Our purpose was to perform a systematic review to assess the prevalence of microvascular angina (MVA) among patients with stable symptoms in the absence of obstructive coronary artery disease (CAD). We performed a systematic review of the literature to group the prevalence of MVA, based on diagnostic pathways and modalities. We defined MVA using three definitions: (i) suspected MVA using non-invasive ischaemia tests; proportion of patients with non-obstructive CAD among patients with symptoms and a positive non-invasive ischaemia test result, (ii) suspected MVA using specific modalities for MVA; proportion of patients with evidence of impaired microvascular function among patients with symptoms and non-obstructive CAD, and (iii) definitive MVA; proportion of patients with positive ischaemia test results among patients with an objectified impaired microvascular dysfunction. We further examined the ratio of women-to-men for the different groups. Of the 4547 abstracts, 20 studies reported data on MVA prevalence. The median prevalence was 43% for suspected MVA using non-invasive ischaemia test, 28% for suspected MVA using specific modalities for MVA, and 30% for definitive MVA. Overall, more women were included in the studies reporting sex-specific data. The women-to-men ratio for included participants was 1.29. However, the average women-to-men ratio for the MVA cases was 2.50. In patients with stable symptoms of ischaemia in the absence of CAD, the prevalences of suspected and definitive MVA are substantial. The results of this study should warrant cardiologists to support, promote and facilitate the comprehensive evaluation of the coronary microcirculation for all patients with symptoms and non-obstructive CAD. Although the traditional cardiovascular risk factors are identified as important modifiable risk factors for this disorder, the underlying pathophysiological mechanisms remains to be elucidated.Patients with this so-called ‘microvascular angina’ (MVA) have an increased risk of major cardiovascular adverse events including cardiovascular mortality.,The diagnosis of MVA can be difficult. Different types of diagnostic modalities include non-invasive ischaemia testing or modalities to diagnose impaired microvascular function  or a combination of both.To our knowledge, no previous systematic reviews or systematic review have addressed the prevalence of MVA among patients with stable symptoms and documented non-obstructive CAD or a positive ischaemia test result. We performed a systematic review of the literature to group the prevalence of MVA, based on diagnostic pathways and modalities. Next, we compared how these groups conform with the recently introduced COVADIS categories.The definitions were based on three levels of information regarding diagnostic pathways and modalities including; presence of stable symptoms, non-obstructive CAD, and a non-invasive stress test result and/or (non)-invasive test result for microvascular dysfunction.Figure 1. Furthermore, no-obstruction, positive ischaemia test result, and impaired microvascular function were defined as per-individual paper (b).The following definitions were used: (i) suspected MVA using non-invasive ischaemia tests; proportion of patients with non-obstructive CAD among patients with symptoms and a positive non-invasive ischaemia tests, (ii) suspected MVA using specific modalities to diagnose MVA; proportion of patients with objective evidence of impaired microvascular function among patients with symptoms and non-obstructive CAD, and (iii) definitive MVA; proportion of patients with positive ischaemia tests among patients with an objectified impaired microvascular function. An overview of the definitions for different types of MVA and the corresponding formula for calculation of the prevalence of each type is depicted in Figure 1.As the primary aim of this study was to assess the prevalence of MVA, only studies fulfilling the following specific criteria for adequate study design and representative sample to retrieve prevalence data were included: (i) patients were consecutively enrolled in data registries or included in trials; (ii) number of participants ≥100. Additionally, per prevalence type, specific inclusion criteria were used regarding the study population. For prevalence of suspected MVA using non-invasive ischaemia tests, the study population needed to consist of patients with symptoms suggestive for CAD for whom a non-invasive stress test was performed and who were referred for computed tomography coronary angiography or invasive coronary angiography. For prevalence of suspected MVA using specific modalities to diagnose MVA, the study population needed to consist of patients with symptoms suggestive for CAD and without obstruction (using computed tomography coronary angiography or invasive coronary angiography) in whom additional (non)-invasive testing for microvascular dysfunction was performed. For the prevalence of definitive MVA, the population needed to consist of patients with symptoms suggestive of CAD, no-obstruction and evidence of impaired microvascular function. A flowchart visualizing the diagnostic pathways of the included studies and the study populations is depicted in Only original studies and studies published in the English language were considered.Studies assessing MVA in other clinical settings, including patients with known obstructive CAD or a history of obstructive CAD, defined as prior myocardial infarction, obstruction on angiography, or other cardiac morbidity were excluded. Furthermore, studies including patients with acute symptoms and/or acute coronary syndrome [myocardial infarction with non-obstructive coronary arteries (MINOCA)] were excluded . No further exclusion criteria based on symptoms were used. Studies including patients with angina-like symptoms, either typical or atypical symptoms were included. Also, no restrictions were made for the duration of the symptoms .Studies reporting data from the same study population were excluded. If study populations were overlapping, the study with the largest number of participants was included.Methods 1. Abstract and full-text screening was performed by two independent investigators. A PRISMA checklist and flow diagram are provided as Methods 2 and 3).We conducted a literature search using five electronic databases  from inception to May 2019 (date last searched). The search strategy for each database was designed by an experienced medical information specialist and consisted of terms for CAD, angiography, no-obstruction, and specific terms for the included invasive and non-invasive diagnostic modalities for diagnosis of MVA including non-invasive stress tests, acetylcholine coronary reactivity test, also called acetylcholine test, hyperaemic microvascular resistance, index of microcirculatory resistance, and TIMI frame count (TFC) and CFR measured invasive, or non-invasively by positron emission tomography, single-photon emission computed tomography, transthoracic Doppler echocardiography (TTDE), and myocardial contrast echocardiography. The full search strategy is provided as Data of the included studies were extracted independently by two investigators from the full papers. Any discrepancies between the investigators were resolved by consensus. The data retrieved included first author, publication year, study design, study population, baseline clinical characteristics, numbers, frequencies, percentages, prevalence, diagnostic modalities, definitions for a positive ischaemia test results, no-obstructive CAD, and impaired microvascular function, prognostic outcomes of patients among patients with MVA. If data were unclear or additional data were needed, authors were contacted by email. Due to expected high heterogeneity across individual studies, studies were grouped in pre-specified subgroups for analysis, including; diagnostic modality, study design , definitions used and sex.Of the 4547 abstracts retrieved by our search strategy, 20 studies reported data on the prevalence of MVA and were included in this study. The flowchart of the study selections is depicted in Three trialsTable 1).Higher percentages were observed for: (i) studies that were no-trials compared to trials , (ii) studies using invasive coronary angiography compared to computed tomography coronary angiography , (iii) studies using broader definitions of non-obstructive CAD compared to studies using the more widely used cut-off of <50% stenosis , and (iv) studies using exercise treadmill test compared to studies using other diagnostic modalities   and for invasive CFR count , lower prevalences were observed for studies using the acetylcholine test  and the TTDE .After stratifying for type of diagnostic modality, a more narrow range was observed for studies using TFC and TTDE CFR.Table 2).After grouping for study design, a higher prevalence was observed for trials compared to non-trials  , while the lowest prevalence was observed for studies using the acetylcholine test (median: 24%). However, studies using multiple non-invasive ischaemia tests reported the highest prevalences (median: 49%).Among the 11 studies reporting data for the prevalence of suspected MVA using specific modalities for MVA, 7 studies (2425 patients) reported data on clinical characteristics and cardiovascular risk factors for patients with MVA and patients without MVA.No large differences were observed for patients with MVA compared to patients without MVA regarding age (mean 62 vs. 60 years) and presence of diabetes (mean 16% vs. 15%).However, a larger proportion of patients with MVA had hypertension (61% for MVA patients compared to 56% for patients without MVA) and were non-current smokers (78% vs. 70%). The proportion of family history of cardiovascular disease was 45% among patients with MVA and 39% among patients without MVA.The frequency of hyperlipidaemia was 50% in both groups.Among the seven studies reporting sex-specific data, one study included more men (59%), five studies included more women , and one study included men and women approximately evenly. Overall, more women were included in the studies reporting sex-specific data; the women-to-men ratio for included participants was 1.29 (median 1.30).Of the studies reporting sex-specific data, three studies were trials and four studies were non-trials. Overall, the average women-to-men ratio was 1.51 (median 1.33) in trials vs. 1.13 in no-trials (median 1.21).The average women-to-men ratio for suspected MVA using specific modalities for MVA cases was 2.50 (median 3.29). All studies reported more female cases, independent of whether these studies had included more women  or not . In trials, a higher women-to-men ratio for cases (median: 4.24) was reported compared to non-trials (median: 2.11). However, all trials assessed microvascular spasm using the acetylcholine coronary reactivity test.n = 6) and only one study used TTDE CFR. No study using TFC in this study reported sex-specific data.Additionally, most studies that reported sex-specific data used the acetylcholine coronary reactivity test , a median prevalence of 28% for suspected MVA among patients with symptoms and no-obstruction  and a median prevalence of 30% for definitive MVA among patients with symptoms, no-obstruction and evidence of impaired microvascular function. Moreover, we also showed that prevalence of suspected MVA using non-invasive ischaemia tests, among patients with a positive ischaemia test result, varies depending on study design , type of stress test used, type of angiography (computed tomography coronary angiography vs. invasive coronary angiography) and the definition used for no-obstructive CAD. Similarly, the prevalence of suspected MVA using specific modalities for MVA, among patients with no-obstruction and symptoms, varied depending on the choice of diagnostic modality for assessing the microvasculature. Our median prevalence of 30% for definitive MVA underlines that a large proportion of patients who present with symptoms caused by MVA will remain undiagnosed if only non-invasive ischaemia testing is used for the diagnosis.,The median prevalence of suspected MVA using non-invasive ischaemia tests; the proportion of no-obstructive CAD among symptomatic patients with a positive ischaemia test result was 43%. A previous meta-analysis reported a high prevalence of 67% for no-obstructive CAD among patients with symptoms. However, regarding the prevalence of the latter study, it should be emphasized that not all patients who present with symptoms have MVA, as not all patients have had ischaemia tests prior to coronary angiography. In another clinical setting, among patients presenting with NSTEMI-ACS and myocardial infarction, only 13% [95% confidence interval (CI) 11–16%] and 6% (95% CI 5–7%), respectively were found to have no-obstructive CAD.et al.,et al. and our study represents data from specialized centres performing additional physiological testing for the assessment of MVA, and therefore included a selected population, large differences in prevalence are observed. The patient population in the report by Sara et al. were referred for clinical testing based on the physician’s decision (so not consecutively) and therefore represent a highly selected population. This is in contrast to the ACOVA study,In our study, the median prevalence of suspected MVA using specific modalities for MVA, the proportion of impaired microvascular functioning among patients with no-obstruction and symptoms was 28%. In the current study, we only included studies that had enrolled patients consecutively. A previous report by Sara ,The median prevalence of definitive MVA, the proportion of patients with positive ischaemia test result among patients with symptoms, no-obstruction and evidence of impaired microvascular function was 30%. A wide range for the prevalence of definitive MVA was observed due to use of different diagnostics modalities, number of tests performed and heterogeneity among study populations. Prior studies have shown that non-invasive ischaemia tests may not correlate with invasive microvascular function tests,,,,Regarding the interpretation of the prevalence of suspected and definitive MVA several factors need to be considered. First, as the international standardized criteria for MVA were published quite recently, various definitions for MVA and non-obstructive CAD were used in the individual studies. This might have led to both under- and overestimation of the true prevalence of MVA in the population. Second, our study focused on specifically MVA among symptomatic patients without coronary obstruction. However, MVA can also occur in other clinical settings,The recently published EAPCI Expert Consensus Document refers to the COVADIS criteria for the clinical diagnosis of MVA.Nevertheless, it should be noted that for the definite diagnosis of MVA in clinical practice, patients with a positive ischaemia test result and no-obstructive CAD should undergo provocative testing for a final diagnosis, as suggested by the more recently established EAPCI Expert Consensus Document.However, as these recommendations were published very recently, adherence of the included studies to these recommendations was not possible. As such, also the implementation of these recommendations in current clinical practice remains unknown.Our categorization is in line with both the COVADIS criteria and the more recently published EAPCI Expert Consensus Document, which similarly suggests use of non-invasive ischaemia tests for ischaemia and no obstructive coronary artery disease patients.Patients with MVA represent a heterogeneous group and several different pathological mechanisms are implicated in MVA. As various diagnostic modalities assess different aspects of MVA, assessment of one single underlying mechanism of MVA may not be sufficient to diagnose or rule out MVA. Moreover, the currently used non-invasive techniques were originally used to detect ischaemia in obstructive CAD and often do not seem sensitive enough to detect MVA, especially the vasospasm of the microvessels. Nevertheless, by performing an invasive assessment of the microvessels, a comprehensive assessment of multiple underlying mechanisms of MVA is possible, including vasodilatory capacity, coronary microspasm and impaired microvascular resistance. A recent study performing such assessment among a consecutive patient population showed indeed a higher prevalence of MVA (52%) among patients with symptoms and no-obstruction.Additionally, many studies have assessed CFR in only one vessel. However, it has been shown that microvascular dysfunction can be heterogeneous in the myocardium (patchy distribution).Although non-invasive and invasive diagnostic modalities are widely accepted and incorporated in the international standardized criteria, the gold standard to diagnose MVA and the accuracy of different non-invasive and invasive diagnostic modalities are still an area of ongoing debate. Due to the suboptimal diagnostic performance of the currently available diagnostic modalities to diagnose MVA, partly caused by the patchy distribution of microvascular disease, a considerable proportion of the patients with MVA might not be diagnosed as such.Furthermore, the use of different types of non-invasive stress tests, including exercise treadmill test, stress echo, and stress single-photon-emission computed tomography (SPECT), positron emission tomography (PET), and cardiac magnetic resonance imaging—with different test sensitivities—could lead to underdiagnosis and variation in the reported prevalences, as the prevalence is dependent on the performance of the diagnostic modalities used. The exercise treadmill test is known to have lower sensitivity compared to other imaging modalities including stress echo and stress SPECT, magnetic resonance imaging, and PET.,Overall, no large differences were observed for patients with MVA compared to patients without MVA regarding clinical characteristics. This suggests that other, as yet unidentified, risk factors could account for MVA. However, as these studies have included selected populations, the results might have been influenced by referral bias. Nevertheless, previous studies have also shown that traditional risk factors explain little of the variation of the measures of microvascular function.Although overall more women were included in the studies, leading to higher proportions of female cases, the women-to-men ratio was higher for cases with MVA compared to the total included population. This suggests that the prevalence of MVA is higher in women compared to men.only reason for the high women-to-men ratio in the included studies. However, trials included more women compared to no-trial studies. Also, in this systematic review, most studies assessed MVA using the acetylcholine coronary reactivity test. Therefore, sex differences seem partly related to both the type of MVA assessed and the referral pattern of patients.As prior meta-analyses have shown that no-obstruction is more prevalent in women compared to men, selection bias in favour of women might not be the ,While our results indicate that MVA might indeed be more prevalent in women, this may also be dependent on the type of MVA under study. However, no data were available to assess the women-to-men ratio in suspected MVA using non-invasive ischaemia tests and definitive MVA patients. Also, no data were available for MVA assessed by the TFC, as these studies were not eligible for inclusion in this study, while this could be more common among men. Moreover, as obstructive CAD is more prevalent among menIn this study, we observed substantially high prevalences for different types of MVA, based on diagnostic pathways and modalities. The majority of the studies only assessed one type of underlying mechanism of MVA. Importantly, it should be noted that, when the limitations of these diagnostic modalities  are taken into account, the prevalence may be even higher. Moreover, our results for definitive MVA also showed that diagnosis based on only non-invasive ischaemia tests will largely lead to an underdiagnosis of MVA patients. As such, our results suggest that a comprehensive (invasive) evaluation of different underlying mechanisms of MVA is needed to adequately diagnose or rule out MVA in these patients.This not only has implications for the diagnosis, but also for subsequent therapeutic strategies. In a recent randomized trial, treatment based on the underlying mechanism of MVA improved treatment outcomes including angina severity and quality of life.This all indicates that modification of the current diagnostic pathways and subsequent clinical care is required to adequately diagnose, manage and treat these substantially large number of patients. Notably, although sex differences were observed in our study, the proportion of men with MVA was also substantial. As such, MVA should also be considered and ruled out in symptomatic men with similar care as in women. However, possible differences in the underlying mechanisms of MVA for men compared to women should be taken into account.We used two approaches to assess the prevalence in two clinically relevant populations; (i) among patients with symptoms and a positive non-invasive ischaemia test result , and (ii) among patients with symptoms and no-obstructive CAD, where additional testing for impaired microvascular function was available .By using a broad definition including the prevalence’s of both suspected and definitive MVA in separate populations, our study provides a complete overview relevant for both community hospitals (e.g. suspected MVA using non-invasive ischaemia tests) and specialized centres .Although we aimed to include all published studies using a broad search strategy, we cannot exclude that we might have missed some studies. Second, due to the nature of this study, our results are dependent on the available published data and thus susceptible to publication bias and selection bias and restricted to heterogeneity between studies, including suboptimal definitions.et al.et al.While selection bias could affect both suspected and definitive MVA reported in our study, it may particularly be relevant for suspected MVA using specific modalities for MVA and definitive MVA. Although we only included studies that recruited patients in a consecutive manner, referral bias and selection bias might still exist. This could be more pertinent to the studies investigating the prevalence of suspected MVA using specific modalities for MVA and definitive MVA as these studies are performed in tertiary specialized centres performing additional physiological testing for the assessment of MVA and might therefore include a selected group of patients with the most severe symptoms. Selection of patients with most severe symptoms could have led to a twice as high prevalence compared to patient populations recruited consecutively as shown by the comparison of the studies by Sara Heterogeneity between studies included assessment of different types of underlying mechanisms of MVA, including endothelial-dependent and endothelial-independent mechanisms (i.e. microvascular spasm assessed by the acetylcholine coronary reactivity test and CFR) and inclusion of specific populations . This may have lead to over- and underestimation of the MVA in the overall population. Importantly, lack of uniform definitions for both no-obstructive CAD and MVA and the use of different definitions for these two conditions are another source of heterogeneity. As in this systematic review, we did not have access to patient-level data, we could not reclassify data at patient-level according to the recent COVADIS criteria. Diagnosis of suspected and definitive MVA requires a refined and extensive diagnostic strategy. The median prevalences of suspected and definitive MVA were derived from studies including patients who had undergone specific diagnostic pathways. As such, the median percentages reported in our study cannot be used to extrapolate these data to patients or populations who underwent different diagnostic pathways (i.e. patients with no-obstruction with no further patient-level data on the stress test performed and microvascular function). However, as the COVADIS criteria (which was first introduced the definition of suspected and definitive MVA) were published very recently, the patient-level information of NOCAD and MVA using the exact cut-off mentioned in the COVADIS criteria was not available in studies published earlier. Therefore, aggregated data based on the definition in each study were used. Nevertheless, different diagnostic pathways were not aggregated in one definition of MVA.Moreover, studies assessed only one type of MVA. Therefore, assessment of overlap between different underlying mechanisms was not possible.Finally, although the inclusion criteria was to have stable symptoms, it should be noted that some studies also included asymptomatic patients , which may have led to underestimation of the results. Furthermore, heterogeneity in the use of different types of non-invasive stress tests with different test sensitivities in various studies should be mentioned as a limitation, as the prevalence is dependent on the performance of the diagnostic modalities used.Our findings indicate that MVA is a common clinical problem among both the general and selected symptomatic patient populations. Although MVA is more prevalent among women compared to men, this might partly be related to referral patterns and the underlying mechanism of MVA.The results of this study should warrant cardiologists to support, promote and facilitate the routine and comprehensive evaluation of the coronary microcirculation for patients with symptoms and no-obstructive CAD. As a first step, routine invasive assessments immediately after coronary angiograms, including coronary reactivity tests, could be safely performed with low complications, for a comprehensive and adequate diagnosis of different underlying mechanisms of MVA.Cardiovascular Research online.cvab061_Supplementary_DataClick here for additional data file.


ECO is released into the public domain under a CC0 1.0 Universal license.The Evidence and Conclusion Ontology (ECO) is a community resource that provides an ontology of terms used to capture the type of evidence that supports biomedical annotations and assertions. Consistent capture of evidence information with ECO allows tracking of annotation provenance, establishment of quality control measures, and evidence-based data mining. ECO is in use by dozens of data repositories and resources with both specific and general areas of focus. ECO is continually being expanded and enhanced in response to user requests as well as our aim to adhere to community best-practices for ontology development. The ECO support team engages in multiple collaborations with other ontologies and annotating groups. Here we report on recent updates to the ECO ontology itself as well as associated resources that are available through this project. ECO project products are freely available for download from the project website ( Biocuration is the act of asserting that a particular piece of information is relevant to, or describes an aspect of, a biological entity . The docBiological annotations consist of at least three parts: the object about which information is being asserted (e.g. a protein), the aspect of the object to be asserted (e.g. a function), and the evidence that supports the assertion (e.g. evidence from an enzymatic assay). The documentation of evidence provides the scientific basis on which the assertion is built and is therefore a key component of the annotation Figure . Evidenchttps://evidenceontology.org/). Through the databases that employ ECO, thousands of individual users interact with, and benefit from, annotations using ECO  , DisProtO Figure . Here weO Figure used_in some automatic assertion.’ Under this structure, all leaf nodes in ECO are terms that combine a type of evidence and an assertion method and all evidence-type terms have both an automated and manual assertion type child term. Figure As described previously , ECO is https://github.com/evidenceontology/evidenceontology/issues) where users can submit requests for new terms or changes to existing terms. We also use this tracker to organize the ECO team's ongoing development efforts. Often we find that a request from a user will alert us to regions of the ontology that can use further refinement or development and we add this to our development queue. Described below are some of the more significant areas of term development since our last update on ECO (ECO is developed in the Web Ontology Language (OWL) using Protégé  for viewe on ECO .One of the newest users of ECO is the DisProt database . DisProthttps://www.psidev.info/groups/molecular-interactions)  of proteins from literature . Curatoractions) . In an eThe collaboration process involved DisProt curators proposing new term labels, definitions and parentage. ECO team members reviewed the suggestions and back-and-forth discussions between DisProt and ECO produced a final set of terms. The DisProt-ECO collaboration resulted in new terms in multiple branches of ECO. While many of the terms were in areas related to microscopy (e.g. ‘fluorescence microscopy evidence’ (ECO:0006271)), spectroscopy ), and crystallography ), there were also terms developed for experimental areas related to physical interactions ) and binding (e.g. ‘competitive binding evidence’ (ECO:0006264)). In fact, multiple new branches relevant for the IDP field were created all over ECO, e.g. ‘circular dichroism evidence’ (ECO:0006177) and ‘cryogenic electron microscopy evidence’ (ECO:0006181), with these new branches often including new child terms of their own. Additional new terms in the direct assay branch of experimental evidence include ‘selective antibody-based structural conformation evidence’ (ECO:0006194) and ‘heat capacity-based evidence’ (ECO:0006192). Of note, not only the experimental branch of ECO received new terms; the new term ‘author inference’ (ECO:0006185) was also created as a child term of ‘author statement’ (ECO:0000204) to better capture the nuances of the source of information used to make assertions. In total, 48 new ECO terms were created as part of the DisProt project. It is important to note that several of the newly created terms describe evidence from experimental techniques widely used in several other fields of biology apart from IDP research and therefore will be of broad utility. Furthermore, investigation of ECO for the creation of the DisProt terms revealed the need for revisions to some existing ECO terms and relationships thus improving ECO as a whole. We look forward to continued collaboration with the DisProt team as they continue their work and identify needs for additional evidence terms.In response to a variety of requests by users, we have reorganized some of the first-level children of ‘evidence’, one of the two root nodes of ECO Figure .A previous first-level child term ‘author statement’ (ECO:0000204) was moved under a newly created first-level child term called ‘documented statement evidence’ (ECO:0006151). The new term has additional child terms for statements from individuals such as ‘medical practitioner statement evidence’ (ECO:0006152) and ‘self-reported patient statement evidence’ (ECO:0006154).Another new first-level child of ‘evidence’ is ‘computational evidence’ (ECO:0007672). This term was created in part to meet the needs for generation of terms involving combinatorial evidence and in part to be the counterpart of ‘experimental evidence’. We are still in the process of identifying ECO terms that should be children of ‘computational evidence’. Towards that goal, we have added ‘computational evidence’ parentage to the ‘sequence similarity evidence’ (ECO:0000044) branch.genomic context evidence’ (ECO:0000177) was previously a first-level child of ‘evidence’. We have recategorized that branch as a child of ‘similarity evidence’ (ECO:0000041). Our review of the terms under ‘genomic context evidence’ indicated that they involved comparing one thing to a related thing in some way, generally involving similarity of function, content, sequence or some combination of those.The term ‘Part of our continued development of ECO involves inspecting the ontology for terms or branches that are redundant, confusing, or misplaced. Here we describe two selected examples of areas where changes were made.Previously, there were terms representing types of evidence related to mutant phenotypes that were not children of ‘mutant phenotype evidence’ (ECO:0000015), but were instead located in other areas. This prompted a review of all terms related to mutant phenotypes. Terms were collected and reviewed, and then revised and rehomed, as appropriate, under ‘mutant phenotype evidence’.The term ‘protein assay evidence’ (ECO:0000039) was a grouping term that had many child terms with second parents in other parts of ECO. Those second parents provided more meaningful information about the type of evidence involved. The ‘protein assay evidence’ term was vaguely defined and allowed the grouping of any type of evidence in which a protein was involved, often grouping terms from very different evidence contexts, for example ‘enzymatic activity assay evidence’ (ECO:0000005) and ‘immunoprecipitation evidence’ (ECO:0000085). The term ‘protein assay evidence’ was deprecated. Any children that didn’t already have second parents were rehomed.We continue to receive requests for new terms and other term-related changes from groups with whom we have collaborated for many years. Examples of the groups for which we’ve added multiple terms since our last ECO update  are: theIn addition to the ontology itself, the ECO project has produced additional resources of help to users and developers. These include mapping files and annotated datasets. This section describes recent efforts in this area.Gene Ontology (GO) evidence codes  were a sgaf-eco-mappings.txt - This file provides mappings of GO evidence codes, or particular combinations of GO evidence codes and ‘GO_references’ (citable abstracts describing scientific methods), to ECO term ids. These are meant to be equivalence mappings.gaf-eco-mapping-derived.txt - This file provides mappings of the more granular ECO terms to the GO evidence codes. This file allows anyone who uses the full ECO vocabulary to be able to convert their evidence information to a format required by the GO and associated tools.Previously, the gaf-eco-mapping-derived.txt file was generated automatically by traversing the ECO graph to collect all descendent terms for each of the ECO terms in the equivalence mappings in the gaf-eco-mappings.txt file. However, we have found that as we continue to develop ECO, some of the more granular ECO terms have been positioned in the ontology such that they are no longer descendants of the same high-level ECO terms from the ECO-GO-evidence-code equivalence pairs. This is indicative of the fact that in some situations, GO groups evidence types under one evidence code that are located in different branches within ECO. This occasionally resulted in granular native ECO annotations mapping to the incorrect GO evidence code.To address this challenge, we have changed the way we generate the gaf-eco-mappings-derived.txt file to allow more flexibility and provide for curation of mappings at the level of every ECO term. This was accomplished through the addition of the ‘has GO evidence code’ annotation property field for ECO terms. To provide initial values for this field for existing terms, we used the last automatically generated version of the gaf-eco-mappings-derived.txt file. Moving forward, populating this field for new ECO terms will be a required part of the term-creation process. All new versions of the gaf-eco-mappings-derived.txt file will now be generated from the values associated with each term in the ontology. This gives us the freedom to move granular terms around to fit the design patterns of ECO, while still retaining the ability to provide correct mappings for GO users by curation of the ‘has GO evidence code’ field. The shift to the new process for generating the gaf-eco-mappings-derived.txt file started as of the September 2021 ECO release.http://ceur-ws.org/Vol-2807/paperF.pdf).The CollecTF data resource captures information about bacterial transcription factors, the DNA sequences they target, and the genes they regulate through curation of published experimental results. These annotations are integrated into resources such as UniProt and the GO annotation repository . As desc). At the request of an ECO user, we created a mapping between ECO and the SRI system. There are 48 terms in the SRI evidence vocabulary as of September 2021. We mapped these to 27 unique ECO terms. During the process of creating the mappings, we identified several specific SRI terms for which there was no correspondingly granular ECO term. These are being explored as areas for potential ECO term expansion. The ECO-SRI mapping file is available from the ECO website (https://evidenceontology.org/annotation_resources/) and GitHub (https://github.com/evidenceontology/evidenceontology/blob/master/sri_eco_mappings.tsv).SRI International (formerly Stanford Research Institute) maintains an evidence vocabulary used for their work . At the https://evidenceontology.org/.Since our last ECO update publication  we have https://evidenceontology.org/) and GitHub (https://github.com/evidenceontology/evidenceontology). ECO is released into the public domain under a CC0 1.0 Universal license.New releases of ECO are made on a generally monthly schedule. ECO is completely freely available and is accessible through the ECO website . PED is a deposition database of structural ensembles of intrinsically disordered proteins (IDPs). PED aims to capture the structural range that an IDP may encompass through the curation of representative sets of conformers that reflect the structural dynamics of a given IDP . Like Dihttps://www.nist.gov/system/files/documents/2019/05/30/nist-ai-rfi-cubrc_inc_002.pdf) ECO terms with an initial focus on the terms that currently have dual parentage. Per community guidelines for best-practices in ontology development (_002.pdf), it is bhttps://github.com/evidenceontology/) and the project's website (http://evidenceontology.org/). ECO is released into the public domain under a CC0 1.0 Universal license.ECO is freely available from GitHub (


Psychological factors may impact recovery in patients undergoing treatment for shoulder complaints. The aim of this review is to systematically analyse the evidence for the effect of modifiable psychological factors (MPF) on outcome, for patients with musculoskeletal shoulder disorders undergoing conservative or surgical treatment. MPF refers to factors that may change with intervention.This is a systematic literature review. Five databases searched , for longitudinal studies investigating the influence of MPF on prognosis of patients with shoulder disorders, all diagnoses, undergoing clinical interventions . Level of evidence was determined using Scottish Intercollegiate Guidelines Network (SIGN) methodology. Moderate and high quality evidence was included. We extracted all MPF, categorized constructs into the following domains: beliefs , coping , and affect . We evaluated constructs for its predictive value of at least one outcome. Outcomes were informed by this review. Evidence was classified into three categories: evidence for, inconclusive evidence, and evidence against.Of 1170 references, 40 distinct publications based on 35 datasets were included . Overall, 22 studies (20 cohort studies and 2 RCTs) were classified as high quality and 18 studies  were classified as moderate quality. Outcomes reported included pain, disability/function, perceived recovery, physical and mental health, and work status. Based on the review, of the psychological constructs explored, these data would suggest that expectation of recovery, catastrophizing, avoidant coping, depression, and anxiety may predict outcome for patients managed surgically. In patients undergoing conservative intervention the evidence was either against  or inconclusive  for the predictive value of psychological factors on outcome.Five constructs were predictive of outcome for surgically managed patients. This suggests that implementing the biopsychosocial approach  may be advantageous for patients recommended for shoulder surgery,,. The same is not indicated for conservatively managed patients as no conclusive association of MPF with outcomes was noted. The importance of other MPF on outcome requires further investigation. Shoulder conditions are the third most common musculoskeletal complaint , 2. Only. Conversely, self-efficacy and positive expectation of recovery are coping resources that have been associated with better functional outcomes in patients with musculoskeletal disorders , two (40%) conservative [two high quality]) catastrophizing predicted at least one outcome. Therefore, based on this review, catastrophizing in surgical cases fell into Category 1, evidence for, while for conservative cases it was Category 3, evidence against.Avoidant coping as a predictor of outcome was explored in eleven publications . In seven publications (four (80%) surgical [three high quality], three (50%) conservative [two high quality]) avoidant coping/fear avoidance predicted at least one outcome. Therefore, based on this review, avoidant coping/fear avoidance in surgical cases fell into Category 1, evidence for, while for conservative cases it was Category 2, inconclusive.Depression as a predictor of outcome was explored in 27 publications . In 14 publications (nine (60%) surgical [four high quality], four (33%) conservative [three high quality]) depression predicted at least one outcome. Therefore, based on this review, evidence for depression in surgical cases fell into Category 1, evidence for, while for conservative cases it was Category 3, evidence against.Anxiety as a predictor of outcome was explored in 16 publications . In eight publications (six (67%) surgical [three high quality], two (29%) conservative [two high quality]) anxiety predicted at least one outcome. Therefore, based on this review, evidence for anxiety as a predictor in surgical cases fell into Category 1, evidence for, while for conservative cases it was Category 3, evidence against.Self-efficacy as a predictor of outcome was explored in two publications . In one publication (50%) self-efficacy predicted at least one outcome. Therefore, based on this review, evidence for self-efficacy as a predictor in conservative cases fell into Category 2, inconclusive evidence.Expectation of recovery as a predictor of outcome was explored in eight publications . In five publications (two (100%) surgical [one high quality], three (50%) conservatives [three high quality]) expectation of recovery predicted at least one outcome. Therefore, based on this review, evidence for expectation of recovery as a predictor in surgical cases fell into Category 1, evidence for, while for conservative cases it was Category 2, inconclusive evidence.In this study we explored the relationship between MPF and outcomes in patients with shoulder disorders, within the context of management  and temporal framework (time from onset). The main finding of this review is that psychological factors affect recovery in patients with shoulder pain managed surgically. However, MPF was not associated with outcome in patients receiving conservative care for shoulder disorders, regardless of duration of pain. This suggests that type of clinical management and time from onset are critically important variables to consider when defining the prognostic value of MPF on outcome in patients with MSD.Previous systematic reviews , 18, 22 We classified studies based on conservative and surgical intervention and all diagnostic phases from acute through chronic. Furthermore, we did not predefine psychological factors or outcomes but rather extracted from the reviewed studies. In addition, we applied no language or publication timeframe restrictions in our search allowing for a broad body of literature from which this topic could be explored. Defining and focusing specifically on psychological factors that are modifiable is relevant as these factors are responsive to short-term intervention, as opposed to more refractory psychiatric diagnoses that are more difficult to manage . For theIn this review six distinct MPF were identified. However, for most of these factors, few studies have explored their relationship with outcome and not all were graded as high quality. For the purpose of this review, our conclusion regarding the effect of each factor on outcome was based on the preponderance of the included references. However, it should be noted that very small numbers of studies or nearly equivocal numbers of studies supporting or refuting the findings were used to determine our conclusions. This was particularly true in the review of those studies on conservatively managed cases.This can be highlighted by examining the findings for individual MPF. Depression was the most widely studied construct with 27 studies  management. In the case of conservative management, four predicted outcome and eight did not, a clear conclusion. In the case of surgical management, nine predicted and six did not, also a clear finding. In contrast, self-efficacy was far less studied with only two studies for conservatively managed cases and none for surgical. In one study self-efficacy predicted outcome and in one it did not, and therefore the conclusion must be weighed carefully. Therefore, it is important to consider the total number of studies reviewed when interpreting the relationships between each individual MPF and outcome . When interpreting the findings, it is important to recognize that typically surgical intervention occurs during the chronic phase, after failed conservative management often recommended during earlier phases . TherefoIn the case of conservative intervention, it is difficult to draw conclusions regarding the temporal impact of MPF on outcome. This is because among those studies that did report time from onset, the findings were either inconclusive or against the predictive value of MPF on outcome. Therefore, we believe time from onset deserves further study in this group.Many included studies were small and may therefore not have sufficient power to capture a clinically relevant influence of the subgroups we have defined for this review. None of the included studies investigated all predefined constructs and therefore the full impact of these variables cannot be completely described. In addition, not all MPF were equally explored. Furthermore, some psychological constructs are complex, such as catastrophizing, which may be considered a belief or a coping strategy. For example, two studies that used the Pain Coping Scale designated catastrophizing as a coping strategy , 50. YetThere is mention of the importance of assessing psychological factors in clinical practice guidelines for managing shoulder pain . HoweverOne consideration is the relationship between psychological factors and the natural history/tissue healing associated with various musculoskeletal conditions. For instance, in patients with low back pain, fear of pain is a strong predictor of outcome , 76. TheBased on this review, expectation of recovery, catastrophizing, avoidant coping style, depression, and anxiety were the MPF most predictive of outcome in surgically managed patients with shoulder complaints. This provides sufficient evidence to suggest that implementing a biopsychosocial care paradigm to this population may be advantageous. In patients undergoing conservative intervention the evidence was either against  or inconclusive  for the predictive value of psychological factors on outcome. However, future high-quality comparative investigations and those assessing understudied constructs may shed more light on the prognostic value of MPF on outcome in this population. There is clearly a place for the study of psychological factors associated with shoulder disorders. Further investigation of all psychological factors may provide deeper insight into understanding patients with shoulder MSD, and best approaches to clinical management.


Recent publications reveal shortcomings in evidence review and summarization methods for patient decision aids. In the large-scale “Share to Care (S2C)” Shared Decision Making (SDM) project at the University Hospital Kiel, Germany, one of 4 SDM interventions was to develop up to 80 decision aids for patients. Best available evidence on the treatments’ impact on patient-relevant outcomes was systematically appraised to feed this information into the decision aids. Aims of this paper were to (1) describe how PtDAs are developed and how S2C evidence reviews for each PtDA are conducted, (2) appraise the quality of the best available evidence identified and (3) identify challenges associated with identified evidence.The quality of the identified evidence was assessed based on GRADE quality criteria and categorized into high-, moderate-, low-, very low-quality evidence. Evidence appraisal was conducted across all outcomes assessed in an evidence review and for specific groups of outcomes, namely mortality, morbidity, quality of life, and treatment harms. Challenges in evidence interpretation and summarization resulting from the characteristics of decision aids and the type and quality of evidence are identified and discussed.Evidence reviews assessed on average 25 systematic reviews/guidelines/studies and took about 3 months to be completed. Despite rigorous review processes, nearly 70% of outcome-specific information derived for decision aids was based on low-quality and mostly on non-directly comparative evidence. Evidence on quality of life and harms was often not provided or not in sufficient form/detail. Challenges in evidence interpretation for use in decision aids resulted from, e.g., a lack of directly comparative evidence or the existence of very heterogeneous evidence for the diverse treatments being compared.Evidence reviews in this project were carefully conducted and summarized. However, the evidence identified for our decision aids was indeed a “scattered landscape” and often poor quality. Facing a high prevalence of low-quality, non-directly comparative evidence for treatment alternatives doesn’t mean it is not necessary to choose an evidence-based approach to inform patients. While there is an urgent need for high quality comparative trials, best available evidence nevertheless has to be appraised and transparently communicated to patients.The online version contains supplementary material available at 10.1186/s12911-022-01777-x. German legislation with the Patients’ Rights Act in 2013 as well as recent trends to involve patients more actively at a micro health care level imply that physicians and patients should follow Shared Decision Making (SDM) communication rules in preference-sensitive treatment situations , 5, PtDAThis publication results from the “Share to Care (S2C)” project conducted at the University Hospital Medical Center Schleswig Holstein (UKSH), Campus Kiel, in Germany from 2017 to 2021 [In this paper we describe the second component of this large scale SDM-project and how it was “filled with life” in some more detail: the development of PtDAs to support patient decision making, provide evidence-based information on the pros and cons of treatment alternatives to patients and facilitate better SDM communication between physician and patient including the exchange of experiences, values and preferences.In our PtDA development process, the International Patient Decision Aids Standards (IPDAS) –10 were In this paper, our aims were to (1) describe how evidence-based PtDAs are developed and how S2C evidence reviews for each PtDA are conducted in this large SDM implementation project (2) appraise the quality of the best available evidence identified in S2C evidence reviews for 71 PtDAs and (3) identify challenges associated with the identified evidence.Each PtDA followed the same development process, which is depicted in this section. This process was developed in the first 6–8 months of the S2C project time. It closely adheres to the IPDAS criteria  aiming aTo better understand for which types of PtDAs S2C evidence reviews were conducted, we describe the baseline characteristics of so far completed PtDAs in the S2C project (n = 71). Firstly, we assessed the type of treatment alternatives compared in the PtDAs including surgeries, non-drug interventions, drug treatments or a do-nothing alternative. Secondly, we addressed whether a real do-nothing alternative was included or an extended do-nothing alternative like, e.g., continue with treatment as before, chose best supportive/palliative care, or watchful waiting. Thirdly, we summarized how often we could use existing evidence reviews as primary source of evidence instead of doing a de novo systematic review. In specific, we accepted reviews that were conducted, e.g., for the development of evidence and consensus-based German treatment guidelines, which apply sound review methods and define treatment standards for physicians in Germany.Finally, we describe features of the 71 completed evidence reviews such as average time needed to conduct such a review, average number of references reviewed and average number of times additional data analyses or searches were conducted since data from identified evidence was incomplete or insufficient.Mostly high-/moderate-quality evidence identified high confidence in findings. This category was chosen if primarily systematic reviews/meta-analyses of good quality RCTs or several such RCTs were identified to be sufficiently reliable to be used as primary data source.Some fair amount of higher-quality evidence identified but also lower quality moderate confidence in findings. This category was chosen if systematic reviews/meta-analyses of other well-done studies were identified or/and one or several RCTs that appeared sufficiently reliableMostly lower-quality evidence identified low confidence in findings. This category was chosen if mostly non-synthesized, non-RCT evidence was identified or data from one or more systematic reviews of lower quality studies or RCT(s) with limitations.Mostly very low-quality evidence identified very low confidence in findings; information mostly based on very low-quality studies, expert opinion, or physician advice, or, e.g., only a consensus-based guideline was available.We critically appraised the quality of the best available evidence used in the 71 PtDAs. We did Cochrane risk of bias assessments and applied the GRADE approach to rate the certainty of the body of evidence , 17. TheApart from the overall quality appraisal of each evidence review, we also appraised the quality of the evidence supporting outcome-specific information. Finally, we specified whether the quality of evidence facilitated quantitative or qualitative statements to be included in the PtDA.While our evidence reviews followed standard processes, the identified evidence posed a number of challenges to us throughout the course of the project. We summarized these challenges to increase understanding of the issues that may arise from communicating best available evidence to patients.71 online PtDAs have been developed so far  were entirely based on an already existing high-quality evidence review, e.g., from German evidence- and consensus-based clinical practice guideline. For the majority of PtDAs , a de-novo review or an update review was conducted. 4% of the 71 PtDAs were based on low-quality consensus-guidelines in combination with expert opinion or non-systematic clinical reviews due to a lack of available higher quality evidence sources.On average, each of the S2C reviews took about 12 weeks to be completed. Each evidence review resulted in an evidence report attached to the PtDA. De-novo reports included on average about 25 references (ranging from 5 to 50 references), including guidelines, systematic reviews/meta-analyses and primary studies.In about 10% of S2C evidence reviews pooled effect estimates were not readily available from the identified evidence but were self-calculated. In another 10% of S2C reviews, absolute numbers were not reported in studies/reviews but self-calculated. For example, these calculations were conducted by using baseline risks for one (control/comparison) group and applying risk ratios for the other group(s) to these baseline rates  ). FinallWe appraised the quality of evidence in all evidence-reviews. Main results are displayed in Fig. Based on the categories of evidence quality, about 30% of the 71 PtDAs were based primarily on overall high- or moderate-quality evidence. The majority were based on lower quality evidence. Of those based on high- or moderate-quality evidence about 1/3 were comparisons between drug treatments. Even if evidence was based on RCTs, about 40% of these were downgraded due to, e.g., certain risks of bias, indirectness or inconsistency.The quality of evidence differed considerably for the different FAQs. 61 of the 71 PtDAs (86%) addressed morbidity-related outcomes, followed by 53 PtDAs (75%) addressing HRQoL and 33 (46%) addressing mortality/survival Table . OutcomeWhile more than 60% of the evidence for side effects (resulting mostly from drug treatments) was moderate or high, mostly low-quality evidence was identified for complications following non-drug interventions/surgeries Table .When transferring the evidence on effectiveness or harm outcomes to PtDAs, most of the information (about 70–80%) based on high or moderate level evidence could be quantified. For the remaining ones, no quantification was possible. This was often due to data being not or inconsistently reported. While for different HRQoL instruments between-group differences in specific scores were reported, these were often difficult to interpret. This primarily resulted from differing underlying HRQoL instruments/scales and a lack of information and analyses regarding whether the reported differences—even if statistically significant—were clinically meaningful or could somehow be used to define response criteria.For effectiveness outcomes, between-group effects from direct comparative studies were available for at least half of PtDAs . For harms outcomes, between-group effects from direct comparative studies were available for about 20% of PtDAs . Due to the variety of included alternatives in PtDAs most of the data for treatment alternatives, however, originated from indirect comparisons.Challenges are summarized in Table This assessment of the evidence base of 71 decision aids for patients treated in a large University Hospital indicates that nearly 70% were—despite conducting a systematic and comprehensive literature review for each topic—based on rather low-quality and indirect evidence. Nevertheless, we consistently provided best available respective information to patients in our PtDAs.Preference-sensitive decisions in a hospital involve very diverse treatment options. Best available evidence for these was often limited to non-RCT, non-directly comparative and likely biased studies. Also, while offering a do-nothing or wait-and-see alternative is recommended by IPDAS , this moAbout 30% of PtDAs were developed based on moderate or high-quality evidence. For mortality/survival outcomes, more than half was based on moderate to high quality, which likely will increase patients’ confidence in these highly patient-relevant findings. However, even RCT-based reviews or RCTs did not seem to be a guarantee for consistently high-quality evidence. RCTs frequently were downgraded due to biases like lack of blinding, the latter being most often an issue in RCTs comparing surgeries or surgeries to other non-drug interventions. In addition, RCTs often insufficiently reported on specific outcomes, especially HRQoL or harms, or used heterogeneous instruments/scales for outcome measurement, which complicated data interpretation and comparison across treatments.On average, the quality of evidence in our reviews was lower than that reported in a recent assessment of Cochrane reviews by Howick et al. 2020 . The latSeveral recent reviews of published PtDAs suggest a lack of well documented evidence review and summarization processes , 12, 24.Best ways of providing balanced information to patients—especially if based on low quality evidence—nevertheless is and will remain an area for research in many respects –27.A major strength of our project is the IPDAS-compliant PtDA development with sound evidence review and summarization in combination with the size of the S2C project involving development of 71 decision aids. The latter facilitated to move to a more standardized approach to deal with the challenges summarized in Table A limitation may be that in this study we assessed results of our own S2C evidence reviews. However, since evidence reviews were conducted by independent external evidence review groups  based on the highest standards of evidence-based Medicine, we do not consider our assessment of the results being at high risk of bias. A major limitation of the S2C project itself, however, might be the development of PtDAs exclusively for a tertiary University hospital setting, which likely resulted in highly selected topics, mostly involving comparisons between surgeries or non-drug interventions. However, the hospital setting in Germany appears to be least familiar with SDM communication and treatment rules and therefore is in need of interventions such as the S2C program, which might have led to state funding of our project in Germany .A real do-nothing alternative was usually not considered an option in this hospital setting. This setting likely explains many of the encountered challenges regarding low-quality—often non-RCT evidence—and the need for indirect comparison across treatments. A recent review of RCTs in surgery by Robinson et al.  concludeHigh standards for evidence review and summarization as part of PtDA development will likely make PtDAs more trustworthy and acceptable to patients and physicians. Evidence reviews and summarization in this project were carefully conducted. However, the evidence identified for our decision aids was indeed a “scattered landscape” and often of poor quality. Facing a high prevalence of low-quality, non-directly comparative evidence for treatment alternatives doesn’t mean it is not necessary to choose an evidence-based approach to inform patients. The experience from this large-scale PtDA development project shows: There is an urgent need for high quality comparative trials in many fields, however, in the meantime best available evidence has to be appraised and transparently communicated to patients in best possible ways.Additional file 1. List of patient decision aid topics in the Share to Care (S2C) project.


Different parameters, such as micellar and the mixed monolayer component composition, the interaction parameters of the solution and the interface, the activity coefficients of the components in solution and at the interface, and thermodynamic parameters, are computed using different proposed theoretical models . The cmc values obtained for the pure components and mixtures (IMP + BZCl) of all the compositions are found to be less in NaCl than in the aqueous solution while found more in the presence of U or TU. TU is more effective in increasing the cmc of the pure and mixed systems than U. The Gibbs free energy The effect of various media  and thiourea (TU)) on the micellization and adsorption activity of varied mixtures of imipramine hydrochloride (IMP) and benzethonium chloride (BZCl) is investigated via tensiometry. In an aqueous medium, the interactions between IMP and BZCl are also evaluated using UV–visible and FTIR spectroscopy. The interaction between components increases with increased mole fraction ( The obtained value of K is further used to determine the free energy change The plot of 1/ .3.22ΔG=G value obtained for the IMP + BZCl mixed system is negative (−19.4 kJ mol−1), which confirms the spontaneity of the complexation process. This may be caused by a reduction in self-electrostatic repulsion among the cationic head group molecules, which shows preferential binding between components. At 0.1 α1 of BZCl, the value of −1 showing the micellization process was more spontaneous as compared with the complexation process.The Δ. 4cmc and cmcid shows non-ideal behaviour, indicating the presence of attractive interactions and synergism between the components. In NaCl media, the cmc of pure components and mixtures decreases compared with the aqueous system, and in U or TU media, the cmc values increase compared with the aqueous solution. Between U and TU, TU is more effective in increasing the cmc of the system. The α1 of BZCl except α1 = 0.9, revealing the higher BZCl contribution in the mixed micelles. The negative values of βm and σβ showed the attractive interactions among components in mixed micelles and the mixed monolayers, respectively. The activity coefficients of both components in solution and at the surface were found to be less than 1, showing the non-ideal behaviour and interaction between components. The Γmax value for IMP is found lower than BZCl, implying that BZCl has an additional surface active than IMP. In all media, the pC20 value for BZCl is higher than IMP, revealing that the BZCl has more surface adsorption efficiency as compared with IMP. The α1; however, Before, establishing a surfactant as a suitable drug vehicle, a broad investigation must be completed to inspect and understand the aggregation behaviours of the surfactant with the projected drug. Herein, the mixed micellization behaviour of the IMP drug and BZCl surfactant mixed system in aqueous and other media is investigated via the tensiometry technique. The relationship between Click here for additional data file.


This narrative review presents recent developments in virtual reality (VR)-based interventions for alcohol use disorders (AUDs). The latest advances in mental healthcare hail an imminent cyber revolution, ushering in novel treatment options, with immersive virtual technology at the very forefront of expected change. With an aim to (a) provide a background on VR use in mental healthcare of AUD patients, (b) summarize existing evidence on conventional approaches to the treatment of AUDs and a trending paradigm shift towards VR applications in their management, and (c) describe key issues and future directions in research on craving assessment and VR cue-induced therapy in AUDs, a search for experimental and meta-analytic evidence was performed in six databases: PubMed and EBSCO . Pooled results were screened for eligibility, and relevant papers were selected for inclusion. The analysis revealed VR’s promising effects in the treatment of AUDs. Its remarkable potential to simulate cues underlying subsequent addictive behaviors makes its application in the assessment and treatment of AUDs an attractive alternative to researchers and clinicians alike. Nevertheless, more evidence is needed before virtual reality cue exposure therapy (VR-CET) can become a clinical standard of care. The latest developments in mental healthcare seem to hail a fast-approaching cyber revolution, giving rise to novel opportunities within existing treatment options, with immersive virtual technology at the very forefront of expected change. As a powerful tool enhancing learning and behavior modification, virtual reality (VR) shows definite promise as an add-on to conventional clinical management of an entire array of mental health problems ,2,3. A cDating back to the 1980s, applications of basic VR hardware were mostly restricted to laboratory settings  and, priThrough high-fidelity simulations of real-time experience-delivered images, sounds, and other sensations imitating a user’s physical presence in a thus augmented or extended reality, VR technology is designed to mimic real-world settings . IncorpoRestrictions linked to staging lifelike settings, however, clearly reduce the scope of interventions offered to patients in standard clinical conditions. Stripped of such limitations, VR shows promise in creating true-to-life simulations of such difficult situations, in which patients can be monitored and navigated to develop more appropriate and healthy responses in an individual, tailor-made, non-threatening, and repeated fashion, depending on the particular type of deficits they are manifesting. The idea behind such a lifelike approach, albeit extending beyond what is feasible in a traditional lab setting, is that the less threatening, easier to manipulate, repeated, and controlled VR conditions enable learning that will be easily transferable into the real-world experience of patients. For even though the reality is “fake”, the elicited mental and physical responses, much like all acquired skills and psychological resources, are not. Clearly, however, if the exposure conditions can be well-controlled and easily manipulated, full VR potential will be apparent not only in improving treatment strategies, but also assessment, diagnosis, and evidence-based capturing of the underpinnings of mental health disorders .Indeed, the past few decades have brought evidence of VR efficacy in the management of a wide range of psychiatric conditions, proving a successful solution for anxiety disorders, depression, psychosis, and eating and substance use disorders ,5, with Exposure therapies involving VR technology are also quite extensively used in the treatment of problematic behaviors, i.e., drug misuse, alcohol dependence, or pathological gambling. The majority of the available evidence demonstrates the virtual environment’s great capacity to induce cravings, amongst others, for alcohol , cocaineGiven VR’s remarkable potential to simulate cues that trigger cravings responsible for subsequent addictive behaviors, its application in the management of substance use disorders seems to attract growing attention of both researchers and clinicians alike. In this review, we summarize the current knowledge on craving assessment and cue-induced therapy in the mental health sector, with a particular focus on alcohol use disorders (AUDs), using VR technologies. To this end, pooled literature search results screened for eligibility and relevant for inclusion in this review were analyzed to meet the following specific aims: (a) to provide a background on VR use in mental healthcare for adults with AUD, (b) to summarize the existing body of evidence on conventional approaches to the treatment of alcohol use disorders and a trending paradigm shift towards VR applications in the management thereof, and (c) to describe key issues and future directions in research on craving assessment and cue-induced therapy in AUDs using virtual, augmented, or extended reality technologies.A literature search was conducted based on Ferrari’s  suggestiTwo researchers (Z.L. and E.T.) independently screened records to be included. Any discrepancies were resolved by consensus. Search results were screened for eligibility first by title and abstract, then by full-text review. Reasons for exclusion were recorded for each excluded study. In addition, we performed a manual search of the references of articles selected for inclusion in this paper.A total of 548 studies were identified from the literature searches (310 in EBSCO and 238 in PubMed). After excluding duplicates, 241 studies were identified and 50 papers were selected for further screening. Finally, 29 articles  were included and analyzed in this narrative review.As a major public health issue of increasing global importance, substance use disorders (SUDs) generate substantial health consequences alongside significant social and economic burden to both individuals and societies worldwide. SUDs remain difficult to treat, their relapse rates reaching an average of 50% despite the use of available treatment . A partiEven though the major addictive compound in AUDs is very well-known and has been studied from both pharmacological and toxicological perspectives, relapse prevention and treatment thereof remain a challenge, as most psycho- and pharmacological therapy approaches continuously fail to warrant satisfactory success rates. While addiction medicine relies quite heavily on the combined use of medication and what can be collectively labeled as cognitive–behavioral interventions, increasing attention seems to be dedicated to establishing novel clinical paradigms with a potential to improve such combinations, thus expanding on both assessment and treatment options c.f., ,31). Alr. Alr31])The ICD-10 guidelines for alcohol dependence include (a) a strong desire or sense of compulsion to take the substance, (b) difficulties in controlling substance-taking behavior, (c) physiological withdrawal, (d) evidence of tolerance, (e) progressive neglect of alternative pleasures or interests, and (f) persisting with substance use despite clear evidence of overtly harmful consequences . This stDue to the fact that the works on the eleventh revision of the ICD have been finalized and the ICD-11 has been released for use, it seems worthwhile to at least make a mention of how it affects AUDs. Similarly to ICD-10, the eleventh revision proposes alcohol dependence disorder as the central diagnostic entity concerning pathological alcohol use. The ICD-11 considers it a disorder of regulation of alcohol use stemming from its repeated or continuous consumption, the key feature being a strong internal drive to drink understood in terms of impaired control, frequently but not necessarily combined with a feeling of urge or craving . Time wiA neurocognitive perspective deems it fit and proper to understand addictions in terms of a certain imbalance between impulsive (or reflexive) and reflective decision-making . Behind A socio-environmental approach, on the other hand, implicates a number of social and environmental cues and certain individual sensitivity to them as involved not only in the very development of AUDs, but also processes of recovery and maintenance of abstinence. It therefore seems that particular substance-related settings  and social interactions may first trigger craving and ultimately relapse in even abstinent individuals . RemarkaGiven the essential role of (largely cue-induced) craving in the mechanisms of AUDs, its assessment becomes crucial for the identification, management, treatment design, and effects. Various approaches cited in the literature have been applied to investigate alcohol cravings, focusing on their neurobiological and psychophysiological underpinnings ,47 with Cue exposure is generally performed in vivo through relevant imagery or via virtually generated settings. The majority of available evidence-based methods of inducing craving include substance-associated visual cues, such as images or videos, alone or combined with other sensory stimuli . To date, most conventional cue exposure therapy (CET) approaches for AUDs have seemingly been based on visual delivery of alcohol-related stimuli, showing limited success in terms of reduced alcohol consumption rates . HoweverEvidence now affirms that intervention in both drug abuse vulnerability and reactivity to environmental or contextual cues is useful in support of pharmacotherapy in the management of SUDs . As descNotably, there seem to be differences in how craving is elicited through the sole exposure to VR environments and how it is modified by possible interactions with avatars across diverse VR paradigms. The former experimental settings may involve images of people performing substance-related actions and VR scenarios of bars, clubs, or parties, with the subjects assuming the roles of mere observers. In turn, more specialized paradigms engage the subjects in interactions with or even control over (elements of) the virtual environment. These experimental designs, however, have been considered somewhat lacking in terms of standardized forms of delivery and subjects’ performance in response to the presented VR setting c.f., ,63). In . In 63])VR cue exposure proves efficacious in craving induction, through cues typically associated with alcohol consumption (including different types thereof, i.e., proximal: alcohol bottles, contextual: bar, or complex cues: party scenario ,65,66,68Interestingly, there is evidence of beneficial effects of a partially immersive game-based VR intervention for recovery from alcohol use, countering alcohol cues through movements . Found eAn interesting conclusion emerged from a systematic review by Durl et al. , who fouNot to fall prey to excessive and uncritical enthusiasm linked to VR use in therapeutic settings and to avoid publication bias, it is advisable to mind potential risks of its application. Following Parsons , those mFurthermore, despite the growing body of evidence regarding VR use in mental health, there still remain certain issues to be addressed, as the development of novel technologies has led to the emergence of new queries and challenges. Amongst those are questions of limited methodological quality, piecemeal evidence, potentially constrained reporting of negative outcomes , or geneTwo other interesting research directions seem to be the so-called co-creation , i.e., aIn this paper, we have shed some light on the current body of evidence on VR applications in the mental health sector, with a particular focus on AUDs. The work is not, however, free from limitations. First and foremost, it is a narrative and not a systematic review, which may be criticized for a less rigorous methodological approach. The rationale behind choosing this form of expression was to offer a broader and up-to-date outline and overview of available meta-analytic and original research results concerning the rapidly evolving knowledge about VR applications in mental healthcare settings. Even though it is stripped of the rigor of a systematic review, we have made every effort for this paper to present an objective and accurate synthesis of the relevant literature in a comprehensive manner, all the while remaining unbiased in our critique thereof.VR immersion techniques seem to offer a good alternative to conventional cue-provoked treatment approaches, and have proven to successfully integrate simulated social interactions in such paradigms. Although both experimental and meta-analytic evidence supports the effect of exposure to VR cues as a promising add-on to standard CET approaches in various mental disorders, and VET in AUD is reported to elicit cravings by exposure to and interaction with environments related to typical alcohol consumption scenarios, its beneficial effect and superiority in the assessment and management of AUDs needs to be further validated, as high-fidelity simulations have been suggested to offer the potential for both desirable and unwanted outcomes. That said, VR-based approaches definitely bear promise in developing applications promoting individualized and accessible care in not so distant future of psychiatry and psychology.