chronic running-related injury is being managed, or where the runner’s preferred step rate is considered by the clinician as being a factor for ongoing injury risk . It is wConsideration must also be given to baseline step rate before determining the appropriateness of implementing a change in step rate. Mean baseline values for step rate reported in studies within this review range from 160  to 172 sClinicians, coaches, and runners need to be mindful that any observed reduction in kinetic, kinematic or loading rate variables per step may be off-set by the increased number of steps taken per minute of running (up to 30% in some studies)—possibly leading to an equal or greater accumulation of loading over a set distance or time. Such consideration is important, as most running-related injuries are proposed to result from an accumulation of tissue load, rather than just the magnitude of each application of load. Of interest, one study has investigated the effects of running with a shortened step length (i.e. increased step rate) on patellofemoral kinetics with each step and over a set distance, finding that patellofemoral kinetics decreased by 15 to 20% with each step and decreased by 9 to 12% per kilometre . DespiteThe findings of this review need to be considered in the context of five key limitations. First, there is limited research on the effects of changes in step rate on injury and performance, which are likely to be the main motivators for changing running step rate among runners, clinicians and coaches. Second, as most studies included in this review investigated the immediate effects of changes in step rate, the longer-term effects remain largely unknown. Third, participants used in most studies were healthy (i.e. uninjured) and relatively young so it remains unclear if the biomechanical and performance effects may differ among injured and / or older runners. Fourth, we excluded studies that combined interventions with changes in running step rate. Importantly, changes in step rate may be accompanied by other running retraining strategies (e.g. change in footstrike) or interventions (e.g. change in footwear) in research and practice. Therefore, our findings may only apply in cases where changing step rate is the sole intervention. Fifth, data were not able to be extracted from some studies and were not provided upon request, which may have led to the omission of potentially relevant data in our results. Finally, we recognise that the association between injury and some of the biomechanical variables included in this review have not been fully established. In consideration of these shortcomings, it would be beneficial for future studies to investigate the immediate and longer-term effects of altered running step rate on biomechanical and performance variables known to, or proposed to be, associated with injury, or actual patient-focused outcomes and running performance.This systematic review highlights that increasing running step rate will, in general, either provide no change or reduce kinetic, kinematic and loading rate variables at the ankle, knee and hip—all common injury sites in runners. In contrast, no change or an increase in kinetic, kinematic and loading rate variables were generally observed when running step rate was reduced. At present there is insufficient evidence to conclusively determine the effects of altering running step rate on injury or performance. While research relating to the effect of changing running step rate on injury and performance appears to be scarce, it does suggest that increasing running step rate could be effective in reducing load through targeted tissues and therefore appropriate in certain injury presentations, such as patellofemoral pain. It also suggests that while increasing running step rate may not improve performance, if utilised as an intervention in the management of an injury, it is unlikely to have a detrimental effect on performance.


While intravenous human immunoglobulin therapy is potentially lifesaving for rare diseases, the significant costs associated with its usage warrant due attention. This study evaluated the costs and prescribing patterns of IVIg.This was a retrospective analysis of medical records in a tertiary hospital. The evidence category IIA and below, as well as strength of recommendations level B and below were classified as lower evidence category and lower strength of recommendation, respectively. Patients’ demographic data, indications, dosing regimen, physician specialty were retrieved from medical records, while the cost was derived based on total prescribed doses.p < 0.001).Out of 78 patients, more than half of the patients were prescribed with off-label IVIg based on MOHM Formulary , FDA indications  and EMA indications . 37 (47.4%) cases used IVIg for indications with lower evidence category and 52 (66.7%) cases with lower strength of recommendation. The total cost of IVIg use within the 2-year period was RM 695,426.36, with RM267,993.40 (38.5%) spent for indications with lower evidence category. Immunoglobulin use in rheumatology and neurology cases were associated with lower evidence category (A high proportion of off-label immunoglobulin use was observed. A timely update of prescribing policy, standardization of prescribing guidelines may promote appropriate immunoglobulin prescribing and justify expenses.The online version contains supplementary material available at 10.1186/s40545-022-00430-2. Intravenous immunoglobulin (IVIg) is a blood product derived from human donor blood that contains a mixture of antibodies (immunoglobulins) in the form of preparation for intravenous injection. IVIg was initially used as a treatment for immune deficiencies, and later for various autoimmune and inflammatory disorders. Currently, there are ten approved indications for the use of IVIg, as established by the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) , 2.Although manufacturing steps have been implemented to enhance the purity of the Immunoglobulin G molecules , its admIn year 2000, Chen and colleagues reported that 52% of the study subjects from twelve institutions were treated with IVIg for off-label indications. Notably, no positive clinical outcome was observed among 12% in the label group and 20% in the off-label group . Even th® (6 g of human protein IgG in 100 ml) and Flebogamma® (10 g of human protein IgG in 100 mL). were listed in the formulary. Currently, more than three-fourth of the local IVIg was supplied by the National Blood Centre, with a subsidized cost of RM 200 per vial, and an actual cost of RM 500 per vial.Within the local context, two brands of IVIg with the proprietary name of IntragramPrescribing of IVIg is primarily guided by the Ministry of Health Drug Formulary, but reference were rarely made to FDA, EMA, American Academy of Allergy, Asthma, and Immunology (AAAAI) evidence category and strength of recommendations for off-label use. There was a paucity of studies on the IVIg prescribing patterns and costs across different groups of patients and prescribers in Malaysia. Hence, this study aimed to evaluate the costs and prescribing patterns of IVIg in term of indications, off-label use, evidence level and strength of recommendation based on established guidelines.This was a retrospective study conducted by the Pharmacy Department of Hospital Taiping, Malaysia. In this study, consecutive sampling method was employed. All neonatal, paediatric and adult patients who received IVIg treatment between 1st January 2019 and 31st December 2020 were included. Patients with untraceable medical records were excluded.From the IVIg registry, a total of 91 patients prescribed with IVIg within the study period were identified. Patients’ demographic data, indications and dosing regimen of IVIg as well as physician specialty who prescribed IVIg were collected from the medical record office. The cost of IVIg was obtained from the supplier.The indications of IVIg were compared to the indications approved by MOHM , FDA 1]1] and EMp value of <0.05 denoted statistical significance.SPSS version 26  was used to perform all the statistical analyses. The cost and utilization of IVIg in accordance to evidence category and strength of recommendation were descriptively analyzed. The Chi Square test was used to determine the association between off-label use, indications and physician specialty with the evidence category and strength of recommendation. All statistical tests were two-tailed. A This study was registered in the National Medical Research Registry (NMRR-21-853-59575) and ethical approval for this study was obtained from the Medical Research and Ethics Committee (MREC), Ministry of Health Malaysia® was used in 76 cases, while Flebogamma® in two cases. Majority were female  and adult . The median treatment duration was 2 days and the median total IVIg dose administered per patient was 54.0 gram. More than half of the patients were prescribed with off-label IVIg based on MOHM Formulary , FDA indications  and EMA indications . There were 37 (47.4%) cases which used IVIg for indications with lower evidence category and 52 (66.7%) cases with lower strength of recommendation . Besides, IVIg prescribing by rheumatology  and neurology  were associated with lower evidence category (p < 0.001) as well as lower strength of recommendation (p < 0.001).Chi-square test was performed and it was found that IVIg use in systemic lupus erythematosus (SLE)  and neonatal jaundice secondary to isoimmunehaemolytic disease (IHD)  were associated with lower evidence category (n = 9), followed by SLE , severe refractory idiopathic thrombocytopenic purpura (ITP)  and Guillain–Barre syndrome  , followed by rheumatology , hematology , pediatrics , dermatology , medical  and intensive care unit (ICU) . Based on indications, myasthenia gravis reported the highest cost  ratio was not performed. This should be considered in future studies.The majority of IVIg in this study was prescribed for off-label use. A timely revision of IVIg use policy, as well as the establishment of a national IVIg prescribing guideline may provide standardization in its usage and encourage evidence-based prescribing of IVIg.Additional file 1: Table S1. IVIg approved indications based on MOHM, FDA, EMA and AAAAI evidence categories. Table S2. Definition on evidence category and strength of recommendation. Table S3. Total expenditures for indications in which evidence for its use was not established