OPRM1 A118G polymorphism as a moderator of naltrexone response. Findings from human and animal studies suggest preliminary evidence for the clinical validity of this association; on this basis, arguments for clinical implementation can be made in accordance with existing frameworks for the uptake of genomic applications. However, generating evidence-based guidelines requires evaluating the clinical utility of pharmacogenetic tests. This goal will remain challenging, largely due to minimal data to inform clinical utility estimates. The pace of genomic discovery highlights the need for clinical utility and implementation research to inform future translation efforts. Near-term implementation of promising pharmacogenetic tests can help expedite this goal, generating an evidence base to enable efficient translation as additional gene-drug associations are discovered.Despite advances in characterizing genetic influences on addiction liability and treatment response, clinical applications of these efforts have been slow to evolve. Although challenges to clinical translation remain, stakeholders already face decisions about evidentiary thresholds for the uptake of pharmacogenetic tests in practice. There is optimism about potential pharmacogenetic applications for the treatment of alcohol use disorders, with particular interest in the  Initial optimism about the prospect of genomic medicine has given way to the realization that clinical applications will be challenging to identify and implement,2. EfforThe clinical translation of pharmacogenetics research also faces numerous challenges-10. One OPRM1 A118G polymorphism as a moderator of naltrexone response is discussed. However, these considerations will be relevant for other gene–drug response associations under study in the context of alcohol treatments, summaries of which are provided elsewhere[A key question concerns the evidentiary thresholds necessary to justify the adoption of promising pharmacogenetic tests in practice,9,17,18.lsewhere-25.OPRM1 A118G, rs1799971) is generally considered the most promising genetic moderator of alcohol treatment outcomes[OPRM1 for phenotypes related to pain and analgesia, stress response, and response to psychoactive drugs[Naltrexone is an opioid receptor antagonist and front-line therapy for alcohol dependence. A widely studied single nucleotide polymorphism in exon 1 of the μ-opioid receptor gene  has also allowed investigations in primate models[OPRM1 with alcohol use disorder etiology remains controversial[OPRM1 for a phenotype of clinical interest: reduction in alcohol consumption during treatment with naltrexone versus placebo[clinical validity of OPRM1 A118G as a marker of therapeutic response.Human laboratory evidence also suggested that  alcohol. This fi alcohol and refle models-37. Prime models,37, prove models,35. Theroversial, finding placebo,35. OverA much-debated issue concerns the degree of evidence necessary to incorporate a promising pharmacogenetic test in practice. This topic has received limited public discussion in the alcohol field, despite that decision-making frameworks for determining the uptake of genomic applications are available. For example, the Centers for Disease Control and Prevention (CDC) endorses the ACCE model for evalOPRM1-naltrexone scenario, since A118G is a single-point mutation and identifiable with commercial assays. As for clinical validity, the evidence for OPRM1 is by no means conclusive, however, initial findings could be considered promising. Importantly, the ACCE model and similar frameworks do not require conclusive evidence from high-quality randomized trials to evaluate clinical validity. More limited sources of evidence  can be considered[OPRM1, the existence of several retrospective trials and subsequent meta-analyses[Analytic validity should not pose a concern in the nsidered. In the analyses,40 is liAssuming an encouraging clinical validity profile, implementation decisions will hinge largely on clinical utility, defined broadly as the net effect (benefits minus harms) of implementation,41. CommA major barrier to the clinical translation of pharmacogenetics is the shortfall of data to inform estimates of clinical utility, contributing to the so-called “evidence dilemma” in genomic medicine,45. ThisBRCA testing in the context of family risk for breast and ovarian cancer). Evidence sufficient to discourage clinical use of a test results in assignment to Tier 3. Tier 2 is used for applications with promising evidence for clinical validity, but insufficient evidence to recommend for or against clinical adoption—often reflecting limited data on clinical utility. The vast majority of pharmacogenetic applications will fall under Tier 2[Most genetic tests are not federally regulated, leaving stakeholders  to navigate implementation decisions, usuallyr Tier 2. Other Tr Tier 2,57.The three-tier scheme is noteworthy in that it accommodates clinical implementation in the absence of sufficient evidence for or against clinical utility,57. To aPlacebo-controlled, prospective randomized controlled trials (RCTs) will remain the gold standard for validating pharmacogenetic applications. These designs reduce sources of bias and are necessary for testing genotype-based treatment algorithms,29. HoweOPRM1. However, in the hypothetical scenario that naltrexone is the only evidence-based treatment available, the evidentiary bar should arguably be higher before restricting use of naltrexone to 118G carriers.Because a noninferiority rationale assumes no foreseeable net harms, an important ethical consideration is whether pharmacogenetic protocols could compromise access to best-practice interventions. Ideal scenarios for early implementation might include those where a genetic test informs assignment to one of two empirically supported interventions. For instance, evidence for comparable efficacy of naltrexone and cognitive-behavioral therapy (CBT) for alcohol dependence could juDrawing from discussions in other disciplines, several recommendations can be made for near-term efforts to promote translation research in addiction therapeutics. A general goal is to evaluate candidate pharmacogenetic applications with approaches that balance methodological rigor with clinical applicability,13,54. TThese considerations support an argument for provisional implementation of promising pharmacogenetic protocols, if and when feasible. Such anOPRM1 and naltrexone response makes this a logical prototype for near-term translation research. At the same time, more research is clearly needed to characterize clinical validity and utility profiles for OPRM1. For example, assessments of clinical validity require specific attention to test prognostics  in relation to the clinical endpoint in question[a priori and evaluated in prospective studies[Preliminary evidence on question. Consensquestion, but altquestion. Ideally studies. Another studies. One con studies.Regarding clinical utility, a key question is whether genotype-based treatment algorithms offer advantages over standard protocols when implemented in clinical practice scenarios. Research protocols that compare genotype-based treatment assignment to conventional methods are needed to address this question. Adaptive treatment designs could beAlthough ethical issues are potentially less obvious in pharmacogenetic scenarios relative to other areas of genetic testing, researcOPRM1, a decade of research following the initial report[OPRM1 for clinical purposes. The question then becomes whether to recommend provisional implementation, for example, in specific clinical scenarios or for purposes of evidence development. Such a decision depends on whether the aggregate evidence, even if limited, is deemed “encouraging” or “discouraging” overall. Importantly, setting the implementation threshold either too high or too low can have adverse implications for future translation efforts[A key end goal is the development of evidence-based guidelines for candidate pharmacogenetic applications. Published guidelines are seen as critical for promoting awareness of candidate applications, enhancing their uptake,9,13, anl report has genel report,40. The l report. Reflect efforts.OPRM1 scenario is the low utilization of naltrexone in both general and specialty settings[Numerous barriers to the clinical implementation of pharmacogenetic tests have been outlined,15,44,50settings, which usettings.The likelihood that pharmacogenetic protocols will see common use in alcohol treatment scenarios remains unknown. However, there is optimism about the potential for personalized approaches and consensus on the importance of predicting treatment response-22,24,67The author declares no competing interests.


Chamaeleo calyptratus), which are highly aggressive to conspecifics, would respond to agonistic displays with increased levels of oxidative damage, but that increased levels of biliverdin would limit this increase. We found that even just visual exposure to a potential combatant resulted in decreased body mass during the subsequent 48-hour period, but that hematocrit, biliverdin concentration in the bile, relative spleen size, and oxidative damage in plasma, liver, and spleen were unaffected. Contrary to our predictions, we found that individuals with smaller spleens exhibited greater decreases in hematocrit and higher bile biliverdin concentrations, suggesting a revision to the idea of spleen-dependent erythrocyte processing. Interestingly, individuals with larger spleens had reduced oxidative damage in both the liver and spleen, demonstrating the spleen’s importance in modulating oxidative damage. We also uncovered differences in spleen size and oxidative damage between wild and captive-bred chameleons, highlighting environmentally dependent differences in oxidative physiology. Lastly, we found no relationship between oxidative damage and biliverdin concentration, calling into question biliverdin’s antioxidant role in this species.Stressors frequently increase oxidative damage–unless organisms simultaneously mount effective antioxidant responses. One putative mitigative mechanism is the use of biliverdin, an antioxidant produced in the spleen during erythrocyte degradation. We hypothesized that both wild and captive-bred male veiled chameleons ( Oxidative damage occurs when biomolecules such as DNA, lipids, and proteins are oxidized , resultiVariation in oxidative damage among individuals may be partially explained by the organism’s exposure to stressors. Stressors result in the up-regulation of the hypothalamus-pituitary-adrenal (HPA) axis, which regulates traits as diverse as nutrient metabolism, immune function, and behavior. However, HPA upregulation can also result in immunosuppression, glycogenolysis, and protein catabolism  to either non-physical agonistic or sham encounters. As part of their territorial response, veiled chameleons undergo dramatic physiological color changes and behavioral responses when exposed to conspecific males [To investigate how biologically relevant stressors affect oxidative damage in relation to biliverdin production and spleen size, we exposed male veiled chameleons .sensu [We hypothesized that aggressive interactions between male veiled chameleons, even in the absence of physical contact, would result in oxidative damage and resultant red blood cell breakdown. Because oxidative damage can result in erythrocyte destruction (hemolysis) which can increase spleen size ,35, we psensu ).unpub data). Therefore, we exposed adult male veiled chameleons in our treatment group (N = 10) to one another via non-physical agonistic encounters to assess the relationship between biliverdin and biologically relevant, behaviorally induced stress. Specifically, we placed the cages of individuals in the agonistic treatment next to one another in a manner that facilitated visual access but prevented physical access. Each chameleon in the treatment group was exposed to three different opponents over the course of a six hour treatment period, facing the cage of each opponent for two hours. Based on the reproductive biology of the closely related common chameleon Chamaeleo chamaeleon, exposure to numerous conspecific competitors on a given day is highly likely [Veiled chameleons are large, territorial lizards native to the southwestern region of the Arabian peninsula ,40. As py likely . In contPrior to any behavioral exposures (see above), we drew 0.5 ml of whole blood from each chameleon from the caudal vein using heparinized syringes. Forty-eight hours after the beginning of the experimental exposure to opponents (or control cages), we collected another blood sample from each animal . Micro-capillary tubes were used to collect a small volume of blood from the Eppendorf tubes and these capillary tubes were used to assess hematocrit levels from each animal. All samples were kept on ice until centrifugation, at which point plasma was drawn off and frozen at -80°C.Forty-eight hours following the behavioral trials, chameleons were anesthetized via inhalation of isoflurane, an anesthetic that has minimal effects on plasma antioxidant levels , until tWe quantified oxidative damage using a thiobarbituric acid reactive substances kit , which measures the end products of lipid peroxidation . While this assay does not capture all metrics of systemic oxidative damage because it lacks the ability to quantify oxidative damage to proteins and DNA, it does capture those markers of oxidative damage that are most pertinent to this study, namely the damage done to lipids in the erythrocyte membranes that would result in the destruction of damaged erythrocytes. We followed the kit instructions, with the following emendations. We homogenized approximately 50 mg of liver  and between 3.8 and 90 mg (wet mass) of spleen in 1 mL phosphate-buffered saline in 1X BHT (kit component). This range in spleen sample weights was due to the large variance in spleen total weight, from 3.8 mg to 760 mg . All liver and spleen MDA values were then corrected for sample mass. We used the butanol extraction method for all plasma, liver, and spleen MDA samples. Some plasma samples were beyond the linear range of the standard curve, but subsequent dilution and reanalysis  resulted in values below the detectable limit, suggesting that the lag in processing time resulted in sample degradation; these samples were omitted from the study. All liver and spleen samples fell within the linear range.Because there are currently no methodologies for quantifying biliverdin in plasma in non-pathological samples , and bil6 /body weight (g) * 106 (sensu ). Not alg, which is commonly referred to as Cohen’s d in the literature [d values greater than 0.8 have traditionally been viewed as large [To test for relationships between spleen size and physiological states, we performed simple linear regressions with average body mass , biliverdin concentration in the bile, change in hematocrit during the course of the experiment, and MDA in all tissues as dependent variables and the log of Spleen-Somatic Index as the independent variable. Because we were explicitly interested in biliverdin’s role in mitigating oxidative damage, we also ran simple linear regressions between biliverdin concentration in the bile and MDA of each tissue. While some metrics are clearly correlated , we elected to analyze all variables so as ensure we did not miss any potentially interesting findings in this initial investigation relating biliverdin and oxidative damage. Effect sizes are calculated as Hedges’s terature , and altas large . All sta1,15 = 7.77, P = 0.0138, effect size = 1.40). However, conspecific exposure did not affect biliverdin levels in the bile, Spleen-Somatic Index, MDA levels in spleen, liver, or plasma, or change in plasma MDA levels over the duration of the experiment . However, individual origin affected multiple metrics, with chameleons collected from the wild population having reduced MDA levels in the liver, an increase of plasma MDA during the 48-hour trial, and larger Spleen-Somatic Indices  than control animals (-3.69g ± 1.27g) over the duration of the experiment . We found that chameleons with greater concentrations of biliverdin in the bile  and larger drops in hematocrit  had smaller spleens, counter to our predictions , but there was no longer any relationship between change in hematocrit and spleen size .Neither change in hematocrit over the course of the experiment nor biliverdin concentration in the bile independently predicted Spleen-Somatic Index . Howeverdictions . However1,18 = 14.18, P = 0.001; 1,18 = 11.42, P = 0.003; 1,17 = 3.54, P = 0.077; Spleen: F1,17 = 6.86, P = 0.018). There was no significant relationship between Spleen-Somatic Index and plasma MDA concentration at the start , at the end , or the change over the course of the experiment . Inclusion of origin as an independent variable did not qualitatively affect these relationships .Spleen-Somatic Index was negatively correlated to MDA concentration in both liver (FP > 0.1).Because there were no treatment effects on oxidative damage or biliverdin concentration, we ran simple linear regressions between these two terms for all chameleons regardless of treatment. There were no significant relationships between biliverdin concentration in the bile and MDA concentration in any tissue . IncludiBison bison; [Dama dama; [Tetrao tetrix; [Veiled chameleons are highly aggressive toward conspecifics, and even in the absence of physical contact, we found that these behaviors have significant costs. Chameleons exposed to non-physical agonistic encounters lost approximately 5 more grams over the subsequent 48 hr period than those that were exposed to empty cages, an increase of approximately 42%. This finding mirrors the costs of aggressive interactions in American bison  and bla tetrix; ) that enAlectoris chukar) suggested that captivity stress reduces hematocrit for 1–3 days post-stressor [Agonistic encounters induce cortiocosterone increases in multiple species , and whistressor  and becastressor . Howeverstressor , it is pin vivo in veiled chameleons. However, the framework of our hypothesis depended upon detecting treatment-based differences in lipid peroxidation in the liver, spleen, or plasma, or documenting a change in biliverdin concentration in the bile. Because no such treatment-based differences existed for either the induction of oxidative damage or a change in biliverdin concentration, biliverdin’s role as an antioxidant in vivo remains unclear. Despite interest in understanding biliverdin’s role as an antioxidant, the vast majority of investigations use mammals, which are a sub-optimal model for this question. Mammals produce large amounts of the enzyme biliverdin reductase, which reduces biliverdin to bilirubin, another molecule with antioxidant properties in vitro [Despite biliverdin's reported antioxidant capability in other species , we founin vitro . Such enin vitro , and thuin vitro and the lack of an antioxidant role in our system. The first is that biliverdin is hydrophilic at physiological pH [in vivo, and our data are consistent with this hypothesis. However, several other hypotheses are also supported by our data. For example, it is possible that our treatment did induce oxidative damage, but chameleons responded by increasing their antioxidant defenses, either via biliverdin production or some other means, thus minimizing or eliminating any detectable change in oxidative damage 48 hours later. To resolve this question, we would need to either manipulate circulating biliverdin levels or oxidative damage more directly, or collect samples from chameleons at repeated time intervals, which is currently methodologically unfeasible considering the current terminal, bile-dependent methodology required to quantify biliverdin in any non-pathological samples [There are several explanations regarding the discrepancy between biliverdin’s demonstrated antioxidant properties gical pH , and MDAgical pH , it is p samples ,44.increasing hematocrit and low biliverdin concentration in the bile. Even after accounting for origin-dependent differences in relative spleen size, the negative relationship between relative spleen size and bile biliverdin concentration persisted. This result stands in contrast to much of the literature, which documents evidence that spleen size increases as erythrocytes are sequestered [Despite the lack of evidence regarding an antioxidant role for biliverdin, we uncovered interesting relationships between biliverdin concentration in the bile, relative spleen size, and hematocrit levels. Specifically, we found an interactive relationship between changes in hematocrit and bile biliverdin concentrations − in direct contrast to our predictions. Originally, we predicted that chameleons’ spleens would become enlarged as they processed a greater number of damaged red blood cells that would, in turn, lead to increased biliverdin concentration in the bile. However, we found that relative spleen size was greater in individuals with uestered  and hemauestered , and thauestered ,60. HoweWe uncovered robust relationships between relative spleen size and levels of oxidative damage in both the spleen and liver, but not plasma. These relationships fit proposed mechanistic pathways, and positive relationships between spleen size and antioxidants ,17 and nThe importance of spleen size in the physiological status of veiled chameleons is underscored by the differences detected between individuals from the wild versus captive-bred source populations. Captive-bred chameleons had relatively smaller spleens, suggesting that either genetic differences or organizational effects of rearing environment  drive variation in spleen size between wild and captive-bred chameleons. Such differences in relative spleen size may be driven by population-dependent differences in sex hormones  or glucoIn sum, we found that even in the absence of physical contact, agonistic encounters can have negative effects  in potential combatants. However, these stressors, which are common in veiled chameleons, failed to induce any other detectable effects in hematocrit, oxidative damage, relative spleen size, or biliverdin production, suggesting that these species are generally robust to such ecologically relevant stressors, or that actual fighting may be necessary to affect these parameters. We also found that relative spleen size is correlated with biliverdin concentration in the bile, but opposite to the direction that we predicted. This suggests that either veiled chameleons have a particularly unique plasticity in spleen size, or that natural variation in spleen size represents an opposite pattern to plasticity in spleen size. Lastly, we found that relative spleen size is negatively correlated with oxidative damage in both the spleen and liver, highlighting the potentially important role the spleen has in managing systemic levels of oxidative damage.S1 Dataset(XLSX)Click here for additional data file.


Sarcoidosis is a complex granulomatous disease that affects virtually every organ and tissue, with a prevalence that varies significantly among the sites involved. The role of conventional imaging, such as computed tomography and magnetic resonance imaging, in the assessment of hepatosplenic sarcoidosis is well established by revealing organ enlargement, multiple discrete nodules, and lymphadenopathy. In this review, we aim to describe contrast-enhanced ultrasound (CEUS) findings in liver and spleen involvement by sarcoidosis, reporting evidence from the literature and cases from our experience, after a brief update on safety profile, cost-effectiveness, and clinical indications of this novel technique. Furthermore, we highlight potential advantages of CEUS in assessing hepatosplenic sarcoidosis that may be useful in the clinical practice. Sarcoidosis is a complex granulomatous disease that virtually affects every organ and tissue, with a prevalence that varies significantly among the sites involved. However, it affects most often compartments such as lungs and mediastinal lymph nodes, manifesting as a pulmonary restrictive disorder in up to 65% of patients, and with pulmonary fibrosis in 20–25% of them –3. The vOrgans, such as liver and spleen, are less frequently affected than lungs, and their involvement often shows a benign course but portal hypertension and loss of liver function may occur –10. HoweAlthough there are no specific recommendations for hepatosplenic imaging studies in patients with sarcoidosis, it is widely accepted to perform exams such as unenhanced ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) when an increase of liver function tests is found or when abdominal symptoms, such as nausea, vomiting, and weight loss, are reported.Liver can be affected in 10–25% of cases, but hepatic involvement is often oligo- or asymptomatic. Various degrees of dysfunction of liver function tests such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-gt, and alkaline phosphatase can be observed . In a reSplenic involvement is uncommon (5–10% of cases) and usually manifests with asymptomatic and mild splenomegaly. Rarely, the enlargement of the spleen is more pronounced with hypersplenism and pancytopenia , 14.Hepatosplenic sarcoidosis is common in patients with systemic disease, but it is often underestimated on imaging techniques, in particular conventional ultrasound, because granulomatous inflammation of the liver and spleen can be minimal and/or manifest with nonspecific patterns. While granulomas have been found in 60–80% of liver biopsy specimen, sarcoid hepatic nodules are found on imaging in only 5% of cases .The most common finding is represented by hepatomegaly with homogenous distribution of echoes and without evidence of prominent nodules. Sometimes, US can demonstrate an increase of parenchymal liver echogenicity, mimicking fatty liver disease  18, 19], 1918, 1Splenomegaly can be observed in either absence or presence of focal splenic lesions, and there is a different prevalence in observing discrete nodules among published studies (6–33%), perhaps reflecting ethnic differences in study populations . SplenicFurthermore, enlarged lymph nodes have been observed in up to 76% of cases, both in hepatic and splenic sarcoidosis, and they appear as single or multiple hypoechoic masses that are located most often in periportal, celiac, paracaval, and paraaortic compartments, with sizes between 1 and 2 cm . We geneInvolved abdominal lymph nodes may show inhomogeneous echotexture, with multiple low-level echoes inside , 28. TheHepatic and splenic involvement by sarcoidosis can be associated with systemic disease or can be isolated. In the latter, the diagnosis is difficult if based only on imaging studies and requires often a biopsy and a histopathological examination of the organs –33.US can also demonstrate some atypical pattern, rarely described in the literature. Some nodules, due to their confluence tendency and irregular appearance, raise the problem of differential diagnosis with neoplastic disorders , 34, 35.Bauones et al. have recently reported a case of incidental finding of multiple hypoechoic and nonvascular splenic nodules that were associated with a significant retraction of the overlying splenic capsule; splenomegaly was not found and no other organ involvement was documented. This atypical finding has mimicked neoplastic disease, and the patient underwent a laparoscopic splenectomy in order to exclude malignancy . In thesThe diagnosis of sarcoidosis can be suspected on the basis of typical clinical, laboratory, and imaging features but is usually achieved with histopathological findings that confirm the presence of noncaseating granulomas and exclude other causes of granulomatous inflammation , 36. EffOther imaging techniques, such as contrast-enhanced CT (CECT) and MRI, are reliable to evaluate the organ involvement in sarcoidosis. CT can confirm hepatosplenomegaly, and, in most cases, the liver appears homogeneous; sometimes, however, the liver appears heterogeneous and a septa-like pattern can be found after contrast agent injection . CECT caIn recent years, the use of ultrasound contrast agents (UCAs) has rapidly increased in the clinical practice. Since the first guidelines regarding the use of CEUS in the assessment of liver lesions, released by European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) in 2004 and lastly updated in 2013 –45, new CEUS has demonstrated a high overall diagnostic accuracy in the differential diagnosis of focal liver lesions, with similar values of sensitivity and specificity as compared to conventional imaging, such as CT or MRI –55. A reFurthermore, several authors have demonstrated that CEUS can provide valuable information in the differential diagnosis of focal splenic lesions with high accuracy –62; Yu eAlthough there is increasing evidence regarding the usefulness and reliability of CEUS, a broad group of disorders have not been investigated so far with this technique. Actually, there is a lack of ad hoc studies in patients with hepatosplenic sarcoidosis, and most evidence derives from description of single case reports or from findings of small case series . Most ofIt is reasonable to expect this lack of data, first of all because sarcoidosis is an uncommon disease, and demonstration of liver and spleen involvement on imaging is even rarer; then, in most of cases, hepatosplenic sarcoidosis appears homogenous on US without evidence of discrete nodules, and second imaging, such as CT and MRI, is preferred to assess the organ involvement in these cases. However, CEUS has documented accuracy to characterize splenic and hepatic parenchymal inhomogeneity, when found , 46.Even if the evidence is limited, hypoechoic hepatic lesions derived from sarcoidosis appear, after UCA injection, as variably arterial enhancing and progressively hypoenhancing nodules in the portal-venous and late phases , 65.Also hypoechoic lesions of the spleen appear most often as progressive hypoenhancing nodules, in arterial and parenchymal phases, compared to adjacent splenic tissue, with increasing lesion-to-parenchyma contrast diffusion while moving to parenchymal phase  58, 65], 6558, 6CEUS can be useful to identify hepatic or splenic isoechoic nodules that are not otherwise evident on conventional US; these lesions appear as progressively hypoenhancing masses  24]. So. So24]. The limited evidence regarding CEUS findings in hepatosplenic sarcoidosis raises the need for further studies that evaluate the role of CEUS in this uncommon disease. Although the most observed pattern is characterized by absence or less enhancement of the nodules with respect to the healthy parenchyma, no studies have reported CEUS findings in hyperechoic lesions derived from hepatosplenic sarcoidosis. It would be interesting to explore these patterns and to see if there is a different behavior after UCA administration; however, we expect similar findings for hyperechoic nodules on CEUS to that of hypo- and isoechoic lesions, because of their similar hypodense appearance on CECT , 24. CT In conclusion, hepatosplenic sarcoidosis remains so far a challenging diagnosis , 70. Ima


The decision to conduct a randomized controlled trial (RCT) in a field raises ethical as well as scientific issues. From the clinical equipoise literature, future trials are justifiable if there is ”honest, professional disagreement in the community of expert practitioners as to the preferred treatment”. Empirical data are sparse about how clinicians apply the principles of equipoise to the justification of future RCTs. For example, selective decontamination of the digestive tract (SDD) is not widely used in critical care practice despite the strength of the evidence base and therefore provides a unique opportunity to learn how clinicians think about the ethics of further RCTs in critical care.In an international interview study of views of healthcare professionals about SDD, we undertook a secondary analysis of qualitative data collected using a Theoretical Domains Framework of clinical behaviour. We adopted a general descriptive approach to explore how physicians determined whether another RCT of SDD is ethical. Following a constant comparison approach, three investigators reviewed 54 purposively chosen transcripts from three international regions. We interpreted the data using thematic analysis.We grouped participants’ responses into four inter-related themes: 1) cultural norms about evidence and practice within healthcare; 2) personal views about what evidence is current or applicable; 3) the interpersonal and relational nature of professional decision making locally; and 4) an a priori commitment to future trials. The analysis also identified several unresolved tensions regarding when a future RCT should be pursued. These tensions focused on a clash between potential benefits to current individual patients and potential future harms to patients more broadly.Our study suggests that ethical decision making about future RCTs in the field of SDD does not rely strongly on appeals to evidence, even when the quality of the evidence is reasonably high. Rather, “extra-evidential” reasons, including social, professional, and relational factors, seem to influence opinions regarding the ethics of future trials. Further work is required to see if these conclusions are applicable to other clinical topics and settings.The online version of this article (doi:10.1186/s13063-015-1137-8) contains supplementary material, which is available to authorized users. Randomized controlled trials (RCTs) help to provide reliable information on the safety and efficacy of healthcare interventions. To have scientific and clinical utility, an RCT of a novel intervention may be considered to have a “window of opportunity” with respect to the accumulating knowledge base. If little evidence exists at the proof-of-principle level, a large definitive RCT may be premature, and it may be unjustifiable to expose patients to a potentially ineffective (or even harmful) treatment in a subsequent trial. On the other hand, if the safety, efficacy, and effectiveness of an intervention have been rigorously established, a further RCT seems unlikely to contribute meaningfully to knowledge. Unnecessary repetition of RCTs is a more common problem than one might think. Fergusson and colleagues describe a series of 64 RCTs of aprotinin versus placebo to reduce preoperative transfusion that were conducted over a 15-year period  now not be willing to change their mind regardless of the evidence because to do so at this point would almost undermine all the years that they actually said it didn’t work.” The reasons given by participants for not following evidence varied but were seldom based on methodological criticism of supporting evidence or appeal to contradictory evidence. For some, resistance to evidence was related to maintaining one’s professional reputation. One critical care physician described how adopting new evidence might call into question the validity of previous practices, suggesting that:quite poor evidence”:“the head of bed elevation…even though [it has] quite poor evidence … and especially even when compared to SDD, people will say, ‘Well, what’s the big deal… in just elevating the head of the bed? It’s an easy thing to do’… the science behind it’s bad, but people just agree….” Many interviewees also described regularly following practices which were not evidence-based. One participant cited collegial agreement and potential lack of harm, to justify engaging in practices for which there is ““I think because the national and international bodies haven’t come out… jumping up and down and saying it’s a good thing to do that everyone’s a bit leery to strike out on their own”. Another cultural norm that emerged from our interviews was deference to guidelines. Many participants were unwilling to trust their own critical appraisal of the evidence if this meant going against norms or guidelines. As one participant argued:“it’s been very interesting that it’s not adopted, yet evidence would suggest it should be and, and it’s almost actively not adopted if you know what I mean. It’s the … best example we have against evidence-based medicine. Despite a level of evidence we’re happy to apply to other things … it still isn’t incorporated into practice…” In relation to the evidence for SDD specifically, some physicians felt that there was strong evidence to adopt SDD yet similarly strong resolve to not adopt it:“I think [there have] been various iterations of SDD over the years and it’s come and gone in terms of fashion. I remember in 1993 … it was quite fashionable to do it at that stage and then it went out of vogue and more recently it’s come back into vogue again and … has been a bit cyclical in its history.” For some participants, their personal view that the effectiveness of SDD is “old news” was a salient factor in their decision making. Although evidence is meant to be cumulative, in practice it turns out that the interpretation of evidence might more often be cyclical. In the current climate of rapidly produced new evidence, “old news” evidence might not be implemented despite its solid grounding in science. As one participant noted:different microbial flora, [and a] different patient population , while a critical care physician in Australia believed that, before making a decision to implement as a “standard of practice”, they would need to see:evidence replicated in a setting outside of Northern Europe, preferably in Australia” “In addition, several participants considered that the results of trials that had been conducted in other countries were not relevant or applicable in their own. This held true even when patient populations and healthcare systems were relatively similar across countries. For example, one Canadian pharmacist indicated that he considered studies conducted in Europe to have “concern about the possibility of resistant organisms” and further indicated that in their hospital, “antibiotic usage is controlled by the microbiologists …” .Participants in Australia and Canada expressed their perception that members of other professional groups had differing beliefs or priorities with respect to SDD. For example, some critical care physicians described their infectious disease colleagues as being singular in their “The intensivists might be embracing this with open arms, but unfortunately the intensivists aren’t really concerned with anything outside the doors of the ICU… a disaster created in the ICU… becomes a disaster on the ward and the rest of the hospital, so the intensivists have to remember that what they do in their little area could have grave implications system-wide.” “On the other hand, some of the infectious disease physicians explained their concerns about SDD and antibiotic resistance, concerns which they felt were overlooked by the intensivists::“And I think also we try where we can to do most things in a sort of … collegiate fashion with consensus rather than having one person implementing things.” Within their professional groups many participants insisted that decisions were made on a team basis:“Because I’m external to the ICU the decisions on protocols are basically made by the director of the ICU … so if the director of our ICU felt very strongly in favour of something and we didn’t like it, you would do it anyway. Nonetheless, many participants also specified that one particular individual (often the head of a unit or department) had decision-making authority within their unit.“[In order to adopt SDD in my unit] someone would have to assassinate me.”Still other participants seemed steadfast in their conviction that they would never adopt SDD.“I don’t know how many times you have to beat people over the head with a stick for them to get it. I guess if there was to be more research, well, what would it be?… at some point I think people either have to buy into it or you have to move on to a different topic”. Several participants expressed their belief that future trials were unnecessary or infeasible:“just wasting everybody’s time because I think the people… have got their mind set up against it” .“We do a lot of research but I guess I can’t really see how [testing implementation strategies] is research. It’s more implementation of a treatment which probably has evidence.” Many participants clearly supported this opinion that a future trial was unnecessary, suggesting that such a trial would be:“I am not convinced there is overwhelming evidence that we should all be doing it because if there was overwhelming evidence that we should all be doing it, then we would all be doing it. Therefore I think there is still a potential for more research.” “Oh absolutely I think there’s, I think there’s equipoise on this issue and so [a trial] is absolutely justifiable.” “I think it [a trial] is ethical because there is a huge, I think there is equipoise within the medical profession.” Paradoxically, many of these same participants expressed a willingness to participate in future effectiveness trials:Our study found that the descriptions which clinicians provided of their ethical decision making and practice were significantly influenced by the “extra-evidential” factors described above . Interestingly, these norms transcended professional and geographical boundaries. Physicians in our study did appeal directly to the concept of clinical equipoise but based their assessment of whether clinical equipoise obtains on socio-organizational types of factors, including practice norms, personal opinion, and clinical experience. Equipoise is a term frequently used in discussions of clinical trials. Yet, despite the discursive centrality of this concept in the ethical justification for clinical trials, there is a surprising lack of empirical research exploring physicians’ views and practices. The current study addresses this gap and provides evidence that such “extra-evidential” reasons influence ethical decision making to a much greater extent than previously recognized.In our analysis we paid particular attention to inconsistencies within and between participants’ accounts of their use of evidence in clinical and ethical decision making. We found many statements that contradicted the notion that clinicians undertook an objective appraisal of scientific evidence when making decisions regarding the ethics of future RCTs on this topic. In general, participants described a widespread tendency to ignore scientific evidence and to accept published guidelines uncritically as a substitute for individual appraisal of evidence. This is particularly interesting, and may seem surprising in light of the longstanding problems related to variability in physician adherence to published guidelines and the difficulty in increasing guideline adherence .The social context in which clinicians practice greatly influences their perceptions. In an important qualitative study by Donovan et al. , researcA number of critics argue that the current thinking on EBM ignores the relational aspects of knowledge and dismisses the role of values in healthcare . For sucOne of the limitations of secondary analysis of qualitative data is a lack of involvement in generating the original data set. Our original use of the Theoretical Domains Framework in the primary study, however, resulted in the generation of rich, in-depth data, which mitigated this challenge. Given the large number of interviews originally conducted, we were able to purposively select transcripts and believe that saturation was reached. We identified “key stakeholder groups” to participate in this study but did not include all possible stakeholders in our analysis. In addition, our choice of SDD as an example presents a case in which strong randomized trial evidence has not been adopted in practice. Therefore, it presents a special case, and our findings may not be generalizable to other interventions. Further limitations may include the study being performed in English-speaking countries only and in countries where SDD implementation is low.We sought to ascertain how clinicians decide whether future RCTs in a field are ethical. This study reveals that, regarding SDD, ethical decision making did not rely strongly on appeals to evidence, even when the quality of the evidence is quite high. Clinicians from different specialities and different geographical regions consistently described having been influenced by extra-evidential factors in their day-to-day practice and in their willingness to participate in future trials. These extra-evidential factors include social, professional, and relational contexts. When clinicians appeal to factors other than the evidence base, it can have a significant impact on their willingness to design, conduct, and enrol patients into future RCTs or may limit their willingness to implement “apparently proven” therapies into their practices. Further work is required to see if these conclusions are applicable to other clinical topics and settings.


Polyarteritis Nodosa (PAN), Granulomatosis with Polyangiitis (GPA), Microscopic Polyangiitis (MPA), Eosinophilic Granulomatosis with Polyangiitis (EGPA) and Takayasu Arteritis (TA) are rare paediatric vasculitides that can lead to significant morbidity. Evidence-based guidelines are sparse and management is mostly based on physician experience. Consequently, treatment regimens differ throughout Europe. In 2012, a European initiative called SHARE (Single Hub and Access point for paediatric Rheumatology in Europe) was launched to optimize and disseminate guidelines for diagnosis and management for children and young adults with paediatric rheumatic diseases (PRD) such as vasculitis within Europe.To provide evidence-based recommendations for diagnosis and treatment of paediatric vasculitides, specifically PAN, GPA, MPA, EGPA and TA.Evidence based recommendations were developed using the European League Against Rheumatism (EULAR) standard operating procedure. An expert committee was formed, consisting of paediatric rheumatologists from across Europe with expertise in vasculitis. The expert committee defined search terms for the systematic literature review, which was performed in summer 2013. Two independent experts scored each article for validity and level of evidence. Recommendations derived from the literature were evaluated using an online survey. Those with less than 80% agreement during the online survey were reformulated. Subsequently, all recommendations will be discussed at a consensus meeting using the nominal group technique [The systematic literature search yielded 7766 articles, including articles on two more common forms of paediatric vasculitis, Kawasaki Disease (KD) and Henoch Schonlein Purpura (HSP). After exclusion of these articles and articles that did not meet inclusion criteria, 93 articles on rare paediatric vasculitides were considered relevant. The expert committee then scored these for validity and level of evidence. Evidence supporting recommendations for diagnosis and treatment was extracted from the literature. Subsequently, statements on clinical symptoms, referral of patients, useful laboratory investigations, imaging techniques and treatment were formulated based on this evidence and expert opinion and were evaluated in an online survey. The outcome of this survey will be discussed at the next consensus meeting with the aim of yielding final recommendations on minimal standards of care for children with vasculitis throughout Europe.The SHARE initiative provides recommendations for diagnosis and treatment of paediatric vasculitides and thereby facilitates improvement and uniformity of care for patients throughout Europe. Currently, similar processes are ongoing to add add guidelines on holistic care for PRD patients. As a final result, SHARE will provide standards of minimal care for different PRDs, including rare vasculitides  as well as more common vasculitides (KD and HSP).None declared.


Sugars intake for adults and children.To determine whether sugar industry-related organizations influenced textual changes between the draft and final versions of the World Health Organization’s (WHO’s) 2015 guideline Stakeholder consultation submissions on the draft guideline from seven sugar industry-related and 10 public health organizations were assessed using the Wordscores program. Document scores were rescaled using the Martin–Vanberg transformation to improve comparability. Draft and final guidelines were compared to identify changes influenced by the sugar industry and public health organizations.There was a small shift in transformed Wordscores score between the draft and final guidelines, from 0.25 to 0.24, towards the industry position. The change was linked to increased use of the word “low” to describe the quality of the evidence, consistent with industry arguments. There was also a shift from use of the word “consumption” to “intake”, irrespective of policy position. Scores for World Sugar Research Organisation and Sugar Nutrition UK submissions  represented strong pro-industry positions and scores for European Public Health Alliance and Wemos submissions  represented the strongest public health positions. Industry tactics included challenging the quality of the evidence, distinguishing between different types of sugar and advocating harm reduction.There was little change between draft and final versions of the WHO sugars intake guideline 2015, following industry consultation. The main change was linked to emphasizing the low quality of the evidence on sugar’s adverse effects. Guideline development appeared relatively resistant to industry influence at the stakeholder consultation stage. Pure, white and deadly,The saccharine disease,,,In 2013, the World Health Organization (WHO) began the process of updating its guideline on sugars intake for adults and children. Sugar consumption has been a contested area of global public health for at least four decades, initially stimulated by Yudkin’s 1972 classic, ,Diet, nutrition and the prevention of chronic diseasesQuite possibly, WHO is the most important public health agency responsible for developing global guidelines. One of its core functions is to ensure that evidence is used appropriately. In the past, WHO has produced guidelines on blood pressure, patient safety, mental health and substance abuse, among other topics. Several are contested because their recommendations conflict with the goals of multinational pharmaceutical companies or tobacco, alcohol, food or beverage companies.,,WHO handbook for guideline development  followed procedures outlined in the The guideline was developed by WHO’s Nutrition Guidance Expert Advisory Group’s Subgroup on Diet and Health. Members of the subgroup included experts who had previously participated in expert consultations for WHO, who were members of WHO’s expert advisory panels or who had been identified through an open call for experts. Representatives of commercial organizations were not invited to participate because their membership of a WHO guideline group was considered inappropriate due to actual, potential or perceived conflicts of interest. The subgroup reviewed and assessed the quality of the evidence available on the existing and new sugars guidelines and advised WHO on selecting outcomes important for decision-making and on interpreting the evidence used to produce recommendations. The overall quality of the evidence was assessed by systematic review and using the GRADE  approach.The WHO Secretariat selected external peer-reviewers from among representatives of public institutions that are members of WHO’s Global Network of Institutions for Scientific Advice on Nutrition, experts in the subject matter and other stakeholders, such as medical practitioners and scientific journal editors. The resulting peer-review group was asked to examine the draft guideline and identify any errors or missing information.The initial public consultation asked for comments on the scope of the guideline and on specific research questions. The request was posted on the website of WHO’s Department of Nutrition for Health and Development and disseminated through the department’s mailing list and the mailing list of the United Nations Standing Committee on Nutrition. A second public consultation was carried out to obtain comments on the draft guideline before it was finalized. Contributors were contacted through the same two mailing lists.To determine whether the sugar industry was able to influence the recent updating of WHO’s sugars intake guideline, we evaluated the textual content of the updated guideline using automated content analysis, a tool that has recently been used to quantify the influence of the tobacco lobby on policy.Between 5 March and 31 March 2014, WHO consulted stakeholders on the new sugars intake guideline. For this analysis, we obtained submissions from organizations linked to the sugar industry and from leading public health organizations that were made publicly available by the organizations themselves. The ultimate selection of sources was the sole responsibility of the authors. Organizations identified as having potential links to the sugar industry were: the World Sugar Research Organisation; Food Industry Asia; the International Food & Beverage Alliance; Nestlé; Sugar Nutrition UK”; Kenniscentrum suiker & voeding; and Wirtschaftliche Vereinigung Zucker. Those identified as having public health interests were: the Centre for Science in the Public Interest; the United Kingdom Health Forum; the European consumers organization BEUC; the International Baby Food Action Network; the Mexican nongovernmental organization El Poder del Consumidor; the Dutch nongovernmental organization Wemos; the World Dental Federation; the World Obesity Federation; and the European Public Health Alliance.,We compared the policy positions taken by stakeholders with the content of WHO’s evolving guideline using the scaling algorithm Wordscores .Box 2w in a reference text r, denoted wrF, is used to compute the conditional probability that we are reading text r if we are reading the word w. This probability is then used to derive a score, wS, for each word w that is the weighted average of the scores for all the reference texts in which the word w appears – the scores are weighted by the calculated conditional probability for each text. Then, the word scores are used to compute an overall document score for each virgin text v, denoted vω, which is the sum of the scores for all the words contained in it weighted by their relative frequency wvF:With the textual analysis program Wordscores, the relative frequency of a word v = ∑w (Fwv . Sw).ω,This approach has previously been validated for political texts and speeches on economic policy.v - ω1)/(ω1 - ω2), of all words in WHO’s final guideline. The word “dental”  featured more prominently in WHO’s guideline than did the acronym “NCDs” for noncommunicable diseases , the word “obesity” , the word “diabetes”  or the acronym “CVD” for cardiovascular disease . Children were discussed more often than adults in WHO’s documentation: the frequency of words associated with children was 0.7% (39/5239), whereas the frequency of words associated with adults was 0.5% (25/5239). Children were referred to more frequently in stakeholders’ submissions. The word “physical”  was mentioned in four of the seven submissions from sugar industry-related organizations but in only one submission from a public health organization (the Centre for Science in the Public Interest). Sugar industry-related organizations appeared to be emphasizing energy expenditure through physical activity in preference to energy intake from food.The final column in Box 3The following textual changes between the draft and final versions of the World Health Organization’s 2015 sugars intake guideline illustrate: (i) increased usage of the word “low”, linked to the addition of descriptors about the weak quality of the evidence; (ii) increased usage of the word “intake”; and (iii) the use of more specific descriptions of the types of sugars.The draft version of the guideline included the recommendations:(1a) The recommendation to limit sugars intake to less than 10% of total energy is based on observational studies with dental caries as an outcome.(2a) The recommendation to further limit sugars intake to less than 5% of total energy is based on ecological studies in which a linear relationship between sugars intake and dental caries was observed.In the final version of the guideline, these were amended to :free sugars intake to less than 10% of total energy intake is based on moderate quality evidence from observational studies of dental caries.(1b) The recommendation to limit free sugars intake to less than 5% of total energy intake is based on very low quality evidence from ecological studies in which a positive dose–response relationship between free sugars intake and dental caries was observed at free sugars intake of less than 5% of total energy intake.(2b) The recommendation to further limit To assess the robustness of our findings, we included all documents from sugar-industry related and public health organizations as reference documents, as described earlier. Although none of the main results were changed, the submission by the Centre for Science in the Public Interest shifted to being closer to the public health position when it was included as a reference text. In addition, we removed any words containing the word “sugar”, as they were relatively common in all documents. This did not alter the direction of the findings because use of these words did not discriminate between policy positions.To identify the tactics used by the sugar industry, we carried out a qualitative analysis of its submissions. One tactic involved direct attacks on the implications of the evidence. The World Sugar Research Organisation’s submission claimed that there was no evidence to support WHO’s statement in the draft guideline that: “There is no harm associated with reducing the intake of free sugars to less than 5% of total energy.” Nevertheless, this statement was retained in the final document. Other industry submissions went further and argued that reducing sugar consumption could lead to higher fat intake.A second tactic was to challenge the validity of the evidence. Several submissions from sugar industry-related organizations argued that the distinction between different types of sugar made by WHO was not scientific. For example, Sugar Nutrition UK stated that the “distinction between ‘free’, ‘added’ and ‘other’ sugars is not based on any sound scientific principles, given that it is impossible to analytically distinguish between sugars present naturally in a food and those which have been added during cooking or manufacturing”. Industry submissions also questioned the validity of the systematic reviews commissioned by WHO because they made recommendations about “free” sugars, whereas they had evaluated “total” sugars.WHO handbook for guideline development. The International Food & Beverage Alliance took a similar approach, arguing that “there is insufficient scientific support that would justify the lowering of the current WHO guideline on consumption of free sugars to 5%”. Sugar Nutrition UK took a similar stance, stating that: “To use… ‘very low quality’ data as evidence to underpin a conditional recommendation of a ‘further reduction to below 5% of total energy’ contradicts WHO’s own guidelines.”A third tactic was to undermine the strength of the evidence. For example, the World Sugar Research Organisation argued that: “The quantitative target of 10% cited in the Draft Guideline is based solely on observational cohort studies of dental caries in children. This is an inadequate basis for public health guidelines because of the certainty of confounding.” The organisation then argued that: “No recommendation can be made because of insufficient evidence” and cited the Finally, several industry submissions sought to place the emphasis on harm reduction. For example, the World Sugar Research Organisation argued that the risk of dental caries from sugar consumption can be mitigated; it stated: “Any effects of consumption of sugars will be attenuated by fluoride protection.” They further argued that“available data do not allow the setting of an upper limit for intake of (added) sugars on the basis of a risk reduction for dental caries, as caries development related to consumption of sucrose and other cariogenic carbohydrates does not depend only on the amount of sugar consumed, but it is also influenced by frequency of consumption, oral hygiene, exposure to fluoride, and various other factors.”Although the majority of sugar industry-related organizations opposed the guideline, Nestlé appeared more supportive, stating that: “We support [WHO’s] recommendation that you reduce the consumption of free sugars throughout the course of your life… [and] should not exceed 10% of your total energy intake, whether you are an adult or a child.” The company also argued for voluntary reductions in the sugar content of food and highlighted its commitment to reducing the sugar content of children’s cereals to 9 g or less per serving by 2015.We found relatively little change overall in WHO’s 2015 guideline on sugars intake for adults and children from before to after the stakeholder consultation in 2014 despite strenuous efforts by industry to modify it. The changes observed were linked to increased use of the word “low” to describe the quality of the evidence and of the word “moderate” to describe the quality of observational cohort studies. Although the sugar industry used several tactics to undermine the guideline’s recommendations, their development was not substantially affected.,,As with any statistical analysis, this study has several important limitations. First, because we examined differences between the draft and final versions of the guideline rather than the details of the texts themselves, we were not able to identify influences on the draft. Future research could investigate the creation of the draft guideline by WHO’s Nutrition Guidance Expert Advisory Group’s Subgroup on Diet and Health and the nature of the initial public consultation. Second, automated content analysis rests on the assumption that word choice reflects an underlying ideology. However, industry may seek to mimic the language of WHO or, conversely, United Nations’ agencies such as WHO may adopt the language of industry. This effect has been observed in textual analyses of the World Bank’s language, which evolved over time to correspond to that of the banking sector.Some aspects of WHO’s policy-making process may protect it against industry influence. First, WHO is exclusively concerned with health. Consequently, there is less scope for industries that produce unhealthy commodities and organizations acting on their behalf, including some governments, to divert attention to competing areas such as trade. For example, in national governments and supranational bodies such as the European Union, health may have to compete with other concerns. Second, WHO commissions independent systematic reviews of the evidence, which are more carefully scrutinized for conflicts of interest than reviews commissioned by peer-reviewed journals. The European Food Safety Authority, for example, bases its guidelines on scientific opinion rather than following the same approach to guideline development as WHO.Many of the sugar industry’s arguments were characteristic of denialism, which is widely practiced by the tobacco and alcohol industries to thwart effective public health interventions.Our findings have important implications. Crucially, WHO’s guideline development process appears robust. This is important in light of ongoing efforts by industry to amend the process, especially because updates to WHO’s guidelines on trans fats and saturated fats are planned. However, it may be prudent to allow greater time for public consultations and to be more explicit from the outset about the quality of the evidence base. In addition, the relative weakness of the evidence cited in the sugars intake guideline underscores the importance of carrying out specific research to provide the type and quality of evidence required to inform the development of public health guidelines. Finally, it is clear that the textual and correspondence analysis employed in our study can play a role in evaluating the independence of the guideline development process, which can vary across United Nations’ agencies and other institutions. It can also help to assess the influence exerted by vested interests, particularly industry-funded organizations.


This study aimed to evaluate the quality of the current clinical practice guidelines (CPGs) in traditional medicine (TM) in South Korea using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument to further enhance the CPG development.A search was performed for guidelines in Korea from inception until March 2014 in the major Korean guideline websites , PubMed and seven Korean electronic databases; the Association of Korean Oriental Medicine (AKOM) was also consulted. Five independent assessors rated the quality of each CPG using the AGREE II instrument and calculated the mean score of each AGREE item. The overall agreement amongst reviewers was evaluated using the intra-class correlation coefficient (ICC).Initially, 17 CPGs were examined for TM in Korea, and only 8 CPGs satisfied the inclusion criteria. The mean scores for each AGREE II domain were as follows: (1) scope and purpose, 60.0 % ; (2) stakeholder involvement, 56.11 % (41.28-70.94 %); (3) rigour of development, 42.7 % (23.48-61.92 %); (4) clarity and presentation, 62.50 % (50.89-74.10 %); (5) applicability, 20.31 % (13.96-26.66 %); and (6) editorial independence, 44.58 % (10.78-78.38 %). All of the CPGs were rated as “recommended with provisos or modifications”. The ICC values for CPG appraisal using the AGREE II ranged from 0.230 to 0.993.To improve clinical practice and health outcomes, well-developed CPGs are needed. The quality of CPGs for TM in Korea has remained suboptimal according to the AGREE II instrument evaluation. Therefore, guideline developers in Korea should make more of an effort to ensure high-quality CPGs.The online version of this article (doi:10.1186/s13012-015-0294-1) contains supplementary material, which is available to authorized users. PubMed was searched as an international database, and KoreaMed, the Korea Institute of Science and Technology Information (KISTI), DBpia, the Korea National Assembly Library, the Korean Studies Information Service System (KISS) and the Oriental Medicine Advanced Searching Integrated System (OASIS) were searched as domestic databases.Other sources such as contact with the AKOM and the Society of Korean Medicine were utilised to receive information on CPGs; additionally, the reference lists of all the obtained papers were searched. Hard copies of all the articles were obtained and read in full. The search terms were  and (guideline* or recommendation or consensus) and . The strategy of Korean search terms is shown in Additional file The included CPGs in this study were original reports published in Korea that described TM interventions and provided sufficient methodological details based on evidence.The inclusion criteria were as follows: (1) Korean language CPGs, which were produced by mainland Korea organisations, and (2) based on a systematic review of relevant research evidence. To determine whether the guidelines were evidence-based, we investigated whether they reported a search strategy, quality and data extraction that classified the evidence quality and graded the strength of the recommendation. If the CPGs had updates, only the most recent version was assessed.CPGs were excluded if they met any of the following criteria: systematic reviews, narrative reviews, primary studies, critical pathways, training manuals for medical doctors, textbook-like publications, guidelines for patients, editorials, translations of foreign guidelines, secondary or multiple publications and short summaries.The AGREE II instrument is a tool used to assess the methodological quality of evidence-based CPGs , 6. It wEach guideline should be assessed by at least two appraisers to increase the reliability of the assessment according to AGREE II. There were five appraisers with experience in the quality assessment of CPGs in this study who independently scored each guideline using the Korean translated AGREE II instrument. To improve the quality of the appraisal of guidelines, the CPG evaluation was pilot tested with the reviewers. All five appraisers, including a guideline methodologist, clinician and research assistant, received a training seminar and workshop that included education on the guideline development methods and the process and application of AGREE II. Additionally, we used the Korean-translated AGREE II. One study had examined the effect of the Korean AGREE II scoring guide and showed that the scoring guide reduced the inter-rater disagreement and improved the overall reliability .The scores of the five appraisers were used to calculate an average for each domain, and these scores were expressed as a percentage. Inter-rater reliability was calculated for each domain of the AGREE instrument using the intra-class correlation coefficient (ICC) with a 95 % CI. Statistical analysis was performed using SPSS for Windows 12.0 .n = 4), training manuals for medical doctors (n = 4) or a review (n = 1) . Three CPGs –26 scoreThis domain evaluates the degree of relevant professional group involvement, whether the views and preferences of the target population have been considered and whether the definition of target users has been clearly presented. The overall score in this domain was low with a mean of 56.11 % . Three CPGs –26 scoreThis domain addresses the method of evidence search, grading, summary and the formulation of the recommendations. The mean score for this domain was 42.7 % . Three CPGs –26 scoreThis domain generally evaluates the presentation and format of guidelines. The mean score was 62.50 % , which was relatively higher than the other domains. Three CPGs –26 scoreThis domain evaluates the consideration of facilitators or barriers to CPG implementation and monitoring criteria. The mean score of this domain was 20.31 % , which was the lowest of all the domains. All the CPGs scored <60 %. All the CPGs failed to sufficiently consider applicability in guideline development.This domain addresses issues and competing interests of the guideline development members. The mean score was 44.58 % . Three CPGs –26 scoreThis assessment concerns “the rating of body quality of the guidelines and whether the guideline would be recommended for use in practice”. According to the appraisal of the individual domains and overall scores, all the CPGs were rated as “recommended with provisos or modifications”.The ICC values for the AGREE II instrument appraisal are listed in Table This study is the first to examine the quality of CPGs for TM in Korea using the AGREE II assessment tool. Our results showed that CPGs for TM are of moderate quality, which varies greatly between guidelines and across domains Table . CurrentThree recently developed CPGs –26 receiSince 2006 in China, with the support of the World Health Organization/Western Pacific Regional Office (WHO/WPRO), multidiscipline panels were convened by the China Academy of Chinese Medical Sciences (CACMS) to develop the first collection of evidence-based CPGs in traditional Chinese medicine (TCM) –30. ThesMost domains showed a high reliability. Thus, inter-appraiser scores showed a strong correlation, and values were high for most domains except for the domain applicability. Because there were few or no implementation strategies or efforts to promote implementation in Korea, differences in awareness and the environment across appraisers are thought to affect inter-rater differences . Future In this study, all the CPGs used different grading systems to assess the quality of evidence and recommendations Table . SpecifiCPGs have been widely developed and support implementation with the aim of improving healthcare processes and patient outcomes, but the use of evidence-based practice remains haphazard. CPGs are both poorly developed and ineffectively implemented. To improve clinical practice and health outcomes, both well-developed CPGs and effective methods of CPG implementation are required . FurtherHigh-quality systematic reviews (SRs) and randomised controlled trials (RCTs) are sources of the best evidence . HoweverThis review has a few limitations. Only a few CPGs regarding TM were found. It was assumed that CPGs that were not identified in this study have little potential use in practice. The CPGs evaluated in this report were primarily retrieved from the AKOM. The search results were examined in conjunction with a mail survey of seven clinical academic associations that are not member societies of the AKOM, which were added subsequently. Despite these limitations, this review is useful because it is the first to assess the current CPGs available in TM, and it evaluates the quality of their development process.Several guidelines were produced in Korea within the last 5 years, but the overall quality was generally low. There are several recommendations for the future. First, an educational training programme should be developed for core confidence of guideline development groups to further familiarise them with guideline development standards such as the AGREE instrument and to incorporate these standards into CPGs. Second, budget preparation and the planning of financial support is required for developing and disseminating evidence-based CPGs, and a strategy for efficient partnership between the private sector and the government should be formulated and executed. Third, a methodology for the development of CPGs based on our TM environment, which lacks supporting evidence, is required, and technical support should be provided. Finally, future CPGs should use a consistent grading system to assess the quality of evidence and strength of recommendations.In conclusion, the quality of CPGs for TM in Korea has remained suboptimal according to the AGREE II instrument evaluation. Specially, the use of AGREE II in the development process ensures that these considerations are incorporated and must make an increased effort to ensure the high quality of CPGs. Therefore, guideline developers should consider adopting evidence-based CPGs for developing trustworthy guidelines to ensure the translation of evidence into practice.


The prevalence of allergic diseases in infants, whose parents and siblings do not have allergy, is approximately 10 % and reaches 20–30 % in those with an allergic first-degree relative. Intestinal microbiota may modulate immunologic and inflammatory systemic responses and, thus, influence development of sensitization and allergy. Prebiotics – non-digestible oligosaccharides that stimulate growth of probiotic bacteria – have been reported to modulate immune responses and their supplementation has been proposed as a preventive intervention.The World Allergy Organization (WAO) convened a guideline panel to develop evidence-based recommendations about the use of prebiotics in the prevention of allergy.The WAO guideline panel identified the most relevant clinical questions about the use of prebiotics for the prevention of allergy. We performed a systematic review of randomized controlled trials of prebiotics, and reviewed the evidence about patient values and preferences, and resource requirements . We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations.Based on GRADE evidence to decision frameworks, the WAO guideline panel suggests using prebiotic supplementation in not-exclusively breastfed infants and not using prebiotic supplementation in exclusively breastfed infants. Both recommendations are conditional and based on very low certainty of the evidence. We found no experimental or observational study of prebiotic supplementation in pregnant women or in breastfeeding mothers. Thus, the WAO guideline panel chose not to provide a recommendation about prebiotic supplementation in pregnancy or during breastfeeding, at this time.WAO recommendations about prebiotic supplementation for the prevention of allergy are intended to support parents, clinicians and other health care professionals in their decisions whether or not to use prebiotics for the purpose of preventing allergies in healthy, term infants.The online version of this article (doi:10.1186/s40413-016-0102-7) contains supplementary material, which is available to authorized users. The purpose of this document is to provide evidence-based recommendations about the use of prebiotic supplements for the primary prevention of allergies.Allergic diseases have a prevalence of 10 % in infants without an allergic parent or sibling, and 20 – 30 % in those with allergy in their relatives. It has been suggested that intestinal microbiota may modulate immunologic and inflammatory systemic responses and, thus, influence the development of sensitization and allergy. Prebiotics are non-digestible food components that have been advocated as preventive interventions for allergic diseases by promoting a balanced growth of the intestinal microbiota.The methods used to develop clinical recommendations in this document follow the GRADE approach , 2. The confidence in the available estimates of health effects or certainty in the evidence) is categorized as: high, moderate, low or very low based on consideration of risk of bias, indirectness of evidence, inconsistency and imprecision of effect estimates. Low and very low quality evidence indicates that the estimated effects of interventions are very uncertain.The guideline panel developed and graded the recommendations and assessed the quality of the supporting evidence following the GRADE approach. The quality of evidence , or conditional (“guideline panel suggests…”) and has the following interpretation:▪ For patients: most individuals in this situation would want the recommended course of action, and only a small proportion would not.▪ For clinicians: most individuals should receive the intervention. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences.▪ For policy makers: the recommendation can be adopted as policy in most situations.▪ For patients: the majority of individuals in this situation would want the suggested course of action, but many would not.▪ For clinicians: recognize that different choices will be appropriate for individual patients and that you must help each patient arrive at a management decision consistent with his or her values and preferences. Decision aids may be useful in helping individuals to make decisions consistent with their values and preferences.▪ For policy makers: policy-making will require substantial debate and involvement of various stakeholders.The GLAD-P guidelines about the use of prebiotics provide the basis for rational, informed decisions for clinicians, parents and other decision makers. Clinicians, parents and other caregivers, third-party payers, institutional review committees, other stakeholders, or the courts should never view these recommendations as dictates. No recommendation can take into account all of the often-compelling unique individual circumstances but provides guidance. However, no one charged with evaluating health care professional’s actions should attempt to apply the recommendations from these guidelines by rote or in a blanket fashion.Note: statements about the underlying values and preferences as well as qualifying remarks accompanying each recommendation as well as the evidence to decision frameworks are its integral parts and serve to facilitate more accurate interpretation; they should never be omitted when quoting or translating recommendations from these guidelines.Question 1. Should prebiotics be used in pregnant women?The WAO guideline panel chose to provide no recommendation at this time owing to lack of experimental and observational studies in which prebiotic supplements would be used in pregnant women.Question 2. Should prebiotics be used in breastfeeding mothers?The WAO guideline panel chose to provide no recommendation at this time owing to lack of experimental and observational studies in which prebiotic supplements would be used in breastfeeding mothers.Question 3. Should prebiotics be used in healthy infants?Recommendation: The WAO guideline panel suggests prebiotic supplementation in not-exclusively breastfed infants, both at high and at low risk for developing allergy .not use prebiotic supplementation in exclusively breastfed infants .The WAO guideline panel suggests that clinicians and parents do The recommendation to use prebiotics in not-exclusively breastfed infants places a relatively higher value on possible prevention of allergies and a relatively lower value on additional cost of prebiotic supplementation. The recommendation not to use prebiotics in exclusively breastfed infants places a relatively higher value on avoiding additional cost and burden of implementation of such supplementation and a relatively lower value on uncertain effect on prevention of allergies .These recommendations should not lead to any change in the practice or promotion of breastfeeding in infants. Formulas supplemented with prebiotics should not be considered a substitute for breast milk. Sole availability of such formulas should not influence the decision to breastfeed and/or the duration of breastfeeding. These recommendations apply to otherwise healthy term infants in whom prebiotics would be used with the goal of preventing allergies.The purpose of this document is to provide guidance on the use of prebiotics for the primary prevention of allergies. The target audience of these guidelines are general practitioners, paediatricians, allergists, pulmonologists and dermatologists. General internists, and other health care professionals and health policy makers may also benefit from these guidelines. Policy makers interested in these guidelines include those involved in developing local, national or international plans with the goal to reduce incidence of allergy and resource direct and indirect costs related to allergic diseases . This doAllergic diseases are considered a worldwide burden in different populations. It is considered that approximately 20 % of the population will have an allergic disease at some point in their lives . The preRecent studies have provided researchers more reasons to move their attention to the intestinal microbiota as one of the main culprits for the rising incidence of allergic disorders; its influence on sensitization and its ability to modulate immunologic and inflammatory systemic responses are the main reasons for this suspicion;  in consePrebiotics have been defined as “non-digestible food components that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon and thereby improving host health” and later redefined as”a selectively fermented ingredient that allows specific changes, both in the composition and/or activity in the gastrointestinal microbiota that confers benefits” , 8, 9.The Guidelines for Atopic Disease Prevention (GLAD-P) is a joint effort of the World Allergy Organization (WAO) and the Department of Clinical Epidemiology & Biostatistics at McMaster University to evaluate the current evidence on the preventive effect of probiotics, prebiotics, and vitamin D on allergic diseases and related clinically important outcomes. This document provides recommendations and the rationale for use of prebiotics.Prebiotics: “a selectively fermented ingredient that allows specific changes, both in the composition and/or activity in the gastrointestinal microbiota, thus conferring benefit(s) upon host health.” [health.” , 8, 9. PHigh risk for allergy in a child: biological parent or sibling with existing or history of allergic rhinitis, asthma, eczema, or food allergy [ allergy .For clarity of communication we used the following definitions throughout the document:http://cebgrade.mcmaster.ca/guidecheck.html) [We followed the procedures and methodology using the GIN-McMaster Guideline Development Checklist (ck.html)  to assemA face-to-face meeting was held in January 2015 coinciding with the WAO Symposium in Rome, Italy. During the meeting the guideline panel discussed specific questions, the existing research evidence and made recommendations.Guideline panel members disclosed all potential conflicts of interest according to the World Health Organization policies. The chairs  reviewed and resolved all potential conflicts of interest of panel members  [We used the GRADEpro Guideline Development Tool (pro.org)  and SurvShould prebiotics vs. no prebiotics be used in pregnant women?Should prebiotics vs. no prebiotics be used in breastfeeding women?Should prebiotics vs. no prebiotics be used in infants?The following questions were chosen to be addressed in this document:The guideline panel selected outcomes of interest for each question following the general approach suggested by the GRADE Working Group . All outwww.gradepro.org). All guideline panel members reviewed the summaries of evidence and made corrections when appropriate. We based the evidence summaries on a systematic review of the literature performed specifically for these guidelines (Reference. in preparation). An updated search strategy  following the GRADE approach and using the Guideline Development Tool  is the effect of natural prebiotics in food different from that of supplements, 2) is there an added benefit from prebiotic supplementation on top of natural prebiotics, and 3) is there a differential effect between the different types of prebiotics.We found no other guidelines or position statements that made specific recommendations about the use of prebiotics in pregnant women.The WAO guideline panel chose to provide no recommendation at this time owing to lack of experimental and observational studies in which prebiotic supplements would be used in pregnant women.We found no systematic reviews or individual randomised trials or observational studies that addressed this question.Similarly to Question 1, the guideline panel decided that under current circumstances they were not able to make an informed judgment about the balance of potential desirable and undesirable consequences of using prebiotic supplements in breastfeeding mothers. The panel determined that there is a need for randomized trials of prebiotics in breastfeeding mothers. The additional questions provided in the discussion of Question 1 related to the effects of natural prebiotics vs. their supplements are equally relevant in the context of Question 2.We found no other guidelines or position statements that would make specific recommendations about the use of prebiotics in breastfeeding mothers.The WAO guideline panel chose to provide no recommendation at this time owing to lack of experimental and observational studies in which prebiotic supplements would be used in breastfeeding mothers.We found three systematic reviews –18 that Five studies reported the effect of prebiotic supplementation on development of eczema , , 34, 35 Prebiotic supplemented during the first year of life reduced the risk of developing asthma or recurrent wheezing  and the risk of developing food allergy . Prebiotics also probably reduce the risk for developing eczema in infants but the estimate is imprecise and confidence interval does not exclude no effect . Studies assessing nutritional status assessed as weight gain found no difference between those receiving prebiotics and control groups . Overall the certainty of these estimated effects is very low owing to the serious risk of bias in the studies and imprecision of the estimates  is the effect of natural prebiotics in food different from that of supplementation, 2) is there an added benefit from prebiotic supplementation in addition to natural prebiotics, and 3) is there a differential effect between the different types of prebiotics. Future research from rigorously designed and well-executed randomized trials may have an important impact on this recommendation.The European Academy of Allergy and Clinical Immunology (EAACI) Food Allergy and Anaphylaxis Guidelines state that “there is no evidence to recommend prebiotics or probiotics or other dietary supplements based on particular nutrients to prevent food allergy.”. The EurThe WAO guideline panel suggests prebiotic supplementation in not-exclusively breastfed infants, both at high and at low risk for developing allergy .The WAO guideline panel suggests that clinicians and parents do not use prebiotic supplementation in exclusively breastfed infants .The recommendation to use prebiotics in not-exclusively breastfed infants places a relatively higher value on possible prevention of allergies and a relatively lower value on additional cost of prebiotic supplementation. The recommendation to not use prebiotics in exclusively breastfed infants places a relatively higher value on avoiding additional cost and burden of implementation of such supplementation and a relatively lower value on uncertain effect on prevention of allergies .These recommendations should not lead to any change in the practice or promotion of breastfeeding of infants. Formulas supplemented with prebiotics should not be considered a substitute for breast milk. Sole availability of such formulas should not influence the decision to breastfeed and/or the duration of breastfeeding. These recommendations apply to otherwise healthy infants in whom prebiotics would be used with the goal of preventing allergies. See the evidence to recommendation table in online Additional file Guidelines are living documents. To remain useful, they need to be updated regularly as new information accumulates. A revision of this document will be needed, because there was limited evidence for many clinical questions. This document will be updated when major new research is published. The need for update will be determined not later than in 2019.The methods used to develop these guidelines are transparent. The recommendations have been developed to be as specific and detailed as possible without losing sight of the simplicity of the document. Since GLAD-P are meant as international guidelines, the guideline panel encourages feedback on all its aspects including their applicability in individual countries. This feedback will be considered when revising the document.▪ Appointing a guideline committee comprising clinicians and methodologists▪ Determining the scope of the local guidelines▪ Defining the relevant clinical questions to be addressed in local guidelines▪ Reviewing and updating the evidence profiles and evidence-to-decision frameworks if necessary▪ Reviewing the recommendations in the GLAD-P guidelines ▪ Disseminating the guidelines, with a clear “use by” date▪ Developing a method to obtain feedback and plans for review and update.Adaptation of these guidelines will be necessary in many circumstances. Depending on when such a process takes place, the following steps should be taken:During the guideline development process we identified a need for more data on specific topics. This resulted in the following recommendations for research. We summarize these gaps in the evidence as research recommendations, to assist those in a position to provide such information through the design and execution of specific research projects.Development of instruments for evaluating the risk of allergy in children (the family history predicts only about 30 % of the population risk).Evaluation of effects of using prebiotics in breastfeeding mothers.Evaluation of effects of using prebiotics in pregnant women.Evaluation of the effects of different ways of administration of prebiotics, e.g. as milk hydrolysed formula, dairy supplements, stand-alone supplements, etc.Performance of rigorously designed, adequately powered, and well-executed randomized trials of the different prebiotics  with well-defined patient important outcomes.Infants at high vs. low risk of allergiesThose being exclusively breastfed vs. not exclusively breastfedThose born by caesarean-section vs. those born by vaginal deliveryThe impact of sub-groups in the effect (if any) of prebiotics on the prevention of allergies, such as:Large observational studies might be the only design feasible for detecting rare adverse eventsSpecific research needs to be addressed: