Long noncoding RNAs (lncRNAs) are emerging as critical regulators in tumor initiation and progression. However, the biological mechanisms and potential clinical application of lncRNA NORAD in endometrial cancer (EC) remain unknown. Herein, we identified NORAD underwent promoter hypermethylation-associated downregulation in EC. Epigenetic inactivation of NORAD was correlated with EC progression (FIGO stage) and poor outcome. Overexpression of NORAD significantly inhibited cell growth and promoted apoptosis in EC cells. Mechanistic studies revealed that multiple regions of NORAD served as a platform for binding with the central domain of anti-apoptotic factor FUBP1. Our findings further indicated that the NORAD/FUBP1 interaction attenuated FUBP1 nuclear localization and thus impaired the occupancies of FUBP1 on its target pro-apoptotic gene promoters, resulting in apoptosis induction in EC. Moreover, knockdown of NORAD promoted tumor growth in the xenograft mice model. While, introduction of NORAD-4 fragment, which bound with FUBP1, successfully reversed tumor growth and apoptosis inhibition mediated by NORAD knockdown in vivo. Our findings provide mechanistic insight into the critical roles of NORAD as a tumor suppressor in EC progression. NORAD could possibly serve as a novel prognostic biomarker and provide the rationale for EC therapy. No acknowledged biomarkers are sensitive and specific enough for diagnosis and prognosis prediction in EC, resulting in the dilemma of risk stratification and further application of adjuvant individualized therapies at early EC stage3. Therefore, it is of great importance to explore the underlying mechanisms in EC progression.Endometrial cancer (EC), originating from the endometrium, is the most common malignant gynecological cancer in women, and its incidence is steadily increasing around the world without improved 5-year survival6. In view of the biological function and specific expression in tumor tissues, lncRNAs are served as biomarkers for tumor diagnosis and therapeutic targets8. Recent studies found that a highly conserved and abundantly expressed lncRNA, NORAD, could maintain genomic stability by decoying PUMILIO1/2 or binding with RBMX to regulate DNA replication and repair11. Genome instability was recognized as one of the cancer hallmarks and involved in tumor initiation and progression12. Several studies have revealed that NORAD had effects on tumor cell proliferation, apoptosis, and migration via binding with miRNAs or proteins13. NORAD was identified as an oncogene in pancreatic and ovarian cancer15, while its roles in lung and breast cancers have been controversial, indicating a context-dependent role in cancer progression16. The function and mechanism of NORAD involved in regulating EC formation and progression remain unexplored.Emerging evidences support the notion that long noncoding RNAs (lncRNAs), a minimum length of 200 nucleotides, are considered as drivers of multiple cancer phenotypes, including tumor cells sustaining proliferation, viability, motility, and angiogenesis18. Mounting evidences suggested that FUBP1 was upregulated and served as a proto-oncogene in solid cancers20. FUBP1 repressed p21 mRNA stabilization and regulated pro-apoptotic genes transcription, served as an anti-apoptotic factor in hepatocellular carcinoma21. Among gyneocological cancers, FUBP1 was associated with progression-free survival in ovarian cancer22. However, there is still an important gap in the understanding of the role of FUBP1 in EC.Far upstream element-binding protein 1 (FUBP1) participated in diverse biological cellular processes as a DNA- and RNA-binding proteinOur study demonstrated that NORAD was gradually decreased with the progression of EC due to promoter hypermethylation, and associated with clinical outcome. NORAD could promote EC cell apoptosis in vitro and knockdown of NORAD resulted in tumor malignant growth in vivo. Mechanistically, NORAD bound with FUBP1 and impaired its nuclear localization. Consequently, the NORAD/FUBP1 interaction impeded FUBP1 enrichment on its target gene promoters, resulting in apoptosis induction.We first analyzed the RNA-seq data of 544 EC tissues and 23 normal endometrial tissues in The Cancer Genome Atlas (TCGA) and found that the expression level of NORAD was lower in tumor tissues than that in normal tissues Fig. . We furtIn addition, we correlated the NORAD expression level with the clinicopathological characteristics of EC patients via a chi-square test Table . Our res24. Bisulfite sequencing PCR (BSP) was performed to investigate the CpG methylation status of normal, peri-tumor, and tumor tissues, including early-stage and advanced-stage tissues. Our results found that the methylation levels at the NORAD promoter were enhanced in tumor tissues compared with those in normal tissues and gradually increased with the progression of EC  located upstream of the transcription start site (TSS) of NORAD Fig. . The CpG EC Fig. . To conf EC Fig. , resulti EC Fig. . These rOverall, our study demonstrated that NORAD was downregulated due to its promoter hypermethylation in EC and potentially served as a biomarker for EC progression and prognosis.To explore the exact function of NORAD in EC, we transfected NORAD into ISK and SPEC-2 cells Fig. . NotablyWe further investigated the functional activity of endogenous NORAD expression rescued by Aza. Our studies first found that the cell apoptosis of EC was induced after Aza treatment for 72 h , possessing multiple binding regions on NORAD11, which is critical for antagonizing apoptosis and promoting cell survival in hepatocellular and colorectal carcinoma21. FUBP1 expression was upregulated in the EC tissues compared with normal tissues according to TCGA data  into 293FT cells to perform RNA pull-down assays  data 25 Fig. . Moreove 25 Fig. . To furtays Fig. . Our resays Fig.  and founays Fig.  and enhaays Fig. . Howeverays Fig. . These rTo further understand the key role of NORAD in EC progression, we first constructed the NORAD knockdown cell lines rescued by NORAD-4 fragment (bound with FUBP1) Fig. . Knockdo17, while increasing evidences indicate that FUBP1 can interact with cytoplasmic RNAs27. Cell fractionation followed by RT-qPCR revealed that NORAD was predominately located in the cytoplasm  into ISK and SPEC-2 cells  showed that upon the high and low expression of FUBP1 in liver cancer, downstream genes were evidently relevant to the apoptosis pathway Fig. . Previounes Fig. , which wnes Fig. , indicatnes Fig. . Consistnes Fig. . Moreovenes Fig. . Taken t6. NORAD was recently discovered to promote cancer cells proliferation, invasion, and metastasis in various cancers 29. While, NORAD retained controversial roles in liver, lung, and breast cancer30, implying that NORAD acted on tumorigenesis and progression in a context-dependent manner. In our study, we analyzed the public data in TCGA and collected the tumor tissues of EC patients, which illustrated that NORAD was downregulated due to promoter hypermethylation in EC patients compared with normal tissues. Moreover, epigenetic inactivation of NORAD was relevant to adverse progression and poor prognosis. Therefore, for the first time, we propose NORAD as a potential molecular marker for the clinical assessment of EC progression and prognosis.LncRNAs have been recently emerged as important players in modulating tumor initiation, progression, and the assessment of prognosis31. Once defective cells failed to repair effectively, cell death pathways  would be activated to eliminate the negative effects of genomic toxicity on cells33. However, during the process of tumor initiation, these defective cells could bypass the cell death pathway to complete the malignant transition, which might be the important cause of tumor formation31. Previous studies revealed that NORAD bound with PUMILIO1/2 or RBMX to maintain genomic stability11. However, inactivation of NORAD downregulated the expression of genes associated with DNA damage and repair, such as RBMX and PARP1, resulting in genomic instability10. Our study indicated that the expression of NORAD was decreased in the transition from normal endometrial tissue to EC tissue. Knockdown of NORAD could promote tumor growth and prevent cell apoptosis in vitro and in vivo. While, both exogenous NORAD overexpression and rescued endogenous NORAD expression by Aza could inhibit cell growth and promote cell apoptosis, as a tumor suppressor. Thus, these results indicated that NORAD was critically involved in the balance between cell proliferation and apoptosis evasion in EC progression.Normal cells suffering from external or internal stress will trigger DNA damage and repair35. NORAD contains multiple repetitive motifs and serves as a molecular decoy for the PUMILIO protein, indicating that NORAD might function as a platform for assembling proteins10. In view of FUBP1 function in EC and its multiple binding regions on NORAD in the MS data11, we confirmed the interaction of NORAD and FUBP1 under exogenous and endogenous conditions in EC, and identified FUBP1 binding with at least three regions of NORAD. We also revealed that binding with FUBP1 was essential for NORAD to induce apoptosis in EC cells. Furthermore, introduction of NORAD-4 fragment (bound with FUBP1) could reverse cell growth and apoptosis inhibition mediated by knockdown of NORAD in vitro and in vivo. These findings suggested that NORAD had the capacity to interact with multiple FUBP1 proteins as a decoy to regulate cell apoptosis.Cytoplasmic distributed lncRNAs can execute their regulatory roles through binding with proteins to affect their function, subcellular localization, or protein–protein interaction21. Our study also revealed that FUBP1 was upregulated in EC, and knockdown of FUBP1 remarkably enhanced cell apoptosis. TAL1 was reported to bind to the FUBP1 promoter and activate its transcription in erythroid differentiation36. FUBP1 was also regulated by the PI3K/AKT/mTOR pathway and caspase protein in liver cancer37 or targeted by miR-16 in breast and gastric cancer38. In addition, FUBP1 was found to be ubiquitinated by p38 in lung cell differentiation or identified as a substrate of parkin in Parkinson’s disease40. Intriguingly, our results showed that NORAD had no impact on the transcription or stability of FUBP1 but attenuated FUBP1 nuclear enrichment, which impaired its occupancies on the promoters of downstream pro-apoptotic genes. Our results further found that FUBP1 interacted with NORAD through its central domain (DNA-/RNA-binding region). Overexpression of the FUBP1 central domain could competitively bind with NORAD and facilitate endogenous FUBP1 trafficking into the nucleus to reverse the cell apoptosis induction mediated by NORAD. FUBP1, primarily located in the nucleus, was prevented to be imported into the nucleus due to caspase-3/7 cleavage during the breast and cervical cancer cells apoptosis41. Herein, we provided an optional mechanism that NORAD decoyed FUBP1 in the cytosol and impaired its translocation to the nucleus, which was responsible for apoptosis induction in EC.To date, FUBP1 was ascertained to be upregulated in colorectal and hepatocellular cancerIn conclusion, we elucidate that epigenetic inactivation of NORAD affects the cytosol–nucleus trafficking of the anti-apoptotic factor FUBP1 and the expression of its target pro-apoptotic genes, resulting in EC cells evasion from apoptosis. In this regard, investigating NORAD crosstalk will lead us to significant insights into the mechanism of EC progression. Moreover, we are the first to highlight the predictive clinical value of NORAD as an EC diagnostic and prognostic biomarker and the possibility of developing NORAD-targeted therapy.n = 56) tissues were collected from patients who underwent hysterectomy at the Tongji University Affiliated Shanghai First Maternity and Infant Hospital  from 2015 to 2019. Peri-tumor endometrial tissues (n = 54) were sampled 1–2 cm away from tumors in the surgeries42. Normal endometrial specimen (n = 20) were collected from women undergoing non-maligmant diseases (uterine leiomyoma) with no underlying endometrial pathology43. The histology of all tissues was verified by two independent pathologists. No patients had undergone endocrine therapy, radiotherapy, or chemotherapy before surgery. All patients have signed the informed consent form before collection. The detailed clinical information of these patients was provided in Supplementary Table EC  and Protein G Magnetic Beads  were incubated with 3 μg of antibodies, rotating for at least 6 h. Lysates were added to the prepared beads in RIP buffer, rotating overnight for immunoprecipitation. Finally, RNA was extracted with RNAiso Plus Reagent. The antibodies in RIP assay were followed as: anti-FUBP1 , anti-IgG-Rb , and anti-flag-Rb .RIP was performed as previously described7 cells in 100 μL of PBS, were subcutaneously injected into the hind flanks of nude mice . On the 7th day after injection, mice were monitored and the tumor volume was calculated using the formula 1/2 (length × width2) twice a week. The mice were sacrificed at day 21 post injection. These studies were approved by the Institutional Animal Care and Use Committee of Tongji University (no. TJLAC-019-103).Five-week-old female BALB/c nude mice were purchased from the National Resource Center for Rodent Laboratory Animals of China. The mice used in animal studies were randomly and blindly allocated into experimental and control group. Five SPEC-2-derived cell lines , suspended at the concentration of 1 × 10t test. Pearson’s chi-square test and nonparametric test were used to analyze the clinical variables. The survival times of different groups of patients were analyzed using the Kaplan-method with the log-rank test. */#, **/##, ***/###, and **** represent P < 0.05, P < 0.01, P < 0.001, and P < 0.0001, respectively.The statistical analyses were performed with GraphPad Prism 7 software. The results were from triplicate experiments, and the data was presented as the mean ± SEM or mean ± SD. The significance of mean values was determined by unpaired two-tailed Student’s Supplementary InformationSupplementary InformationSupplementary InformationSupplementary InformationSupplementary InformationSupplementary InformationSupplementary Information


It is argued that in this case study, the available evidence of underlying mechanisms did in fact play a role in providing evidence in favour of a medical intervention. This paper therefore adds a novel and recent case study to the literature in support of evidential pluralism in medicine.Some philosophers have argued that evidence of underlying mechanisms does not provide evidence for the effectiveness of a medical intervention. One such argument appeals to the unreliability of mechanistic reasoning. However, mechanistic reasoning is not the only way that evidence of mechanisms might provide evidence of effectiveness. A more reliable type of reasoning may be distinguished by appealing to recent work on evidential pluralism in the epistemology of medicine. A case study from virology provides an example of this so‐called  It will also be argued that in this case study, the available evidence of underlying mechanisms did in fact play a role in providing evidence in favour of a medical intervention. This paper therefore adds a novel and recent case study to the literature in support of evidential pluralism in medicine.Mechanistic reasoning is not the only way that evidence of underlying mechanisms might provide evidence for the effectiveness of a medical intervention. A more reliable type of reasoning may be distinguished by appealing to the recent work on evidential pluralism. In this paper, it will be argued that a case study from virology provides an example of this so‐called 2mechanistic reasoning, where mechanistic reasoning is the process of making a claim that an intervention will cause a particular effect on the basis of evidence of the underlying mechanisms (pp124‐130).evidence of the underlying mechanisms rather than simply a psychologically compelling story of a mechanism [pp349‐350].)A prominent criticism of evidence‐based medicine is that it downplays the research into pathophysiological mechanisms provided by the basic sciences.s pp124‐10.evidencnon‐evidential role in a more complete epistemology of medicine than that articulated by current evidence‐based medicine. Let us call this the non‐evidential approach to mechanistic reasoning. This is the approach that is preferred by Solomon (p124).propose medical interventions, which are then evaluated in terms of their effectiveness by the methods of evidence‐based medicine (p132).One way to reconcile these lines of thought is to maintain that mechanistic reasoning fulfils an important olomon p14.2 She tthe context of discovery and the context of justification. This distinction is often traced back to the work of Hans Reichenbach.correlational reasoning is the process of making a claim about the effectiveness of a medical intervention on the basis of such evidence of correlation. Indeed, Solomon says that “[h]ealth care interventions are judged effective when there is a correlation between the intervention and positive outcomes. Often it is not too much of a leap to infer that the intervention causes the positive outcome” (p117).Solomon refers to the distinction between Solomon acknowledges that the distinction between the context of discovery and the context of justification characterizes a romantic view of science. She says that “[s]ince the time of the logical empiricists, we have come to appreciate that the context of justification is not so rigorous, and that the context of discovery is not so unconstrained” p125).5.2 Indeethe evidential approach to mechanistic reasoning. This is the approach taken by Jeremy Howick.low‐quality mechanistic reasoning, because that reasoning was based upon insufficiently complete knowledge of the relevant mechanisms: “[M]echanistic reasoning based on partially understood mechanisms will not provide reliable evidence that an intervention caused a patient relevant outcome” (p139).high‐quality mechanistic reasoning should be distinguished from low‐quality mechanistic reasoning, where mechanistic reasoning is high quality when it is based upon sufficiently complete knowledge of the relevant mechanisms and their behaviour under intervention (pp937‐938).evidence, we need to know enough about the relevant mechanisms to predict how they will react to novel medical interventions” (pp129‐130).An alternative approach therefore maintains that certain instances of mechanistic reasoning can provide some evidence for the effectiveness of a medical intervention. Let us call this utcome” p9.high‐quutcome” p9.high‐quA general problem with mechanistic accounts is that they are typically incomplete, although they often give an illusion of a complete, often linear, narrative. Incompleteness is the consequence of there being mechanisms underlying mechanisms, mechanisms inserted into mechanisms, background mechanisms that can fill out the mechanistic story, and mechanisms that can hijack regular mechanisms. That is, there is complex interaction of multiple mechanisms in a chaotic and multidimensional system. There are possible hidden mechanisms everywhere in mechanistic stories, despite an easy impression of narrative or causal completeness. Since we do not have a theory of everything, it is not possible to know in advance whether or not a particular mechanistic intervention will have the intended result.Solomon argues that this evidential approach conflates evidence of the underlying mechanisms with mechanistic evidence, where mechanistic evidence is any evidence about the effectiveness of a medical intervention that is provided by mechanistic reasoning p123).3.2 She tSolomon even suggests that in the case of cystic fibrosis, as the evidence of the underlying mechanisms increased, this only served to stand in the way of providing mechanistic evidence for the effectiveness of an intervention because it revealed the high level of complexity of those mechanisms pp126‐132).6‐132.2 TIs this a good reason to think that evidence of underlying mechanisms cannot provide evidence for the effectiveness of a medical intervention? At best, it has been shown that standalone mechanistic reasoning cannot provide evidence for the effectiveness of a medical intervention. However, evidence of underlying mechanisms may still provide evidence of effectiveness by playing a role in an alternative reasoning process. Indeed, evidential pluralists have argued that evidence of underlying mechanisms can provide mechanistic evidence for the effectiveness of a medical intervention, at least when it is taken together with other types of evidence, for example, evidence of correlation from comparative clinical studies.A and B is genuinely causal. But evidence of correlation helps to determine the net effect of a mechanism, and to show that it is not masked by further unknown mechanisms. Together, evidence of these two different things is very much stronger than evidence of one alone.Evidence of a linking mechanism helps show that the overall relationship between [I]f steel is placed in concrete to produce reinforced concrete, we get a composite material where the concrete resists the compression and the steel resists the tension. The combination of two different materials produces a material that is much stronger than either of its components. In the same way, we argue that it is the combination of two different types of evidence which produces much stronger overall confirmation than would either type of evidence on its own. The important point is that this depends on the evidence being evidence of two types of things–correlations and mechanisms–that are different in character.The basic idea is that each type of evidence comes with its own characteristic weakness for reasoning about the effectiveness of a medical intervention. On the one hand, thanks to the complexity of the underlying mechanisms, it can be difficult to determine the overall effect of a medical intervention on the basis of evidence of underlying mechanisms alone. On the other hand, it can be difficult to determine whether an observed correlation is causal on the basis of evidence of correlation alone. This is the familiar claim that correlation is not causation. However, evidence of an underlying mechanism that explains the extent of the observed correlation can help to address the characteristic weakness of evidence of correlation by making more plausible a causal interpretation of the correlation. And evidence of correlation helps to address the characteristic weakness of evidence of mechanisms by giving evidence of an overall effect.They say that “[t]ogether, evidence of these two different things is very much stronger than evidence of one alone” p351).51.3 The Reinforced reasoning is the process of making a claim about the effectiveness of a medical intervention on the basis of both evidence of a correlation and evidence of the underlying mechanisms. Importantly, it is plausible that reinforced reasoning does not share the weaknesses of mechanistic and correlational reasoning for drawing conclusions about the effectiveness of a medical intervention. In particular, this type of reasoning helps to address the characteristic weaknesses of both mechanistic and correlational reasoning by combining evidence of underlying mechanisms together with evidence of correlation. Reinforced reasoning therefore promises to be a process by which evidence of the underlying mechanisms may provide evidence in favour of the effectiveness of a medical intervention.This evidential pluralism allows a novel type of reasoning in medicine to be introduced in contrast to both mechanistic and correlational reasoning. To sum up, it has been argued in this section that the present objection to mechanistic reasoning leaves untouched an alternative possible way that evidence of underlying mechanisms may provide evidence for the effectiveness of a medical intervention. Of course, it has not yet been shown that this alternative reinforced reasoning can in fact provide some evidence of effectiveness, that is, mechanistic evidence of effectiveness. In the next section, it will therefore be argued that a case study from virology provides a clear example of the differences between correlational, mechanistic, and reinforced reasoning in medicine. It will be argued that this case study demonstrates that evidence of mechanisms can in fact provide evidence for the effectiveness of a medical intervention by playing a role in an instance of reinforced reasoning.3chronic version of the infection. This chronic infection is a major cause of liver cancer and other diseases.Hepatitis C is a liver disease caused by infection from a single‐stranded, blood‐borne RNA flavivirus known as HCV.combination therapy of interferon alfa and ribavirin. Interferons are a family of cytokines that are a key component of the innate immune response against viruses. Interferons bind with receptors on the cell surface, leading to the expression of genes that prevent virus replication, facilitate viral clearance, and initiate the protection of neighbouring cells from further viral infection.A short time ago, the recommended optimal treatment for the chronic disease was a pegylated combination therapy of peginterferon alfa and ribavirin, where pegylation aims to improve the therapeutic potential of the interferon by attaching to it a water‐soluble polymer called polyethylene glycol (PEG).What was the reasoning that justified this change in recommendation?Recently, there was a change in the recommended optimal treatment from the standard combination therapy to a biological half‐life of interferons, that is, the time it takes biological processes to remove half of the substance.A proponent of mechanistic reasoning may say that the change in recommendation was justified on the basis of evidence of the underlying mechanisms linking pegylated combination therapy to an improvement in rates of sustained virological response compared with the standard combination therapy. An acknowledged shortcoming of standard interferon therapy is that the antiviral activity of interferons is limited by the fact that they only remain in the body for a short amount of time.However, this standalone mechanistic reasoning plausibly provides no mechanistic evidence that pegylated combination therapy is more effective than the standard combination therapy at improving rates of sustained virological response. Although there is evidence of the underlying mechanisms linking pegylated combination therapy to increased antiviral activity, there is the same worry as discussed above, namely, that the complexity of the relevant mechanisms is not well understood. In particular, there may be other unknown, complicating mechanisms that make it difficult to determine any overall increased beneficial effect for pegylated combination therapy. For example, a standard problem for pegylated therapeutics is that increasing the size of a protein through pegylation has been shown to reduce its biological activity by disrupting the ability of the protein to bind with the relevant receptor.Of course, the fact that this standalone mechanistic reasoning did not provide mechanistic evidence for the increased effectiveness of the pegylated combination therapy is unlikely to come as a surprise to the critic of the evidential approach to mechanistic reasoning: It is simply another case where incomplete knowledge of the complexity of the underlying mechanisms precludes providing evidence of an overall beneficial effect. The case provides further evidence that mechanistic reasoning is at home in the context of discovery rather than the context of justification. Instead, the critic might recommend looking towards evidence of correlation in order to provide this evidence of a beneficial effect, where this evidence of correlation is typically obtained from comparative studies pp124‐125).4‐125.2 Tcorrelated with a statistically significant improvement in rates of sustained virological response when compared with the standard combination therapy.correlated with a significant improvement in rates of sustained virological response.causal effectiveness of the pegylated combination therapy compared with the standard combination therapy. It may be that there are more plausible alternative explanations of the observed correlation, such as bias in the available trials. Indeed, the systematic review also concluded that there was only moderate evidence of the increased effectiveness of pegylated combination therapy (p23).Unfortunately, it also looks like the change in recommendation was not justified solely on the basis of correlational reasoning. A number of randomized trials had concluded that pegylated combination therapy was reinforced reasoning. Although the available evidence of correlation at best provides only moderate evidence for the increased effectiveness of pegylated combination therapy, it might be that this evidence is more conclusive when it is taken in combination with the available evidence of underlying mechanisms. In particular, the evidence of a correlation between pegylated combination therapy and improved rates of sustained virological response is inconclusive because it may be explained by bias in the available trials.Although neither standalone correlational reasoning nor standalone mechanistic reasoning can justify the change in recommendation from standard to pegylated combination therapy, it should not be concluded that there was insufficient justification for this change in recommendation. It might be that the change in recommendation was justified on the basis of an instance of It might be objected that it is illegitimate to rely upon evidence of mechanisms to help rule out bias as an alternative explanation of the observed correlation. It has already been shown that standalone mechanistic reasoning is unreliable in this case because it cannot determine an overall beneficial effect: It may be that any additional beneficial effect brought about by increasing the bioavailability of the interferons is outweighed by the reduction in biological activity brought about by disrupting the binding potential of the interferons. However, this problem for the reliability of standalone mechanistic reasoning is not a problem for the reliability of reinforced reasoning, because reinforced reasoning relies also upon evidence of correlation, and this evidence of correlation gives evidence of an overall beneficial effect. In particular, the available systematic review shows a robust correlation between the pegylated combination therapy and improved rates of sustained virological response.To sum up, there is some good evidence of the underlying mechanisms linking pegylated combination therapy to improved rates of sustained virological response. But standalone mechanistic reasoning on this basis provides no evidence for the increased effectiveness of pegylated combination therapy, because the complexity of the underlying mechanisms makes it impossible to determine the overall effect of the pegylated therapy. Of course, evidence of correlation can help to better determine such an overall effect. Unfortunately, standalone correlational reasoning in this case also provides insufficient evidence for the increased effectiveness of pegylated combination therapy. Although there was moderate evidence that the pegylated combination therapy is correlated with improved rates of sustained virological response compared with the standard combination therapy, there was still a possibility that this correlation was best explained as a result of bias in the available trials. However, this explanation looks less plausible in the light of the evidence of the underlying mechanisms linking pegylation with improved antiviral activity. Reinforced reasoning therefore provides more conclusive evidence of the increased effectiveness of pegylated combination therapy. Importantly, this instance of reinforced reasoning provides greater evidence for the increased effectiveness of pegylated combination therapy than standalone correlational reasoning. Moreover, this difference between standalone correlational reasoning and reinforced reasoning is the addition of evidence of mechanisms. This shows that evidence of underlying mechanisms can provide some evidence in favour of the effectiveness of a medical intervention.4Reinforced reasoning involves making claims about the effectiveness of a medical intervention on the basis of both evidence of a correlation and evidence of the underlying mechanisms. In this paper, it has been argued that a case study from virology provides an instance of such reinforced reasoning. It has also been argued that reinforced reasoning is one way in which evidence of underlying mechanisms can provide evidence for the effectiveness of a medical intervention. Much of the literature on evidential pluralism concerns historical case studies.Daniel Auker‐Howlett: Arts and Humanities Research Council Consortium for Humanities and Arts South‐East England (CHASE) Doctoral Training Partnership (AH/L503861/1).Michael Wilde: Arts and Humanities Research Council Project: Evaluating Evidence in Medicine (AH/M005917/1).The authors declare no conflict of interest.


Our aim was to evaluate the safety and efficacy of biodegradable polymer everolimus-eluting stents (BP-EES) compared with durable polymer everolimus-eluting stents (DP-EES) in midterm.  There are few data about midterm clinical outcomes of BP-EES compared with DP-EES. P=0.23). Regarding the individual components of the TLF at 3 years, the cumulative incidence of target vessel MI was significantly lower in BP-EES than in DP-EES (0% versus 1.9%: adjusted HR 0.83 (95% CI 0.71–0.97), log-rank P=0.01), but there was no difference between BP-EES and DP-EES in the incidence of cardiac death and clinically indicated TLR. The cumulative 3-year incidence of definite ST was significantly lower in BP-EES than in DP-EES .  Between January 2016 and December 2017, 395 consecutive patients were treated with BP-EES and 391 consecutive patients were treated with DP-EES in Nagoya Heart Center. The primary endpoint was a 3-year cumulative incidence of target lesion failure (TLF) defined as cardiac death, target vessel myocardial infarction (MI), and clinical indicated target lesion revascularization (TLR). Moreover, clinical indicated target vessel revascularization (TVR) and definite stent thrombosis (ST) were also evaluated as the secondary endpoints. After propensity score matching, 327 patients were selected in each group. At 3 years, the cumulative incidence of TLF was 4.5% in the BP-EES group versus 6.5% in DP-EES (adjusted HR 0.67 (95% CI 0.33–1.30), log-rank  There were no significant differences of TLF between BP-EES and DP-EES within 3 years. In this study, BP-EES seems to prevent definite ST and be safer than DP-EES in midterm. The everolimus-eluting stents (EES) that deliver antiproliferative everolimus analogue from durable polymer (DP) were associated with superior safety and efficacy outcomes compared with the first-generation drug-eluting stents (DES) , 2. HoweThe biodegradable polymer EES (BP-EES) were developed with the hope of providing similar safety clinical outcomes to bare metal stents (reduced risk of ST), while maintaining an efficacy profile of DP-EES (reduced risk of target lesion revascularization). Currently, several papers have described the long-term outcome using BP-EES, , 5 but tThe objective of the current study was to evaluate the safety and efficacy of BP-EES compared with DP-EES in the midterm.This is a retrospective, observational, and single-center study enrolling patients after successful BP-EES or DP-EES implantation. Between January 2016 and December 2017, 786 consecutive patients underwent percutaneous coronary intervention (PCI) with BP-EES (395 patients) or DP-EES (391 patients) at Nagoya Heart Center. After propensity score matching, 327 patients were selected in each group . All patThe PCI strategy was left to the discretion of the operating surgeon. Patients who were scheduled for PCI received oral daily administration of aspirin (≥81 mg/day) and P2Y12 inhibitor (75 mg/day clopidogrel or 3.75 mg/day plasugrel). Ticlopidine 200 mg/day was only allowed for those who did not tolerate clopidogrel and plasugrel. Patients with acute coronary syndromes  received loading doses of aspirin (200 mg) and P2Y12 inhibitor (300 mg clopidogrel or 20 mg/day plasugrel). During the procedure, unfractionated heparin (100 U/kg) was administrated to all the patients in order to achieve an activated clotting time of 250 seconds were used according to the operator's judgement. After the procedure, all the patients were recommended to receive optimal pharmacologic therapy including statins, beta-blockers, or renin-angiotensin system blockade following the current guidelines. Moreover, duration of dual antiplatelet therapy (DAPT) also depended on the operator's discretion.All the patients were followed up at 1, 3, 6, and 12 months after their index procedure and annually thereafter. Additional information was obtained by telephone contact or medical records, if necessary. A follow-up angiography 6 to 12 months after stent implantation was recommended to the patients according to clinical symptoms and findings.The primary endpoint in this study was target lesion failure (TLF) at 3 years after the index procedure, defined as a composite of cardiac death, target vessel myocardial infarction (MI), and clinically indicated target lesion revascularization (TLR). The secondary endpoint included the individual components of the composite primary endpoints and definite stent thrombosis (ST) at various time points.Death was considered as cardiac unless an unequivocal noncardiac cause could be established. MI and ST were defined according to the Academic Research Consortium definitions . TLR wasP value of <0.05 was considered statistically significant.Categorical variables were presented as number and percentage and continuous variables were expressed as mean value ± SD or median with interquartile range. Cumulative incidence was estimated by the Kaplan–Meier method and differences were assessed with the log-rank test. To evaluate the late events beyond 1 year, we used landmark analysis at 1 year. Those patients with the individual endpoint events before 1 year were excluded in the landmark analysis. We then included them simultaneously in the multivariable models and obtained the adjusted hazard ratios and their 95% confidence intervals. To match the patients for various clinical and angiographic characteristics, we used the propensity score matching method using a multivariate logistic regression model. The selected variables included demographics (gender and age), clinical presentation, comorbidities at baseline, prior treatment (PCI or CABG), angiographic and procedural characteristics, and medications administered at discharge. The patients were matched in a 1 : 1 ratio on the propensity score; we did an exact match for region and used a 5% caliper matching for the propensity score for the other variables . The matBaseline characteristics were not significantly different between the BP-EES and DP-EES groups after propensity score matching . The medP=0.23). However, the cumulative 1-year incidence of the TLF tended to be lower in BP-EES than in DP-EES  (P=0.01), but there was no difference between BP-EES and DP-EES in the incidence of cardiac death and clinically indicated TLR  assigned to BP-EES and 21 of 327 patients (6.5%) assigned to DP-EES (BP-EES versus DP-EES: adjusted HR 0.67 (95% CI 0.33–1.30), log-rank  P=0.07) . Regardiated TLR . Landmarated TLR  showed nP=0.02), while that of clinically indicated TVR was not significantly different between the 2 groups (P=0.04)  .The main findings of the current study are that compared with DP-EES, use of BP-EES was associated (1) with similar efficacy regarding TLF; (2) with superior safety regarding definite ST reduction in midterm.Several randomized control trials and recent meta-analysis study comparing BP-DES with DP-DES showed that BP-DES have similar efficacy profiles to DP-DES , 8.μm, 3.0–3.5 mm;79 μm, 4.0 mm; 81 μm) is as thin as DP-EES , which might demonstrate the similar efficacy outcomes for the both stents regarding TLR in particular.In this study, BP-EES proved to be comparable to DP-EES for TLF at 3 years. The rates of cardiac death, clinically indicated TLR and TVR up to 3 years were similar for the both stents. The thickness of the stent strut strongly was reported to influence the incidence of stent restenosis . CompareP=0.02)  . The ST There are several important limitations in this study. First, this study was a retrospective, single-centre study, which may have significantly affected some results due to confounding factors. Although we performed propensity score matching analysis to adjust the potential confounding factors, we did not correct for all possible and unmeasured variables. Therefore, the results of the current study should be considered as hypothesis generating only, being a post-hoc analysis of a trial. Second, the clinical event rates of BP-EES or DP-EES were relatively low and the power of the present study was inadequate to draw any definite conclusion, especially for stent thrombosis. This limitation might be originated by use of imaging device for the most patients. Third, we did not have information on bleeding complications during the follow-up. Finally, current follow-up duration is limited to only 3 year. Indeed, longer follow-up in more complex patient/lesion subsets may better differentiate between stent platforms with different structural design or polymer-healing attributes.In conclusion, the 3-year cumulative incidence of TLF had no significant differences between BP-EES and DP-EES. In this study, BP-EES might prevent definite ST and be safer than DP-EES in the midterm.


Dirofilaria spp. including Dirofilaria immitis and Dirofilaria repens, human ocular dirofilariasis due to D. immitis is relatively rare in the world. This study was aimed to present a case of ocular dirofilariasis caused by D. immitis in southeastern Iran.Dirofilariasis is a zoonotic parasitic infection transmitted from animals to humans by culicid mosquitoes. Although the disease can be caused by Dirofilaria parasite was detected. Afterwards, a piece of worm body was cut and DNA was extracted and a 680-bp gene fragment amplification and nucleotide sequencing were performed. Phylogenetic analysis revealed a D. immitis roundworm as the causative agent of infection. The patient was treated with antibiotics and corticosteroid and followed up for 1 month.A nematode extracted from the right eye of a 69-year-old man referred with clinical symptoms including itching and redness was examined. After the morphometric analysis, D. immitis isolated from a human in southeast Iran. Based on the available evidence, dirofilariasis in dogs has significantly increased in endemic areas such as Iran. Therefore, physicians should be aware of such zoonotic nematodes so as to take proper and timely action and treatment against the disease.The present study provides the second report on ocular dirofilariasis caused by  Dirofilaria spp. is a zoonotic parasitic infection transmitted by species of mosquitoes (Diptera: Culicidae) [Dirofilaria genus, more than 27 species of which have been identified, belongs to the family of Onchocercidae [Dirofilaria species, the disease is commonly caused by Dirofilaria immitis and Dirofilaria repens, which can create pulmonary and subcutaneous nodules/ocular, respectively [Dirofilariasis (heartworm disease) caused by licidae) . The Directively , 4.Dirofilaria is not completed in the human body, and microfilariae have not been observed in humans [The life cycle of n humans .Loa Loa, Dirofilaria and Onchocercae, showing such traits across the world [. Reports of ocular dirofilariasis (OD) due to D. immitis are rare, whilst D. repens is a typical agent found in humans. Orbital, subconjunctival, and intraocular infections are clinical forms of ocular dirofilariasis in humans [Orbital infection by parasites is not common in humans, but there are reports of different genera of parasites, in particular, he world . Reportsn humans .D. repens [Clinical signs including subconjunctival and subcutaneous and rarely breast and testicular hydrocele have been reported and documented in patients with . repens –14.D. immitis, and it has been well documented that infection of dogs can potentially increase the risk of human infection [D. immitis and D. repens in dogs has also been reported [Dirofilaria spp. was first reported in a dog in 1969. According to the available data, stray dogs are also infected with D. immitis at different rates. Not only dog owners, but the entire community is considered to be at risk of infection [D. immitis and this fact potentially increases the incidence of the disease in humans in this region [Canines and felines and other carnivores mammals are the main reservoirs of nfection . Mixed ireported . The prereported . Iranianreported . In Irannfection , 16. Sers region .Dirofilaria [There are various methods such as stained blood smears, modified Knott’s technique, Wylie’s filtration, or isolation of adult worms in addition to morphological and molecular methods for the diagnosis of dirofilariasis in the definitive host. Such parasitological methods are applicable for all species with blood-circulating microfilariae. Enzyme-linked immunosorbent assay (ELISA), western blot, and other immunological tests are capable of detecting antigens of adult female nematodes in the final host. In the last decade, molecular identification techniques have been developed for specific diagnosis of various species of ofilaria .D. immitis infection in the human eye through the molecular identification method in Bam, southeast of Iran.This study was performed to report the detection of a A 69-year-old man referred to Pasteur Hospital in Bam, southeastern Iran, with clinical symptoms including itching and redness of his eye. On further examination by slit lamp, a white roundworm was seen in the nasal subconjunctival space in the right eye . A 680-bp cox1 gene fragment was amplified using primers (Forward) 5′- CCTTTGAGTGTA-GAGGGTCAGC-3′ and (Reverse) 5′-ATTCCGCTCAAACCTCCAAT-3′ as previously described .Amplification was conducted under the following cycling conditions: 94 °C for 3 min, 40 cycles of 30 s at 94 °C, 35 s at 58 °C, and 1 min at 72 °C, followed by a final extension of 7 min at 72 °C. The quality of the PCR products was assessed by gel electrophoresis.http://www.ncbi.nlm.nih.gov/BLAST). In addition, the cox1 gene fragment was submitted to the GenBank under the accession number MH920260 as D. immitis. Additionally, the phylogenetic analysis produced a sister clade as compared to D. immitis sequences recorded in the GenBank . Sequencing results were aligned using BioEdit (ver.7.0.9.0) and MEGA 6.0 software and sequence identity was evaluated using the , and molecular methods in Iran , 25, 26. in Iran . In all  in Iran . It is wD. immitis isolated from a human in the southeast of Iran, which has favourable climatic conditions for the proliferation of the parasite. The epidemiology of parasitic ocular diseases is directly related to sanitation, environmental conditions, and the habits of the patient [To our knowledge, the present study provides the second report on ocular dirofilariasis by  patient . In thisReducing the infection of reservoirs (stray and domestic dogs), public awareness, informing dog owners, and reducing mosquito populations can be beneficial for control and prevention of dirofilariasis. Due to the increasing number of human infection reports in recent years on the one hand, and the high population of stray dogs and the increase in the rearing and keeping domestic dogs and cats in Iran on the other, it is necessary to pay more attention to this zoonotic disease, especially in hyperendemic areas. It should be noted that in Iran, the lack of dog population management has resulted in an increase in stray dogs.It should be taken into account that the epidemiology of parasites plays a major role in the implementation of control strategies. The most effective measure for preventing zoonotic diseases in dogs and cats is anthelmintic treatment, where prophylactic doses of ivermectin or milbemycin are given to animals regularly in the framework of the program prepared by the World Health Organization , 28.D. immitis could cause ocular dirofilariasis in human in areas where the climate conditions are favorable for disease propagation. The present study provides the second report on ocular dirofilariasis by D. immitis isolated from a human in southeast of Iran whereas most reports in Iran have indicated OD cases transmitted by D. repens. This fact highlights the importance of conducting epidemiological studies using geographic information systems (GIS) and remote sensing (RS) methods for dynamic and distribution prediction of dirofilariasis in Iran. Therefore, physicians should be aware of such zoonotic nematodes so as to be able to take proper action against this disease.In conclusion,


To synthesise international research that relates to midwives' use of best available evidence in practice settings and identify key issues relating to the translation of latest evidence into everyday maternity care.Midwifery is a research‐informed profession. However, a gap persists in the translation of best available evidence into practice settings, compromising gold standard maternity care and delaying the translation of new knowledge into everyday practice.A five‐step integrative review approach, based on a series of articles published by the Joanna Briggs Institute (JBI) for conducting systematic reviews, was used to facilitate development of a search strategy, selection criteria and quality appraisal process, and the extraction and synthesis of data to inform an integrative review.The databases CINAHL, MEDLINE, Web of Science, Implementation Science Journal and Scopus were searched for relevant articles. The screening and quality appraisal process complied with the PRISMA 2009 checklist. Narrative analysis was used to develop sub‐categories and dimensions from the data, which were then synthesised to form two major categories that together answer the review question.The six articles reviewed report on midwives' use of best available evidence in Australia, the UK and Asia. Two major categories emerged that confirm that although midwifery values evidence‐based practice (EBP), evidence‐informed maternity care is not always employed in clinical settings. Additionally, closure of the evidence‐to‐practice gap in maternity care requires a multidimensional approach.Collaborative partnerships between midwives and researchers are necessary to initiate strategies that support midwives' efforts to facilitate the timely movement of best available evidence into practice.Understanding midwives' use of best available evidence in practice will direct future efforts towards the development of mechanisms that facilitate the timely uptake of latest evidence by all maternity care providers working in clinical settings. Understanding midwives use of best available evidence will direct future efforts to facilitate the practice of EBH in maternity servicesEvidence‐informed maternity care improves the standard maternity services and health outcomes of women and newbornsInterdisciplinary collaboration between health organisations and practitioners will lead to improved uptake of latest evidence in practice settings1Evidence‐based practice (EBP) is embraced internationally as the ideal approach to improving healthcare outcomes for consumers, using the best available evidence to inform policy and the practice of persons responsible for providing care  checklist  for qualitative studies. The question developed for this review was “Do midwives (P) always use best available evidence (I) in practice (Co)?A search strategy was derived from keywords using a logic grid Table  that wer2.2n = 133). These were screened by journal, title and abstract to establish the success of the search string and also eliminate irrelevant articles (n = 109). From this, a manual search for relevant publications by title and abstract in key midwifery journals (e.g. “Midwifery” and “Women and Birth”) was conducted, which retrieved four additional papers (n = 4). Twenty‐eight papers (n = 28) were retained for full‐text review based on relevance to the review question and adherence to selection criteria. This process was conducted by authors one and two (AD and SB).The process of study selection and quality appraisal was guided by the PRISMA framework  were considered suitable for quality appraisal and were assessed against the JBI Critical Appraisal checklist for both cross‐sectional studies and qualitative research papers . This was conducted by all three authors independently. No papers were excluded following the appraisal process (n = 0). Therefore, a total of six studies (n = 6) were included in the review. These comprised of one qualitative research paper and five reporting cross‐sectional studies  implementing evidence‐based innovations in midwifery practice settings. Using Glaserian grounded theory, the paper explored change‐helping or change‐hindering factors, which were compared to the seminal Consolidated Framework for Implementation Research (CFIR), a tool developed within the context of Implementation Science (IS) to identify environmental factors that influence the use and implementation of change initiatives. The study comprised change‐leader midwives who had tried to initiate a practice innovation in their workplace. Participants were interviewed via Skype or telephone by single in‐depth interviews guided by semi‐structured questions. Findings were analysed and developed into sub‐categories, which were then formed into major categories that described the phenomenon of interest.The first included paper, authored by Bayes et al. , reporten = 297) use of evidence‐based guidelines in clinical practice. Authored by Toolhill, Sidebotham, Gamble, Fenwick, and Creedy  from a single university in the UK and was conducted between June–December 2013. The web‐based software Qualitrix™ was used to develop the survey, which comprised of five sections: (a) participant professional profiles, (b) attitudes towards EBP, (c) use of latest evidence to inform clinical practice, (d) accessibility to resources and (e) skills to implement and EBP. The study found participants displayed positive attitudes towards the use of evidence‐based information in practice settings. However, factors hindering EBP were noted to include lack of resources (e.g. computer software and Internet access) to search for latest evidence and insufficient time to research during working hours. Additionally, perceived resistance from colleagues and managers was also considered to be a significant barrier to using latest evidence in practice. The author concluded that using evidence‐based information to inform practice is fundamental and providing time away from bedside responsibilities may improve midwives and nurses capacity to search and apply research findings to practice.The third paper by Veeramah  examinedn = 169) completed an online questionnaire comprising five domains: (a) practice knowledge bases, (b) barriers to finding and reviewing evidence, (c) barriers to changing practice, (d) support to implement change and (e) EBP skills. Descriptive analysis was conducted using spss software. The findings reported low levels of acceptance and understanding of evidence‐based knowledge, and inaccessibility to research material. Additionally, time‐related barriers were reported by participants to be a significant issue in preventing the uptake of latest evidence into practice settings. The authors concluded that knowledge not underpinned by best available evidence remains the most common basis for nursing and midwifery practice decisions. Recommendations for capacity building strategies such as research mentorships and ongoing education in evidence interpretation were considered valuable to improving both midwives and nurses confidence to incorporate best available evidence in clinical environments.The fourth paper, authored by Fairbrother, Cashin, Conway, Symes, and Graham , reporten = 24) during normal labour and childbirth across four public hospitals in Tehran. Pazandeh, Huss, Hirst, House, and Baghban (n = 100) were interviewed about their care during labour and childbirth prior to discharge. Findings described the use of non‐evidence‐based practices including routine augmentation, induction of labour and application of fundal pressure during the second stage of labour and routine episiotomy. Other clinical practices such as facilitating removal of the placenta during the third stage of labour, immediate skin‐to‐skin contact postpartum between mother and newborn, and early initiation of breastfeeding were observed to be aligned with latest evidence. Authors concluded that closing the evidence‐to‐practice gap remains challenging for maternity care providers. Recommendations for further research into strategies and solutions specific to care provider needs were suggested to facilitate the use of latest evidence in practice. Notably, opinion leaders and experienced midwives were emphasised to have a key role in changing care provider behaviour.The fifth paper evaluated the provision of care provided to women ( Baghban  investign = 240), using two questionnaires, one collecting demographic information and the second examining participant's knowledge, skills, attitudes and use of EBP. spss software was used to analyse the data collected. Major findings identified that although most nurses and midwives express moderately positive attitudes towards EBP, sub‐optimal use of evidence‐based care in clinical settings was reported. Organisational culture was also influential to the attitudes and practice of EBP amongst participants, emphasising the need for EBP training and education in clinical settings. Recommendations were made to promote future collaboration between clinical practitioners, academic centres and researchers to improve the use of evidence‐based information in practice. Table The final study by Heydari, Mazlom, Ranjbar, and Scurlock‐Evans  reported3.2Sixty findings and interpretive statements were extracted from the six articles selected for inclusion in this review. From these, six sub‐categories emerged that were then collapsed into two major synthesised categories. One sub‐category, number four, is four‐dimensional. Collectively, the findings confirm that using best available evidence in practice is challenging for midwives and is subsequently not always applied to everyday maternity care. This demonstrates the evidence‐to‐practice gap persists in midwifery and that resolution of this issue requires interdisciplinary collaboration and timely actions.3.2.1This synthesised finding was developed from two sub‐categories (numbers one and two) that emerged from 19 findings and reflects the sub‐optimal use of best available evidence in practice, despite midwives' value of EBP and the costly outcomes of non‐evidence‐based care on maternity services. For the majority of participants, the philosophy of midwifery care aligns with promoting EBP; however, midwives recognise that using latest evidence in practice is sub‐optimal, which can result in midwifery care that is harmful to the well‐being of women and neonates, and difficult to justify.3.2.2Four categories, which were derived from four sub‐categories  and 41 findings, merged to develop this synthesised finding. While various factors limit midwives efforts to use best available evidence in practice, organisational characteristics such as workplace culture, interdisciplinary collaboration and attitudes towards EBP have been recognised as crucial drivers of change. A multidimensional approach is needed to resolve the existing evidence‐to‐practice gap in maternity care, with midwives' key stakeholders in closing the gap and changing care provider behaviours.3.2.3This category conveys midwifery's value of EBP and the cost of non‐EBP to both women and health organisations. Pazandeh et al.  establis3.2.4These data describe midwives' use of best available evidence in practice. It emerged that midwifery care is not always reflective of EBP, nor used routinely in everyday care of patients , an area of scientific study promoting the systematic uptake of best available evidence into healthcare practice Nilsen, . Seminal, highlights the challenges of initiating EBP changes and the interdisciplinary approach needed to optimise the use of best available evidence in maternity services. Factors preventing the uptake of EBP are well documented in the literature and often prevent the adoption of best practice by clinicians (Colquhoun, Squires, Kolehmainen, Fraser, & Grimshaw, The second synthesised major category “Factors preventing EBP are varied, and closure of the evidence–practice gap in maternity care requires a multidimensional approach”This review identified organisational and interdisciplinary co‐operation to be crucial components of initiating the implementation and use of best available evidence by midwives. As illustrated by Hespe, Rychetnik, Peiris, & Harris , organisIn maternity contexts, midwives are considered key stakeholders in the regulation of EBP initiatives (Renfrew et al., 5The consensus, both nationally and internationally, is that using best available evidence in practice is a priority issue for midwives and other maternity care providers. If the uptake of latest research findings continues to flounder, optimal health outcomes for women and newborns cannot be assured. However, supporting midwives with time away from the bedside, a workplace supportive of EBP and resources to facilitate their efforts may see the provision of evidence‐based maternity care become a reality. To close the persistent evidence‐to‐practice gap in maternity care, interdisciplinary collaboration and action between health organisations, midwives and researchers are recommended.6The pathway towards evidence‐based maternity care is inextricably linked to the emergence of new and innovative evidence. This review highlights that despite ongoing development and dissemination of high‐quality evidence, the translation of latest evidence into clinical practice remains sub‐optimal. Despite positive attitudes by midwives and other maternity care providers towards the use of best available evidence, concern regarding insufficient time, administrative barriers and lack of collegial support influence their capacity to implement EBP in clinical settings. The evidence‐to‐practice gap in maternity services remains a global issue for midwives and demands prompt action from both knowledge producers and knowledge users. Investing in strategies that support collaboration between midwives, researchers and maternity services could see the development of a resource designed by midwifery change leaders to bridge the gap from evidence‐to‐practice in maternity services.The authors declare no conflict of interest.Study design, literature search and screening process, quality appraisal and manuscript preparation: A. De Leo; literature analysis and manuscript preparation: S. Bayes; study design, quality appraisal and editing: S. Geraghty; quality appraisal and editing: J. Butt. Click here for additional data file.


Implementation of evidence-based practice is crucial to enhance quality health care, professional development, and cost-effective health service. However, many factors influence the implementation of evidence-based practice. Therefore, this study aimed to assess the implementation of evidence-based practice and associated factors among nurses and midwives.Institutional-based cross-sectional study design was conducted to assess the implementation of evidence-based practice and associated factors from February 15 to March 15, 2019, among 790 nurses and midwives. Data were entered into EpiData version 3.1 then exported to SPSS version 20 for statistical analysis. Categorical variables were presented as frequency tables. Continuous variables were presented as descriptive measures, expressed as mean and standard deviation. Cronbach’s alpha was used to measure reliability, mean, standard deviation, and inter-items correlation of the factors. Independent variables with a probability value  of less than 0.2 in the Chi-square analysis were entered in the multivariable logistic regression model. Statistically significant associated factors were identified at probability value  less than 0.05 and adjusted odds ratio with a 95% confidence interval.The mean age of participants was 28.35 (SD ± 4.5) years. This study revealed that 34.7% (95% CI 31.5–38%) of participants implemented evidence-based practice moderately or desirably. Age of participants , barriers of implementation of evidence-based practice , the attitude of participants , nursing/midwifery work index , self-efficacy of implementation of evidence-based practice skills  and knowledge of participants  were statistically significant associated factors of implementation of evidence-based practiceImplementation of evidence-based practice of nurses and midwives was poor. Age of participants, barriers of implementation of evidence-based practice, the attitude of participants, self-efficacy of implementation of evidence-based practice skills, nursing/midwifery work index, and knowledge of participants were found to be predictors of implementation of evidence-based practice. Insufficient time and difficulty in judging the quality of research papers and reports were the most common barriers to the implementation of evidence-based practice. Implementation of evidence-based practice (IEBP) is defined as the use of the best available, current, valid, and relevant evidence like research, work experience, and updated standard guidelines in the clinical decision-making practice –3. EvideIt is about 26 years since EBP has been introduced by a medical working group that published the first paper on evidence-based practice in 1992 . WorldwiCareful managing resources and the demand for maximum quality healthcare increases the pressure on health care professionals to ensure evidence-based clinical decision-making practice. Increasing volume of research information, availability of sophisticated medical care, client expectation to get the best possible care, and the rising health care expenditure compel the governments around the globe to embrace EBP. Therefore, EBP is an important way to deliver quality healthcare . EBP is Poor access to good quality research and lack of time are the most frequently reported barriers. In addition to this, there is a lack of collaboration between researchers and policymakers, and improved relationships and skills , 14. ShoThere is a challenge for policymakers to use evidence for developing policy and strengthening the healthcare system . There rAn institutional-based cross-sectional study design was conducted to assess the implementation of evidence-based practice and associated factors from February 15 to March 15, 2019, among nurses and midwives working in Amhara Regional State public hospitals. The study considered three specialized hospitals, four general hospitals, and 20 primary hospitals. Each of the specialized hospitals serves more than three million people. Each of the general and primary hospitals serves two million and one hundred fifty thousand people respectively.Nurses and midwives working in Amhara Regional State public hospitals were the study population. The sample size was calculated using single population proportion formula and the required sample size for this study was determined using the following assumptions; desired precision (d) = 5%, Confidence level = 95% , and 57.6% of nurses implemented evidence-based practice in their clinical practice in Tikur Anbessa Specialized Hospital . TherefoThe regional state has 13 zones. From these administrative zones, thirty-one percent (four zones) were selected randomly by lottery method. There were 27 public hospitals in the selected zones and 27 public hospitals were included in the study. In the selected hospitals, there were 1567 eligible nurses and midwives. The sampling frame, which includes a list of 1567 nurses and midwives, was prepared using a registration file (staff folder). Finally, participants from each hospital were selected using a computer-generated random number sampling technique from the sampling frame.Nurses and midwives working in private health institutions were excluded from the study to avoid double counting. This is because public health workers could be part-timers in private institutions. Moreover, nurses and midwives whose level of education was diploma were not familiar with research due to a lack of research method and epidemiology in their curriculum. Participants who were ill and unable to respond during the study period were also excluded from the study. A sample of 790 nurses and midwives whose educational status was degree and master were included to participate in this study during the study period.All questionnaires were developed following a detailed literature examination –23. ValiEighteen statements developed by Gerrish  and the The attitude of participants towards IEBP, barriers of implementation of EBP, and nursing/midwifery work index related questionnaires were answered as strongly agree, agree, neither agree nor disagree, disagree, and strongly disagree on a five-point Likert scale , 23. QueThe IEBP of participants was measured from the total amount of answers to eighteen IEBP related questionnaires on a 5-point Likert scale, with a minimum score of 18 and the greatest score of 90. The attitude of participants towards IEBP was measured from the total amount of answers to six attitude-related questionnaires on a 5-point Likert scale, with a minimum score of 6 and the greatest score of 30. Self-efficacy of IEBP skills, and barriers of IEBP of participants were measured from the total amount of answers to nine self-efficacy of IEBP skill-related questionnaires and nine barriers of IEBP related questionnaires on a 5-point Likert scale, with a minimum score of 9 and the greatest score of 45. Nursing/midwifery work index of participants was measured from the total amount of answers to 31 nursing/midwifery work index related questionnaires on a 5-point Likert scale, with a minimum score of 31 and the greatest score of 155. The IEBP, the attitude of participants towards IEBP, the self-efficacy of IEBP skills, the barriers of IEBP and the nursing/midwifery work index were considered ‘poor (unfavorable)’, ‘moderate’, and ‘desirable if the participants answered below 60%, 60–80% and greater than 80% for the IEBP, the attitude, the self-efficacy of IEBP skills, the barriers of IEBP, and the nursing, and midwifery work index questions, respectively .Data collectors were selected based on the criteria of previous exposure to data collection and the level of education. Their level of education was a degree, master and Ph.D. They were trained to be familiar with the aim and the methods of the research. To simplify data collection and data handling, data were collected via face-to-face interview technique using semi-structured questionnaires. The pre-test was conducted among 41 (5%) of participants at Woldia Hospital before the actual data collection day. Data collection was started with a greeting and good communication. Data quality was checked at the time of the interview during data collection. The content validity and internal reliability of the questionnaires were assessed using Cronbach’s alpha coefficients. The Cronbach’s alpha coefficient was between 0.698 and 0.98. The supervisors and investigators were closely supervising the performance of data collectors for the actual data collection. Data were checked again after data collection for completeness and internal validity.The investigators and supervisors checked the data manually for completeness. Data were entered into EpiData version 3.1 then exported to SPSS version 20 for statistical analysis. Categorical variables were presented as frequency tables. Continuous variables were presented as descriptive measures, expressed as mean and standard deviation. Cronbach’s alpha was used to measure reliability, mean, standard deviation, and inter-items correlation of factors. A principal components analysis was employed to identify important variables that explain the total variance of the factors. A chi-square test was done to identify factors associated with the dependent variable. Independent variables with a probability value  of less than 0.2 in the Chi-square analysis were entered in the multivariable logistic regression model to identify the independent predictors of the implementation of evidenc-based practice. Crude and adjusted odds ratios were used to identify the strength and direction of the association at a 95% confidence interval. A P-value of less than 0.05 was used to decide the significance of the association.This means that respondents implement evidence-based practice when they score greater than 60% (moderately or desirably) , 20, 22.No implementation of evidence-based practice means respondents’ score was less than 60% (poor).Half and more than half of the questions were answered by the respondent from the total of knowledge-related questions .Half and more than half of the questions were not answered by the respondents from the total of knowledge-related questions.The term mild and severe is used instead of poor and desirable to make sense for the meaning of barriers of IEBP.Out of the expected 826 participants, 790 of them gave a complete response with a response rate of 95.64% and the non-response was due to quit to participation. The mean age of the participants was 28.35 (SD ± 4.5) years. More than half (54.3%) of the study participants were between the age of 25–29 years. About 52% of the study participants were single or not married and 379 (48%) of them were married. About two-thirds (65.4%) of the participants were a nurse and 273 (34.6%) of them were midwives. Most of the participants 97.1%) were BSc nurses or midwives and 23 (2.9%) of participants were MSc nurses or midwives. Regarding the participants’ source of income, 771 (97.6%) of them got their income from salary only, and 19 (2.4%) of them got their income from monthly salary and private business (private clinic and drug vendor). The remaining frequency and percentage of socio-demographic characteristics are presented on the next page . From the total participants, 33.2% of nurses and midwives had a total IEBP score of 60–80% (moderate) and 1.6% of them had greater than 80% (desirable). From the total sample, 396 50.1%) of participants were knowledgeable whereas 394 (49.9%) of them were not knowledgeable. Among the total respondents, 374 (47.3%) of them claimed poor nursing/midwifery work index whereas 355 (44.9%) and 61 (7.7%) of them had moderate and desirable nursing/midwifery work index respectively. The remaining composite variables related characteristics are presented on the next pages  of attitude-related items was 0.703. The most important attitude towards IEBP was participants believed that evidence-based practice is fundamental to professional practice. However, participants did believe less likely that clinical decision-making practice based on evidence is time-saving (it was the least important factor). The mean attitude score of participants was 75.6% and it was taken as a moderate attitude towards the implementation of EBP  of them implemented evidence-based practice moderately or desirably and 18.1% (95% CI 15.3–20.9) of them implemented evidence-based practice often or always. The finding of this study also revealed that 65.2% of the participants had a poor implementation of evidence-based practice. Independent variables that had a statistically significant association with implementation of evidence-based practice were the age of participants between 25 and 29 years , poor barriers of implementation of evidence-based practice , desirable attitude of participants , knowledge of participants , self-efficacy of implementation of evidence-based practice skills , desirable nursing/ midwifery work-index  and moderate nursing/midwifery work-index  (See Table This study revealed that implementation of evidence-based practice was poor and it was lower as compared to other studies conducted in Ethiopia and United Kingdom , 24. ThiThe odds of implementation of evidence-based practice among nurses and midwives who had desirable attitude were better than those who did have a poor attitude towards the implementation of evidence-based practice. This study finding coincides with the studies conducted in China, Oman, Nigeria, and Ethiopia , 25–28. The odds of implementation of evidence-based practice among nurses and midwives who had desirable attitude were better than those who did have a poor attitude towards the implementation of evidence-based practice. This is in line with the studies employed in Nigeria and China , 30. ThiIt was established that nurses and midwives who had poor and moderate barriers to the implementation of evidence-based practice were more likely to implement evidence-based practice than those who had desirable barriers to implementation of evidence-based practice. Factor analysis also indicated that the most important barrier of IEBP was difficulty in finding time to search for and read research articles and reports, guidelines, hospital protocols and book and having difficulty in judging the quality of research papers and reports. This finding is supported by the studies conducted in Singapore, Oman, Norway, Turkey, and Iran , 28, 32.First, the study employed in hospitals and there is more advanced human resource dynamic, quality medical service and organization structure in hospitals than the lower level of health facilities. Hence, it is difficult to generalize for all health facilities. Second, there could be socially desirable bias to the study particularly during the measurement of IEBP, self-efficacy of IEBP skills, and attitude towards IEBP.This study showed that the implementation of evidence-based practice was poor. Age of participants, barriers of implementation of evidence-based practice, the attitude of participants, self-efficacy of implementation of evidence-based practice, nursing/midwifery work index, and knowledge of participants did have a statistically significant association with implementation of evidence-based practice. Insufficient time and difficulty in judging the quality of research articles and reports are the most common barriers to the implementation of evidence-based practice. Therefore, the promotion of adopting implementation of evidence-based practice and training on the identified predictors such as knowledge, self-efficacy of IEBP skills, nursing/midwifery work index, and barriers of IEBP are mandatory.