Background: In contrast to current methods of expert-based narrative review, the Navigation Guide is a systematic and transparent method for synthesizing environmental health research from multiple evidence streams. The Navigation Guide was developed to effectively and efficiently translate the available scientific evidence into timely prevention-oriented action.Objectives: We applied the Navigation Guide systematic review method to answer the question “Does fetal developmental exposure to perfluorooctanoic acid (PFOA) or its salts affect fetal growth in animals ?” and to rate the strength of the experimental animal evidence.Methods: We conducted a comprehensive search of the literature, applied prespecified criteria to the search results to identify relevant studies, extracted data from studies, obtained additional information from study authors, conducted meta-analyses, and rated the overall quality and strength of the evidence.Results: Twenty-one studies met the inclusion criteria. From the meta-analysis of eight mouse gavage data sets, we estimated that exposure of pregnant mice to increasing concentrations of PFOA was associated with a change in mean pup birth weight of –0.023 g  per 1-unit increase in dose (milligrams per kilogram body weight per day). The evidence, consisting of 15 mammalian and 6 nonmammalian studies, was rated as “moderate” and “low” quality, respectively.Conclusion: Based on this first application of the Navigation Guide methodology, we found sufficient evidence that fetal developmental exposure to PFOA reduces fetal growth in animals.http://dx.doi.org/10.1289/ehp.1307177Citation: Koustas E, Lam J, Sutton P, Johnson PI, Atchley DS, Sen S, Robinson KA, Axelrad DA, Woodruff TJ. 2014. The Navigation Guide—evidence-based medicine meets environmental health: systematic review of nonhuman evidence for PFOA effects on fetal growth. Environ Health Perspect 122:1015–1027;  Background. In clinical research, systematic reviews have played a transformative role as a transparent, robust method for synthesizing the available evidence for incorporation into more efficient guidelines and recommendations related to medical interventions. Whereas systematic review methodology has been developed and tested in the clinical sciences for making evidence-based decisions for medical interventions, the methods are not fully transferable to environmental health science, largely because of their primary application to randomized controlled clinical trials, which are, for primarily ethical reasons, unavailable in environmental health. The Navigation Guide was developed to bridge this gap between clinical and environmental health sciences. The methodology provides the capacity to systematically and transparently evaluate the quality and strength of evidence from both human and nonhuman streams of evidence about the relationship between the environment and reproductive and developmental health  on fetal growth. The results of applying the method to the human evidence and integrating the animal and human data into an overarching strength of evidence rating are presented elsewhere .Rationale for selecting PFOA. Environmental exposures to the industrial chemical PFOA are widespread, and PFOA has been detected in the blood of > 95% of the U.S. population  in systematic review methods used in the clinical sciences. An initial “high” quality rating for experimental animal studies was supported by the level of study control exercised in such studies and the limited heterogeneity within an experimental animal study population. This is also consistent with Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines for clinical evidence that consider randomization a key determinant of a “high” grade . UpgradeThe overall body of evidence was evaluated for downgrading based on the presence of five factors :Risk of bias across studies: a substantial risk of bias existed across the body of evidence.Indirectness: Evidence was not directly comparable to the question of interest . Beforehand, we decided not to downgrade experimental animal studies for indirectness because studies find that humans are as sensitive or more sensitive to chemical exposures than animals, strengthening the applicability of findings from experimental animal studies to human health outcomes . HoweverInconsistency: Estimates of effect were widely different (heterogeneity or variability in results).Imprecision: Studies had few participants and few events (wide CIs).Publication bias: Studies were missing from the body of evidence, resulting in an overestimate or underestimate of true effects from exposure.According to GRADE, these five factors address nearly all issues that bear on the quality of evidence . Each ofIn systematic reviews in the clinical sciences, rating the quality of evidence is the final step because only one stream of evidence is considered in a decision. However, given that our purpose was to ultimately integrate the strength of multiple streams of evidence used in environmental health decision making  leading to a concise “bottom line” statement about a chemical’s toxicity that brings all of the relevant evidence to bear, the Navigation Guide systematic review method specifies an additional step: moving from quality of evidence to strength of evidence.a) quality of the body of evidence, b) direction of effect estimates, c) confidence in effect estimates (likelihood that a new study would change our conclusion), and d) other compelling attributes of the data that may influence certainty , 1,982 were excluded through title and abstract screening and 46 articles were excluded during full-text review, resulting in 21 studies describing 32 data sets included in the review . A summaPopulations. Of the 21 studies, 15 were conducted on mammalian species (11 mouse and 4 rat) and 6 studies were conducted on nonmammalian species    and 4.Mammalian exposures. For all 15 mammalian studies, pregnant female dams were exposed to PFOA, and fetal growth was measured in the resulting progeny  18 for mice and GD21 for rats, to at or near the time of birth, typically postnatal day (PND) 0 to PND2. The methods used to monitor parturition varied widely across birth weight studies, from constant monitoring to daily cage checks. PND1 was defined as either the day of birth or the day after birth.The method of weight measurement varied across studies as well, from weighing offspring individually, grouped by litter, or grouped by sex, to weighing a subset of offspring from each litter. Offspring survival was statistically significantly reduced  at exposure to doses > 5 mg/kg BW/day in five studies; one study did not provide statistics or comment on litter sizes at birth.Mammalian risk of bias assessment. On the basis of our risk of bias assessment, we concluded that the majority of studies had “probably high” risk of bias for allocation concealment and blinding, and “probably low” risk of bias for incomplete outcome data and selective reporting. Ratings for sequence generation and conflict of interest were mixed across studies, and ranged from low to high risk of bias. All studies had low risk of bias for the “other bias” domain ; for salmon studies, eggs and larvae were exposed to PFOA-containing water for 48 days; for fruit fly studies, female flies were placed in vials with PFOA-containing food and allowed to lay eggs for a period of 2 hr, and eggs were allowed to hatch and develop through 110 hr after egg laying (ael) or to the white pupae stage, depending on data set.Nonmammalian comparators. Chicken studies used saline, dimethyl sulfoxide (DMSO), or sunflower oil as vehicle controls, and some studies included an uninjected control  (iameter) . BecauseThe time points of outcome measurement varied: from shortly before time of hatching, shortly after hatching, and multiple time points during larval development.PFOA exposure delayed hatching and larval emergence in the zebrafish and fruit fly studies and induced mortality in the zebrafish study and in one chicken study. Pipping success  and the developmental stage at embryo death were unaffected by PFOA exposure in one chicken study, whereas in a second chicken study, embryonic mortality was increased but hatchling mortality and hatching success were not affected. The salmon study did not provide details on larval survival rates.Nonmammalian risk of bias assessment. On the basis of our risk of bias assessment, we found that the majority of studies had probably high risk of bias for sequence generation, allocation concealment, and blinding, and probably low risk of bias for selective reporting. Ratings for incomplete outcome data were mixed across studies, and ranged from low to high risk of bias. Finally, all studies had probably low or low risk of bias for conflict of interest and low risk of bias for the “other bias” domain  per 1-unit increase in dose (mg/kg BW/day)  . The I2 From the sensitivity analysis, where we removed one data set at a time, we found relatively small changes in the effect estimate, with a maximum of 9% change in the meta-analysis estimate (from –0.023 to –0.021) when the data set from We created separate scatter plots to summarize all the mammalian study data for near-term, fetal weight measurements  and for We also created scatter plots to summarize nonmammalian study data separately for weight measurements  and for Quality of evidence. We downgraded the overall quality rating of the mammalian evidence from “high” to “moderate” based on risk of bias across studies, because the majority of studies were deemed to have “probably high” risk of bias for allocation concealment and blinding. Our ratings and rationales for the overall quality of mammalian evidence are presented in a) risk of bias across studies, given that most studies were deemed to have “probably high” risk of bias for the sequence generation, allocation concealment, and blinding domains; and b) indirectness—for the purposes of this case study, we did not have a rationale or evidence to support that all the nonmammalian species and their corresponding routes of exposure were directly applicable model systems for evaluating human fetal growth. Our ratings and rationales for the overall quality of nonmammalian evidence are presented in We downgraded the overall quality rating of the nonmammalian evidence from “high” to “low” because of Strength of evidence rating. We excluded the nonmammalian data from the final strength of evidence rating. Our rationale was that the nonmammalian evidence was judged to be of low quality for the purposes of addressing our study question, and we had higher quality direct evidence on which to base a decision. Our strength of the evidence considerations were as follows:Quality of body of evidence: moderateDirection of effect estimates: decreasing birth weight with increasing exposure to PFOAConfidence in effect estimates: confidence based on the consistency of the results and overlapping CIsOther compelling attributes of the data that may influence certainty: none.We compared these considerations with the definitions in Based on this first application of the Navigation Guide systematic review methodology, we found “sufficient” evidence that fetal developmental exposure to PFOA or its salts reduces fetal growth in animals. Our finding that the data were “sufficient” was based on “moderate” quality mammalian evidence, reduction in mean offspring birth weight from dams exposed to increasing concentrations of PFOA during pregnancy, and our confidence in the effect based on the consistency of the results and overlapping CIs. Analysis of the scatter plots of the studies excluded from the meta-analysis supported that the majority of these studies also found consistently small reductions in measures of fetal growth following maternal exposure to PFOA.From the meta-analysis of eight mouse gavage data sets, we estimated that exposure of pregnant mice to increasing concentrations of PFOA was associated with a change in mean pup birth weight of –0.023 g  per 1-unit increase in dose (mg/kg BW/day). To assess the biological significance of this estimate, we pooled birth weight measurements from each of the eight control groups to estimate an overall mean birth weight of 1.57 g for the pups in control groups. A 0.023 g decrease in body weight is equivalent to an approximate 1.46% decrease in average body weight per 1-unit increase in PFOA dose. Thus, for example, according to this model, a dose of 10 mg/kg BW/day PFOA to pregnant dams is estimated to result in approximately a 15% decrease in the litter’s average birth weight.To address the heterogeneity of the available evidence, we limited the meta-analysis to data from mouse studies. The rationale for this decision was based in part on findings from pharmacokinetic studies documenting that the rate of elimination for PFOA is much faster for female rats compared with other mammalian species, including humans . Many ofThe heterogeneity of the nonmammalian animal data precluded combining these studies quantitatively. Our identification of studies among such diverse species was unexpected, and for this case study, we combined all nonmammalian species into a single body of evidence. This did not impede decision making about toxicity of PFOA and fetal growth because more direct mammalian and human data were available. However, for other chemicals, heterogeneous indirect evidence may be the only data available on which to base a decision. This points to the need to anticipate and plan for the analysis of heterogeneous data—including whether it is appropriate to evaluate each species separately—and to determine relevance to human health beforehand in future protocols.We found the application of the Navigation Guide method to be effective in producing a concise statement of health hazard in a systematic and transparent manner. Although our review did not identify any studies relevant to our study question that were published in languages other than English, it is difficult to predict in which cases excluding non-English studies may bias a systematic review . TherefoDespite a steep learning curve, designing and completing the search, eliminating duplicate records, screening studies, and extracting study characteristics and data took 2–3 months, including time to train review authors. Contact with study authors to obtain additional information took place over the course of approximately 3 months. Risk of bias assessment, data analysis, and evaluation of quality and strength of evidence took approximately 2–3 additional months.a) sought an empirical basis for a judgment; b) conducted further analysis ; c) relied on GRADE’s principle to be conservative in the judgment of rating down; and d) always documented the rationale for our judgment. Anticipating and defining prespecified criteria for as many judgments as possible will improve the method; however, it seems unlikely that all judgments can be anticipated. Thus, the principles we used for judgments subsequent to the analysis will be integrated into future protocols to transparently allow for such circumstances.An inevitable limitation of this first case study was that we were simultaneously developing and applying the method. As a result, we did not anticipate or define beforehand all the benchmarks we ultimately used for making judgments when rating the quality and strength of the evidence, and we found that our decision making was more difficult in the absence of prespecified definitions. To guide our judgments when assessing quality and strength of evidence factors that had not been prespecified, we In applying the Navigation Guide systematic review methodology, we found that the high prevalence of suboptimal study design and reporting in experimental animal studies that has been empirically documented in the preclinical literature  may alsoThese findings underscore the urgency of calls for improved experimental-animal study design and reporting in the preclinical arena , 2011. Ta) make clear the evidence that informs the authors’ judgments and b) require transparency and an explicit accounting of the judgments involved.This case study documents that the Navigation Guide methodology can be used to effectively apply the rigor of evidence synthesis methods in use by the clinical sciences to questions in environmental health. The Navigation Guide methodology does not eliminate the need for expert judgment, but it does In addition to this review of the animal evidence, a separate systematic review was conducted evaluating the human evidence relevant to PFOA exposure and fetal growth, which resulted in a “sufficient” evidence of toxicity rating . In anotThe ultimate goal of our efforts is to refine the Navigation Guide systematic review methodology across diverse streams of evidence and to support the development of recommendations for prevention in clinical and policy spheres. As has been demonstrated in the clinical field, the adoption of systematic and transparent methods to synthesize the scientific evidence in the environmental health field would speed incorporation of research into decision making.(581 KB) PDFClick here for additional data file.


BMC Medicine, which reported results of a randomized controlled trial comparing SSTP to care-as-usual. Although the paper described what should be an important replication trial of SSTP, there are significant shortcomings to the scientific approach of the reporting that need to be addressed. The paper initially cites only a few published SSTP studies and describes evidence for the efficacy of the program as “very scarce”. A meta-analysis of studies evaluating SSTP published prior to submission of this paper was not cited. The results are inconsistent with previous evidence for SSTP, yet the authors provide scant interpretation for this inconsistency. Similarly, the unusually high dropout rate of 49% was not adequately explained. The claims that previous research has only been conducted by the developers, has not included children with intellectual disability, and has not used care-as-usual comparison groups, are inaccurate. This commentary explores these issues further in order to place the findings from the recent trial into context.The Stepping Stones Triple P (SSTP) parenting program is an evidence-based program for parents of children with a disability. A trial of SSTP was recently published in http://www.biomedcentral.com/1741-7015/12/191.Please see related article:  Stepping Stones Triple P (SSTP) is an evidence-based parenting program for parents of a child with a disability. The system of programs available includes brief “light touch” versions as well as more intensive group and individual programs. All programs have been subjected to evaluation in randomized controlled trials (RCTs). Kleefman, Jansen, Stewart, and Reijneveld recently published a paper in this journal describing an RCT evaluating the SSTP in a population of parents of children with borderline to mild intellectual disability in the Netherlands . The autAlthough SSTP seems promising, evidence of its effectiveness is very scarce” [The authors describe the previous research on SSTP as being ‘weak’ or ‘very scarce’, stating: “ scarce” . While t scarce” . Figure  scarce”  on child scarce” . It is cthe Australian developers were involved in all the effectiveness studies” [In further descriptions of SSTP evidence, the authors state that “studies” . Howeverstudies” , Japan [studies” , Germanystudies” -9, and Cstudies” . The autstudies” -14); thastudies” ; and thaThe authors reported that, while there were some short-term effects for the intervention, there were no long-term effects for SSTP compared to CAU. This is inconsistent with the results of previous research on SSTP -9,11-15;The study had an unusually high dropout rate of 49% in the SSTP group. This dropout rate is considerably higher than previous RCTs on SSTP. The average rate of attrition in the intervention group from available data in 11 studies in the SSTP meta-analysis was 13.7% . The autdid not start the intervention after the intake” [It is reported that 34 participants “ intake” , and of  intake” ,17).BMC Medicine need to be interpreted in the context of the issues identified with reporting. The recent SSTP trial provided a misrepresentation of the current evidence base for SSTP and failed to fully explore the reasons for the inconsistency of the findings with previous research. It is imperative that future trials of SSTP are conducted following clear and transparent protocols, providing fidelity reports of program delivery, and managing the issue of dropout that seems to have befallen this trial.The results from the recent SSTP trial reported in In the interests of maintaining scientific integrity, it is also important to acknowledge that a null finding requires replication to the same extent as a positive finding.


BMC Med 13:250, 2015) for aspirin can overcome some of these difficulties and is therefore an important step towards personalised medicine. Although a good proof-of-concept, this tool has some important limitations that presently preclude its use in practice or for further research. One of the major benefits of aspirin that has become apparent in the last decade or so is its effect in preventing cancer and cancer-related deaths. However, this benefit is clear and consistent in randomised as well as observational evidence only for specific cancers. Additionally, it has long lag-time and carry-over periods. These nuances of aspirin’s effects demand a specific and a more sophisticated model such as a time-varying model. Further refinement of this tool with respect to these aspects is merited to make it ready for evaluation in qualitative and quantitative studies with the goal of clinical utility.Guidelines from different organisations regarding the use of aspirin for primary prevention vary despite being based on similar evidence. Translating these in practice presents a further major challenge. The benefit–harm balance tool developed by Puhan et al. (http://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-015-0493-2Please see related article:  Public health or patient management guideline recommendations are based on broad risk groups and very often take only a few dimensions into account, i.e. one or two major benefits and one or two major harms. It is therefore no surprise that recommendations of different organisations vary despite these being based on similar evidence as they may consider different dimensions or use different risk group categorisation. Guidelines for the use of aspirin in primary prevention are an excellent example of such divergent recommendations –5. FurthThis benefit–harm balance tool  is a gooPuhan et al.  also modThe flexibility to adjust weights as per individual preference is a major strength of Puhan et al’s study . HoweverThe authors discuss some of the limitations discussed above, although these should not have existed in the first place, even for a proof-of-concept study. A more thorough approach in reviewing the current evidence as well as an in-depth understanding of the nuances of aspirin’s benefits and harms would have eliminated most of these limitations, making this conceptually excellent tool ready for the next steps of qualitative and quantitative research studies to assess the clinical utility of such an approach.Puhan et al.  have demGI, Gastrointestinal; MI, Myocardial Infraction; RCTs, Randomised Controlled Trials; WHS, Women’s Health Study


Angiostrongylus vasorum is responsible for verminous pneumonia and also for neurological, cardiovascular and coagulation disorders while Dirofilaria immitis is responsible for right side heart failure. Portugal is an endemic country for D. immitis. However, prevalence data concerning A. vasorum is scarce. Considering that documented cross-reactions between these parasites may lead to incorrect or misfit diagnoses, we aimed to assess the prevalence and potential co-infections of both canine heartworms.Angiostrongylosis and dirofilariosis have recently revived the attention of the scientific community due to their emergence in several geographical areas. A. vasorum antigens by a sandwich-ELISA using mono and polyclonal antibodies  and for specific antibodies against purified A. vasorum adult stage antigen . In order to detect the presence of D. immitis circulating antigens, a commercial kit WITNESS® Dirofilaria  based on rapid immunomigration technology was used. Statistical analysis was performed with SPSS program and estimated prevalence was obtained using Agresti-Coull method.An epidemiological survey was conducted, involving 341 sera collected from shelter dogs housed in three coastal districts of Portugal: Coimbra, Santarém and Setúbal. Sera were tested for circulating A. vasorum, a total of 1.17%  of the animals were positive in both ELISAs, while 1.76%  were only antigen-positive and 2.35%  only antibody-positive. Positive dogs were from the three surveyed areas. Concerning D. immitis, a total of 7.92% of the animals were positive , also from the three areas. Out of the 341 sera analysed, one dog was positive for D. immitis circulating antigen and A. vasorum antibody-positive only.Regarding These results show a slightly higher seroprevalence of angiostrongylosis in Portugal in comparison with seroprevalence found in UK, Italy, Germany and Poland, probably explained by the fact that this study was performed with shelter dogs, usually not under prophylaxis and therefore at a higher risk of infection.A. vasorum seroprevalence in dogs and D. immitis co-infection. We expect that the obtained data will enhance the awareness of veterinary practitioners concerning these diseases and reinforce the importance of a more targeted preventive therapy for heartworms in companion animals in Portugal.To the authors' knowledge, this is the first study performed in Portugal to assess PhD research grant SFRH/BD/85427/2012; Project PTDC/SAU-SAP/113523/2009 supported by Fundação para a Ciência e a Tecnologia (FCT), Portugal.


P = .002, I2 = 16.9%), with a similar hazard of myocardial infarction , all-cause mortality  and major adverse cardiac events . Bivalirudin was associated with a reduced hazard of major bleeding . The dose of heparin in the control arm modified this association; when the dose of unfractionated heparin in the control arm was ≥ 100 units/kg, bivalirudin was associated with a reduction in major bleeding , but when the dose of unfractionated heparin was ≤ 75 units/kg, bivalirudin was not associated with reduction in bleeding . Among patients undergoing PCI, bivalirudin was associated with an increased hazard of stent thrombosis. Bivalirudin may be associated with a reduced hazard of major bleeding; however, this benefit was no longer apparent when compared with a dose of unfractionated heparin ≤ 75 units/kg.Percutaneous coronary intervention with bivalirudin plus bail-out glycoprotein IIb/IIIa inhibitors has been shown to be as effective as unfractionated heparin plus routine glycoprotein IIb/IIIa inhibitors in preventing cardiac ischemic events, but with a lower bleeding risk. It is unknown whether bivalirudin would have the same beneficial effects if compared with heparin when the use of glycoprotein IIb/IIIa inhibitors was similar between treatment arms. We searched the MEDLINE, Web of Science, and Cochrane databases from inception until March 2015 for randomized trials that compared bivalirudin to heparin in patients undergoing percutaneous coronary intervention. We required that the intended use of glycoprotein IIb/IIIa inhibitors was similar between the study groups. Summary estimates were principally constructed by the Peto method. Fifteen trials met our inclusion criteria, which yielded 25,824 patients. Bivalirudin versus heparin was associated with an increased hazard of stent thrombosis (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.15-1.92,  Unfractionated heparin has been widely used for anticoagulation during percutaneous coronary intervention (PCI). The addition of glycoprotein IIb/IIIa inhibitors to unfractionated heparin has been shown to reduce peri-procedural ischemic events compared with heparin alone; however, this approach can increase bleeding risk .The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial demonstrated that bivalirudin, a direct thrombin inhibitor, was non-inferior to unfractionated heparin combined with a routine glycoprotein IIb/IIIa inhibitor in preventing major adverse cardiac events (MACE), but with a lower risk of bleeding ,4.A recent meta-analysis compared a bivalirudin-based regimen with a heparin-based regimen during PCI . The stuEuropean Heart Journal, Circulation, and Journal of the American College of Cardiology from 2012 onwards using the same keywords. To ensure that no potentially important studies were missed, the reference lists from the retrieved articles and prior meta-analyses were also checked.We performed a computerized literature search of the MEDLINE database without language restriction from inception until March 2015 using the search strategy shown in We selected studies that reported clinical outcomes at 30 days  in which patients were randomized to receive either bivalirudin or heparin during PCI. We required that patients were randomized to 1) bivalirudin plus a bail-out glycoprotein IIb/IIIa inhibitor versus heparin plus a bail-out glycoprotein IIb/IIIa inhibitor or 2) bivalirudin plus a routine glycoprotein IIb/IIIa inhibitor versus heparin plus a routine glycoprotein IIb/IIIa inhibitor. Bivalirudin was given as a bolus (0.75 mg/kg), followed by infusion (1.75 mg/kg/hour for the duration of the procedure). Heparin could be administered as either unfractionated or low-molecular-weight heparin. The dose of unfractionated heparin ranged from 60 to 140 units/kg. We excluded studies that randomized patients to bivalirudin plus a bail-out glycoprotein IIb/IIIa inhibitor versus heparin plus a routine glycoprotein IIb/IIIa inhibitor, and studies that used different adenosine diphosphate (ADP) receptor antagonists between treatment arms. Additionally, in order to focus on contemporary practice, we excluded trials that did not routinely use stents.Two authors (IYE and AM) independently extracted data on study design, sample size, and other study characteristics from the included randomized-controlled trials using a standardized form. A third author (MPJ) verified the data. Any discrepancies were resolved by consensus of the authors. When necessary for data or article clarification, personal communication was made with select study authors. For all clinical outcomes, we tabulated the number of events that occurred for each outcome of interest in each arm of each trial.The efficacy outcomes that were tested were stent thrombosis, MACE, all-cause mortality, non-fatal myocardial infarction (MI), and revascularization, while major bleeding, minor bleeding, and net adverse clinical outcomes (NACE) were assessed as safety outcomes.MACE and NACE were variably defined according to the individual trials  29–43].–43.29–432 statistic. I2 statistic values < 25%, 25% to 50%, > 50% were considered as low, moderate, and high degree of heterogeneity, respectively [We analyzed outcomes by the intention-to-treat analysis. Summary estimates were principally constructed by a fixed-effect model. We used the Peto method for construction of a fixed-effect summary odds ratio (OR) ,46. Addiectively . We asseectively . We condectively . All p-vIn addition to the primary analysis that involved all of the retrieved trials that compared bivalirudin to heparin, we conducted a sensitivity analysis that excluded 1) trials that allowed for upstream use of non-study anticoagulation prior to randomization, and 2) trials that had a modest difference in glycoprotein IIb/IIIa inhibitor use between treatment arms. We also conducted subgroup analyses to explore for possible effect modification: 1) acute coronary syndrome versus elective cases on stent thrombosis and major bleeding, 2) unfractionated heparin (≤ 75 units/kg) versus unfractionated heparin (≥ 100 units/kg) on major bleeding, and 3) majority radial versus majority femoral procedures on major bleeding.Overall, we identified 15 studies with 25,824 patients available for analysis: 13,255 in the bivalirudin arm and 12,569 in the heparin arm –43. For P = .002, I2 = 16.9%) with no evidence of publication bias with Harbord’s test (P = .57). This association remained the same in a sensitivity analysis that excluded trials that allowed for upstream use of anticoagulation  and in a sensitivity analysis that excluded trials with a modest difference in glycoprotein IIb/IIIa inhibitor usage between study arms . Bivalirudin versus heparin was associated with an increased hazard of acute stent thrombosis (within 24 hours) , but not with sub-acute stent thrombosis (> 24 hours) . The excess hazard of stent thrombosis with bivalirudin versus heparin was observed in acute coronary syndrome trials , but not in elective trials    .P = .001, I2 = 63.5%), with no evidence of publication bias with Harbord’s test (P = .36). This association remained the same in a sensitivity analysis that excluded trials that allowed for upstream use of anticoagulation , but not in a sensitivity analysis that excluded trials with a modest difference in glycoprotein IIb/IIIa inhibitor usage between study arms . The reduced hazard of major bleeding with bivalirudin versus heparin was observed in 1) elective trials , and in acute coronary syndrome trials ; 2) unfractionated heparin ≥100 units/kg , but not with unfractionated heparin ≤ 75  (P = .004), and with majority radial procedures .The incidence of major bleeding was 3.1% in the bivalirudin arm versus 3.8% in the heparin arm   ; and 3) P = .11, I2 = 35.8%), all-cause mortality , revascularization , MACE , minor bleeding , and a decreased hazard of net adverse cardiac events . Outcomes are reported in Bivalirudin versus heparin was associated with similar hazard of myocardial infarction  values are routinely checked and the drug is titrated to achieve therapeutic effect. With bivalirudin, it is generally not recommended to follow ACT values. However, this blood value provides a safety check to ensure that the drug has been infused through a patent peripheral intravenous line and is exerting a systemic effect. In both the Novel Approaches in Preventing or Limiting Event III (NAPLES III) and the How Effective are Antithrombotic Therapies in Primary Percutaneous Coronary Intervention (HEAT-PPCI) trials, which comprised approximately 14% of the study weight of this analysis, ACT values were checked in both study groups ,33. Had Another potential explanation for the increased hazard of stent thrombosis with bivalirudin is that unfractionated heparin has been shown to be a more potent inhibitor of the thrombin-inducible platelet protease-activated receptor (PAR)-1 than bivalirudin. This might result in more potent anti-platelet activity and hence less stent thrombosis with unfractionated heparin .In the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, the risk of stent thrombosis was higher with bivalirudin versus unfractionated heparin plus glycoprotein IIb/IIIa inhibitor . The invOur study has some limitations. We included trials that compared bivalirudin plus a routine glycoprotein IIb/IIIa inhibitor versus heparin plus a routine glycoprotein IIb/IIIa inhibitor. Although bivalirudin is not routinely used with a glycoprotein IIb/IIIa inhibitor in clinical practice, this randomization was consistent with our study design which eliminated bias from unequal use of glycoprotein IIb/IIIa inhibitors. We included trials that allowed for upstream non-study anti-coagulation . This is also not consistent with clinical practice and may result in bias since ACT values are more routinely measured with heparin; however, our results were materially unchanged in a sensitivity analysis that excluded these trials. In the ARNO trial, all heparin treated patients received protamine following the procedure. This could have caused bias in favor of bivalirudin; however, the findings remained the same after this trial  were excluded in a sensitivity analysis that excluded studies with a modest difference in glycoprotein IIb/IIIa inhibitor usage between study arms. We included the entire spectrum of PCI patients ; however, we considered this approach valid since bivalirudin has been studied and is approved for all of these indications. Lastly, some of the included studies had small sample size, although we included all available studies to avoid any risk of publication bias .In conclusion, among a broad spectrum of patients undergoing PCI, bivalirudin compared with heparin was associated with an increased hazard for stent thrombosis. This was mostly due to acute stent thrombosis and during acute coronary syndromes. Bivalirudin may be associated with a reduction in major bleeding when compared with unfractionated heparin ≥ 100 units/kg.S1 Table*REPLACE-2 criteria: massive bleeding or life-threatening hemorrhage, such as intracranial hemorrhage, retroperitoneal bleeding, clinically overt bleeding that resulted in a decrease in hemoglobin >3 gram% or transfusion of 2 or more units of packed red blood cells or whole blood. †TIMI criteria: intracranial bleeding or clinically overt bleeding associated with a decrease in hemoglobin >5 g/dl. CABG = coronary artery bypass graft surgery; MI = myocardial infarction; NR = not reported.(DOCX)Click here for additional data file.S2 Table*The clinical events committee was blinded to the treatment allocation. Data are formatted as bivalirudin arm/ unfractionated heparin arm. MI = myocardial infarction; NR = not reported.(DOCX)Click here for additional data file.S1 FigReports the location in the paper of each item as outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses.(DOC)Click here for additional data file.


The exceptional compilation of healthy aging articles contained within this Research Topic are timely, and highlight many important ongoing health care reform initiatives to improve the healthy behaviors of older adults and aging boomers. The national discussion understandably focuses on chronic conditions including cost containment, improved patient outcomes, and quality of life measures. However, I would suggest that the prevention of older adult falls and related injuries should be an integral part of the discussion. By broadening the discussion of effective management of chronic diseases and focusing on how to help inform, educate, and support aging Americans, we could also reduce the growing number of falls and falls-related injuries and deaths in this vulnerable population .While the evidence is strong that a small number of targeted prevention programs have significantly reduced falls in older adults, few of these programs followed participants for longer than 12 months  mattered . So, it It is evident that adequately managing expressions of chronic conditions and supportive medication regimens can affect the risk of falls and fall-related injuries in older adults. I believe that there is urgency to broaden the discussions on chronic disease management and how to best apply disease management guidelines to fall prevention. Further, there is an opportunity to capitalize on the investments of the U.S. Administration on Community Living in the dissemination of sustainable, evidence-based health promotion, and chronic disease self-management programs.As the population of elderly grows to over 70 million by 2030 , there iWhat is needed now is a more inclusive approach to the effective management of chronic disease and reduction of fall risk; an approach that values and enfolds the broad spectrum of healthy aging program offerings. I believe that by providing evidence-based prevention programs to help older adults and their caregivers make better choices, improve their health, and increase their quality of life will ultimately affect the rate of elderly falls.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.This paper is included in the Research Topic, “Evidence-Based Programming for Older Adults.” This Research Topic received partial funding from multiple government and private organizations/agencies; however, the views, findings, and conclusions in these articles are those of the authors and do not necessarily represent the official position of these organizations/agencies. All papers published in the Research Topic received peer review from members of the Frontiers in Public Health  panel of Review Editors. Because this Research Topic represents work closely associated with a nationwide evidence-based movement in the US, many of the authors and/or Review Editors may have worked together previously in some fashion. Review Editors were purposively selected based on their expertise with evaluation and/or evidence-based programming for older adults. Review Editors were independent of named authors on any given article published in this volume.


Child health and wellbeing is influenced by multiple factors, all of which can impact on early childhood development. Adverse early life experiences can have lasting effects across the life course, sustaining inequalities and resulting in negative consequences for the health and wellbeing of individuals and society. The potential to influence future outcomes via early intervention is widely accepted; there are numerous policy initiatives, programmes and interventions clustered around the early years theme, resulting in a broad and disparate evidence base. Existing reviews have addressed the effectiveness of early years interventions, yet there is a knowledge gap regarding the mechanisms underlying why interventions work in given contexts.This realist review seeks to address the question ‘what works, for whom and in what circumstances?’ in terms of early years interventions to improve child health and wellbeing. The review will be conducted following Pawson’s five-stage iterative realist methodology: (1) clarify scope, (2) search for evidence, (3) appraise primary studies and extract data, (4) synthesise evidence and draw conclusions and (5) disseminate findings. The reviewers will work with stakeholders in the early stages to refine the focus of the review, create a review framework and build programme theory. Searches for primary evidence will be conducted iteratively. Data will be extracted and tested against the programme theory. A review collaboration group will oversee the review process.The review will demonstrate how early years interventions do or do not work in different contexts and with what outcomes and effects. Review findings will be written up following the RAMESES guidelines and will be disseminated via a report, presentations and peer-reviewed publications.CRD42015017832PROSPERO  Child health and wellbeing is influenced by multiple combining factors—physical, social, environmental, behavioural and psychological—all of which can impact on early childhood development and the acquisition of vital physical, socio-emotional and cognitive-language skills , 2. AdveThe potential to influence or even alter future outcomes via early intervention is recognised in many countries including the UK, where addressing the social determinants of health in the early years forms part of a wider commitment to improving lifelong outcomes for children and young people –9. WithiThe fact that the literature in this area appears to be disparate is one of the issues that we aim to explore in this review; it is anticipated that the gathering of relevant data is likely to support the hypothesis that the evidence base is indeed fragmented. This suggests the need to collate information on the settings and circumstances in which interventions are effective and identify the successful components that potentially are generalizable across different programmes. Dissemination of such knowledge would support a more holistic approach to the design, implementation and monitoring of early years health and wellbeing programmes, incorporating the influence of local context into the design of new interventions and the evaluation of existing programmes and taking into account the linkages between factors such as children, family, culture, community, and wider social, economic and welfare policies, in order to achieve the social change necessary to improve early childhood outcomes .Many existing literature reviews in this field have focused on specific categories of early years interventions, for example, parenting, maternal and child nutrition, early years education or mental health interventions –21. OtheGiven the potentially broad scope of the topic area and the need to include a wider range of types of evidence than can be accommodated within a traditional systematic review framework, a realist approach  was deemThe primary aims of this realist review are (i) to critically examine the impact of early years interventions on the health and wellbeing of children and (ii) to transform the wealth of data in this area into a cohesive evidence base of ‘what works, for whom and in what circumstances’, in terms of implementation in given contexts. Drawing on their previous work in maternal and infant health, child neglect/protection and realist evaluation –30, the A further, secondary aim concerns the interface between research, policy and practice. After completion of the review, findings will be translated into evidence-based, practical knowledge and recommendations that can be shared with and applied by policy-makers, practitioners and service users. The scope of such dissemination is likely to be varied: one example of a practical application of findings is the proposed development of a set of short-term outcome measures, meaningful to practitioners and families, for the evaluation of the efficacy and impact of initiatives to improve wellbeing and reduce inequalities.For the purposes of this realist review, ‘early years’ will be defined as pre-conception to 5 years of age. The definition of wellbeing will be drawn from the SHANARRI indicators , devisedAt the beginning of the review process, a collaboration group will be set up to oversee progress and to help develop consensus by providing a forum for monitoring, discussion and the sharing of feedback at all stages. This group will consist of the research team and members of the Scottish Midwifery Research Collaboration, a network of midwifery researchers based at various Scottish universities. The composition of the group may change or expand during the course of the review; other identified stakeholders, such as policy-makers, practitioners or service users, may be invited to collaborate with the research team as the review progresses. The group will contribute to all aspects of the review, from theory development to interpretation of findings.This review protocol is registered on the PROSPERO database (reference number: CRD42015017832).The review will follow realist methodology, a theory-driven interpretive approach that seeks to explain the root causes of programme outcomes and diverse patterns of impacts and effects, by evaluating evidence from a range of sources , 37. TheIn realist thinking, programmes are theories . The hypClarifying the scope of the review: exploratory searching and theory development.The review will be conducted following the five key stages of Pawson’s realist review template : (1) claAs the review topic is potentially very wide-ranging, a priority at the first stage will be to refine and narrow the research question via a broad-based scoping exercise. It is at this point that key themes and concepts are defined as the focus of the review begins to take shape and the reviewers begin to develop a theoretical understanding of the research topic. Following Pawson’s methodology , relativ(2)Search for primary evidence.As the scoping exercise progresses and findings begin to emerge, the reviewers will develop an outcome-focused realist programme theory, based on the identified existing programme theories and structured around CMO configurations, to explain how and why early years interventions can work, in multiple contexts, to generate outcomes that improve child health and wellbeing and reduce inequalities. In keeping with realist methodology, key stakeholders and experts, including government policy-makers, Scotland’s Commissioner for Children and Young People and representatives from non-profit/charitable children’s organisations, will be consulted throughout this first stage in order to bring in a range of additional perspectives that can contribute to the developing programme theory. Theory development will also be informed by meetings of the review collaboration group. The resulting theoretical, explanatory model and its component contexts, mechanisms and outcomes of interest will be used as the framework for the succeeding stages of the review.(3)Appraise evidence and extract data.Systematic searches for primary studies that are relevant to the programme theory will then be carried out. This second search phase will involve seeking additional relevant evidence , primarily for testing and refining the programme theory. In keeping with the iterative nature of realist methodology, searching will be progressively extended and refined as the review evolves. Selection of sources will be based on relevance to aspects of the programme theory. A combination of search strategies will be utilised. Internet search engine and electronic database searching will be carried using keywords based on the themes, concepts and programme theories identified in the exploratory search. This will be supplemented by a ‘cited by’ article search and a search of citations included in the reference lists of included papers. Sources of grey literature, including unpublished reports, will also be investigated. The reviewers will make use of snowballing techniques and consultation with experts and stakeholders. Given that a wide range of documents may contain evidence that can contribute to a realist review , multiplThe realist appraisal and extraction process differs from a traditional systematic review, as inclusion and exclusion criteria are based on the programme theory and what the literature is able to contribute to it. In a realist review, the units of analysis are not the interventions themselves per se but the theories underpinning the interventions (or families of interventions). Accordingly, evidence will be selected for inclusion based on its relevance to the programme theory; the screening process will be based on an assessment of ‘fit’ to the research question, with the aim of identifying the elements of interventions that are, or could potentially be, effective. ‘Bespoke’ data extraction forms  will be (4)Analysis and synthesis of evidence: test/refine theory and draw conclusions.Again, in contrast to the traditional review process, during this stage, the project team will revisit and if necessary revise the focus of the review based on emerging findings. This may require further refinement of the inclusion/exclusion criteria and conducting further purposive searches if necessary in response to any revisions of the programme theory, followed by the integration of any additional evidence.(5)Dissemination of findings.The key analytic process in a realist review involves iterative testing and refinement of theoretically based explanations (i.e. the programme theory) using empirical findings in data sources . The goaFindings will be translated into evidence-based, practical knowledge and recommendations that can be shared with and applied by policy-makers, practitioners and service users. They will be disseminated in the form of a final report, presentations to stakeholders and peer-reviewed publications.This study will use a realist review approach to synthesise the early years intervention literature and to enable a greater understanding of ‘what works, for whom, in what circumstances and why’, in terms of preventive interventions to improve child health and wellbeing and reduce inequalities. The use of a realist approach will allow the review to demonstrate how and why early years interventions do or do not work in different contexts, by exploring the underlying programme theories and the interactions between context, mechanism and outcomes. The dissemination of findings to stakeholders and policymakers will facilitate the practical application of evidence-based concepts to improve health and wellbeing outcomes for children, parents and families.


The evidence underpinning public health policy is often of low quality, leading to inconsistencies in recommended interventions. One example is the divergence in national policies across Europe for managing contacts of invasive meningococcal disease. Aiming to develop consistent guidance at the European level, a group of experts reviewed the literature and formulated recommendations. The group defined eight priority research questions, searched the literature, and formulated recommendations using GRADE methodology. Five of the research questions are discussed in this paper. After taking into account quality of evidence, benefit, harm, value, preference, burden on patient of the intervention, and resource implications, we made four strong recommendations and five weak recommendations for intervention. Strong recommendations related not only to one question with very low quality of evidence as well as to two questions with moderate to high quality of evidence. The weak recommendations related to two questions with low and very low quality of evidence but also to one question with moderate quality of evidence. GRADE methodology ensures a transparent process and explicit recognition of additional factors that should be considered when making recommendations for policy. This approach can be usefully applied to many areas of public health policy where evidence quality is often low. Neisseria meningitidis, is low in Europe, but case fatality is high  [ N. meningitidis is transmitted from person to person and the risk of disease is highest in contacts from the same household as a case [The incidence of invasive meningococcal disease (IMD), caused byin 2011) . N. menis a case , 5. In 2s a case , 7. Discs a case .Divergences in national policies are particularly problematic in cross-border settings, as they lead to differences in disease management among population groups with the same exposure. For instance, passengers sharing an aeroplane flight with a case of IMD might or might not receive chemoprophylaxis depending on their country of residence . The EurIt was clear from the outset that high quality evidence in this area would be limited as in many areas of public health . This isHere we share our experience and lessons learned in using different types and quality of evidence to develop guidance on the public health management of IMD for European countries within a short time period using GRADE methodology. The aim of this guidance, available on the ECDC website, was to assist countries across Europe in making decisions about appropriate measures to control and prevent IMD in contacts of cases at national and subnational levels .We adapted existing methods for producing evidence-based guidelines to deal with the short time frame and the scarcity of direct evidence see  10, 13––13–17. TWe set up a consortium of national experts: four in the area of epidemiology and public health surveillance and one in the area of microbiology of meningococcal disease. The consortium members represented five EU countries, previously involved in the assessment of national practices for IMD management across the European Union . The conThe consortium identified other national epidemiologists and microbiologists working with meningococcal disease from all EU countries through two established European networks . These EU experts were asked to provide any related grey literature and technical advice during the process. Additionally, the consortium consulted two patient group networks, both based in the United Kingdom, on patient-related values and preferences.The consortium defined research questions for guidance focused on the prevention of subsequent cases following sporadic cases of IMD and based on the needs identified through two previous surveys among public health representatives of EU countries , 18. FivResearch Questions for Evidence AssessmentWhat is the effectiveness of chemoprophylaxis to a case of IMD before discharge from hospital in preventing further cases of IMD?What is the effectiveness of chemoprophylaxis to household contacts of an IMD case in preventing further cases?What is the effectiveness of chemoprophylaxis to contacts of an IMD case in pre-school and school settings in preventing further cases?What is the effectiveness of chemoprophylaxis to those sharing the same transport vehicle as an IMD case in preventing further cases?Which antibiotic regimes are most effective in eradicating carriage among adults, children and pregnant women?We opted for GRADE  methodology to assess evidence and produce guidance; we used the GRADE guidance available at the time of this study 2008-09) , 17, 19.08-09 , 1The consortium developed protocols, templates, and checklists for screening abstracts/papers retrieved in the literature searches to ensure a homogenous process across the research questions and across reviewers. The process was also reviewed against the criteria for guideline development as defined by the AGREE collaboration .When defining the most suitable terms for the population, intervention, comparison, and outcome (PICO) to define our research questions for the search strategy  and giving priority to systematic reviews . If a reWe examined reference lists of the selected papers for other relevant publications and searched Google Scholar for citations of identified key papers. For instance, for the research question on effectiveness of antibiotic regimens (Question E), we found a nonindexed but peer reviewed trial on antibiotic prophylaxis by using Google Scholar, though this study had not been retrieved by a previous Cochrane systematic review .As studies measuring direct evidence on outcomes could not be found in four of the five research questions discussed in this paper, we defined and searched for indirect evidence on outcomes. For example, the relevant direct outcome for the question on the effectiveness of chemoprophylaxis before hospital discharge in preventing further cases among contacts (Question A) would be the incidence of subsequent cases in household contacts of the IMD patients who received antibiotics prior to discharge from hospital. A prior systematic review did not identify relevant studies measuring this outcome but showed that eradicating nasopharyngeal carriage in household contacts reduced the risk of further cases . We thusWe also did not find direct evidence on the research question regarding whether chemoprophylaxis of contacts in school settings would prevent further cases (Question C). However, we obtained indirect evidence by comparing the risk of subsequent cases in school contacts (not receiving chemoprophylaxis) with the background incidence rates of IMD in the relevant population .Even when the literature search provided direct evidence on the benefits of an intervention , the evidence was often insufficient on its harm. In particular, direct evidence on the adverse events of antibiotics administered as chemoprophylaxis (Question E) was insufficient, but we found and reviewed indirect evidence on adverse events of these antibiotics when administered for indications other than chemoprophylaxis .We extracted and summarized the evidence on benefits and harm and prepared evidence profiles. When possible, we pooled estimates retrieved from selected studies. For instance, for Question B on chemoprophylaxis for household contacts, we extracted results from a recent study published after a systematic review and analysed these together with the three former studies from the review , 27–29. If the retrieved systematic reviews did not provide the level of detail needed to calculate pooled estimates of effectiveness or to fully answer the research questions, we extracted the necessary data from primary studies when appropriate. For instance, in the research question on antibiotic regimes for different subgroups (Question E), we identified Cochrane systematic review on antibiotics for preventing meningococcal infections, but this review did not present detailed analyses by antibiotic dosage and duration of therapy and did not stratify estimates by subgroups such as children and pregnant and lactating women . We thusEvidence was classified for all questions as either direct or indirect. We graded bodies of evidence according to GRADE guidelines and classified them as high, moderate, low, or very low, based on study design and quality, inconsistency, indirectness, imprecision, and strength of the association , 19. In We found high or moderate quality evidence for only two of the five research questions, that is, regarding chemoprophylaxis to household contacts (Question B) and antibiotic regimes (Question E). Only low or very low quality of evidence was found for the remaining three research questions . Because these factors varied across settings , 22, we We found little information in the literature on burden of intervention perceived by patients and on their values and preferences. We searched for alternative data sources: for instance, information on perceived burden and values was requested from EU experts and national IMD representatives as well as from two meningitis patient associations. This confirmed that IMD is perceived as a severe disease that generates a high level of anxiety, and thus prevention measures are widely accepted, even if associated with some level of discomfort.The consortium met face-to-face to develop recommendations according to GRADE, based on the quality of evidence and the balance between the benefits and harm, taking into account burden, values, preferences, and costs . Despite the very low quality evidence on the benefits, the consortium considered that harm, cost, burden, and values were strongly in favour of the intervention: the low cost of the intervention, the low number of patients not treated with an eradicating antibiotic regimen prior to discharge, and the potential benefit in reducing risk from a life-threatening disease were balanced against limited harm from antibiotics . In geneConsensus on the recommendations and grading of their strength was difficult to reach regarding chemoprophylaxis in day care settings (Question C). Here, the quality of evidence was low, and divergent recommendations were in place in the consortium members' native countries. Thus each expert was probably influenced by his/her existing national policy. This highlighted that recommendations are built not only on rigorous scientific reviews but also on expert interpretation and judgment of the evidence. An advantage of the GRADE approach is to promote useful dialogue and ensure transparency by making these value judgments explicit , 21.We involved stakeholders and potential users of the guidance in the final steps. As our aim was to produce guidance that could be adapted to the needs of different EU countries, the draft document was circulated through EU experts and patient groups and reviewed by representatives of EU countries in the ECDC Advisory Forum. The feedback from ECDC and EU experts on the draft report allowed useful additions to the guidance . For insWe described how the guidance would potentially change current practice in EU countries. For instance, for the research question (E) on effectiveness of antibiotic regimens in IMD prophylaxis, we described what policy changes would be required and potential obstacles to the implementation of this guidance in a EU setting, based on whether the intervention or the specific drug is available and whether the recommended regimen differs from those currently recommended. In particular, some effective dosages did not correspond to recommendations and formulations available in EU countries and would require a change in current guidance. For instance, high quality evidence was available for the effectiveness of a single dose of 750 mg ciprofloxacin for the eradication of meningococcal carriage. However, in many countries, ciprofloxacin is recommended as a 500 mg single dose, although the effectiveness of this lower dosage has not been assessed in a controlled trial.The guidance was successfully completed within six months and was approved and endorsed by ECDC in 2010 . The GRAAn advantage of GRADE process in developing public health recommendations is the integrated appraisal of related values, preferences, burden to the patient, and resource implications in addition to quality of evidence and the balance between benefits and harm. Based on GRADE 2004–08 guidance, we made strong recommendations for some areas in which the quality of evidence was low or very low. The long deliberations often required to arrive at final agreement of recommendations were facilitated by frequent communication, mainly by e-mail. It should be noted that GRADE work published later provides a systematic approach by describing circumstances in which a strong recommendation is warranted despite low or very low confidence in effect estimates, but these were not available at the time of developing our guidance , 31.The influence of national policies on the judgment of each consortium expert to formulate recommendations (described above) was dealt with by explicitly discussing each recommendation in the entire group. One advantage of having experts from five EU countries in the consortium was also that they had knowledge of current practices and health systems when considering implications for practice of the guidance.The development of this guidance led to the identification of areas of uncertainty and research gaps, and we identified priorities for further research in each area. It was also a unique opportunity to progress towards common European health policy. Divergent health policies may cause confusion among the public and the media. The most objective argument for common health policies consists of a systematic and transparent search for and evaluation of available evidence. In 2013, we evaluated the impact of this guidance on the recommendations for public health management of IMD in European countries and found out that 90% of the 31 EU countries or regions found it useful at the national level and that 50% used it to update their national guidelines within the three years following the publication of the guidance .WHO adopted a very similar process for developing evidence-based immunization recommendations, published after we initiated this work . ImmunizThe consortium included mostly experts in epidemiology and microbiology. It could have benefited from including clinical experts and members of patient organization groups, but the short time frame was already challenging for finalizing the project.The limited time (6 months) and available resources imply that our literature reviews could not meet the standards of a full systematic review. In addition, we could not cover all aspects of IMD public health management.Indeed, the comprehensive application of the GRADE methodology including exhaustive systematic reviews may require substantial resources and more time is often required for rigorous development of guidelines . Thus, iWe relied mostly on systematic reviews (including one Cochrane review) for the quality appraisal of individual studies for Questions B and E , 25, butAs explained above, one of the challenges was that we only found a low quality of evidence (according to GRADE) in most areas, as evidence from RCTs was only available on the effectiveness of antibiotic regimes in eradicating carriage.The GRADE guidance required defining the burden of the intervention to the patient as well as patients' values, preferences, and resource implications to aid in the development of recommendations. However, the GRADE guidance available at the time of developing these recommendations did not provide a methodology to collect and appraise the evidence in these areas. We found scarce information in the literature on the burden, values, and preferences surrounding interventions and limited data on cost in a few countries, and these may differ across countries. Although we questioned EU representatives and two UK-based meningococcal patient organizations, a representative survey of patients across Europe would be required for obtaining sound and representative evidence. However, we did not have the resources to initiate a multinational public survey on these issues. Furthermore, the GRADE guidance did not standardize how the data on burden and values should affect the recommendation; this is left to deliberation on the part of the decision-making group and has been criticized as a weakness of the GRADE process . The updWe developed evidence-based guidance on the public health management of meningococcal disease for EU countries in a short time frame and with limited resources. A number of recommendations in this guidance were based on a low quality of sometimes indirect evidence due to the impracticability of conducting clinical trials on interventions for outcomes that are rare or that have become standard practice. However, the recommendations were generated systematically and transparently, following GRADE and AGREE standards. This approach, that explicitly integrates additional criteria with the quality of evidence, can be usefully applied to the many areas of public health policy in which quality of evidence is often low or indirect. A recent survey of European countries showed that the majority found the guidance based on this process useful, about half had used the guidance to update their national recommendations, and a higher proportion of countries since 2013 compared to that in 2007 recommended evidence-based measures for IMD public health management .


Evidence-based medicine (EBM) has developed as the dominant paradigm of assessment of evidence that is used in clinical practice. Since its development, EBM has been applied to integrate the best available research into diagnosis and treatment with the purpose of improving patient care. In the EBM era, a hierarchy of evidence has been proposed, including various types of research methods, such as meta-analysis (MA), systematic review (SRV), randomized controlled trial (RCT), case report (CR), practice guideline (PGL), and so on. Although there are numerous studies examining the impact and importance of specific cases of EBM in clinical practice, there is a lack of research quantitatively measuring publication trends in the growth and development of EBM. Therefore, a bibliometric analysis was constructed to determine the scientific productivity of EBM research over decades.NCBI PubMed database was used to search, retrieve and classify publications according to research method and year of publication. Joinpoint regression analysis was undertaken to analyze trends in research productivity and the prevalence of individual research methods.Analysis indicates that MA and SRV, which are classified as the highest ranking of evidence in the EBM, accounted for a relatively small but auspicious number of publications. For most research methods, the annual percent change (APC) indicates a consistent increase in publication frequency. MA, SRV and RCT show the highest rate of publication growth in the past twenty years. Only controlled clinical trials (CCT) shows a non-significant reduction in publications over the past ten years.Higher quality research methods, such as MA, SRV and RCT, are showing continuous publication growth, which suggests an acknowledgement of the value of these methods. This study provides the first quantitative assessment of research method publication trends in EBM. From the 1900s until now, evidence-based medicine (EBM) has developed into the dominant paradigm for clinical practice . AlthougThe basic principle of EBM is simply that we should treat when the evidence indicates that perceived benefits outweigh the perceived risks and conversely not treat when the risks are higher than the benefits. Assessments using EBM have to be conducted in 5 key steps: defining the clinical question, finding the best evidence, critically appraising the evidence, applying the evidence to the patient and evaluating the performance of the decision ,23. FinaThere is no single, universally-accepted hierarchy of evidence . Yet mosDespite its critical role in medical teaching, research, and clinical practice, there is a dearth of literature measuring the interest of researchers in EBM. The contribution of published research focusing on EBM over time has not been examined. Moreover, any changes in the proportions of the various study methods in the EBM hierarchy remain unclarified. The current study involved a bibliometric investigation to evaluate trends in research productivity and the contribution of different research methods to EBM. This study used the US National Library of Medicine’s PubMed database to find articles published over a period of 68 years (1945–2012) sorted by journal of publication, taking advantage of the fact that PubMed facilitates filtering by article type. This study allows quantitative assessment of the issues outlined above and highlights significant trends in EBM research publication.http://www.ncbi.nlm.nih.gov/PubMed) was used to search and classify all publications according to their article types with the following strategy: typing “all [sb]” in the search field, we initially searched All PubMed publication (APP). Searches were then limited by selecting only one of these article types: Case Report (CR), Clinical Trial (CT), Controlled Clinical Trial (CCT), Randomized Controlled Trial (RCT), Guideline (GL), Practical Guideline (PGL), Systemic Review (SRV) or Meta-Analysis (MA) in the filter tool. Hence, the annual number of publications of APP, CR, CT, CCT, RCT, GL, PGL, SRV and MA were retrieved regardless of text attainability, study design, publication date, language or species. Other types of publications, which account for up to 86.94% of APP, are neither well categorized by PubMed nor included in the hierarchical system of classifying evidence, and therefore are not included in this research. The level of evidence is varied and depends on many factors, e.g. the area that being researched, study quality, size of study population, etc… [In this study, the filter tool available as part of PubMed   to examiWe assigned the year of publication as an independent variable and the annual number of publications in every category and relative publication number as dependent variables for each Joinpoint session. Within the Data File Import Wizard, we established the Delimiter box as “Comma”, Missing Characters box as “Space”, Dependent Variable Information as “Provided”. The number of publications  was set as “Count” whilst proportion in each article type (such as the proportion of CT to APP) was set as “Proportion”. In the Specifications tab, “Shift data points” was set as “0”, “Number of Joinpoints” ranged from “0” to “3”, “Heteroscedastic Errors Option” was set at “Constant Variance”. There has been no research on the effect of setting maximum joinpoints on the analysis results and but a number of studies have utilized three as the maximum Joinpoints –46. TherThe analyses were also conducted using SPSS version 22.0 . The software was utilized to perform a descriptive statistics of productivity of each method in the EBM hierarchy ,48. An aIn this study, the main parameter Annual Percent Change (APC) was used to describe trends. The APC was used to measure trends in medical research ,49–52. Tt is the rate in year t and α is the slope coefficient in the linear equation below:Where Rp-value ≤ 0.05 was considered statistically significant [When describing trends over a fixed pre-specified interval, a nificant ,54.From the PubMed database, a total of 22,134,520 publications were extracted from the years 1945–2012. PGL and CR accounted for 0.08% and 6.75%, respectively, of APP, and comprised the smallest and largest categories of publication. The most recent year examined (2012) had the highest annual number of publications in each article type, except for CCT, which peaked in 1997. Among all publication types, PGL accounted for the least number of total papers . RCT, SRV and MA accounted for a relatively small number of total publications . Non-RCTs accounted for 364,315 papers.  Fig 2)..Fig 2).The timeline of APC for APP presented with an initial period of striking annual increase , followed by a more sustained long period of more moderate increase  . The APCThe proportion of CT, SRV and MA publications to APP publications has been increasing significantly during the most recent joinpoint period . The CCT/APP and CR/APP proportion showed a downward trend in 1999–2012  and 2007–2012  while other proportions including RCT/APP, GL/APP, PGL/APP show no significant change (p>0.05).The proportion of CCT to CT had been exhibiting a gradually declining trend during the observed period from 1966 to 2012 . The proportion of RCT to CT showed a different pattern: the number of publications rose continuously in 1966–1992 as well as in 1996–2012  while in 1992–1996 declined, but fell short of statistical significance . The proportion of PGL/GL showed rising trends during two time periods  with a downward trend during the intervening period . In recent years, the PGL/GL proportion has remained unchanged .This study demonstrates that article types with higher levels of evidence accounted for fewer publications than those with lower levels of evidence. One possible reason for this observation is that systematic review (SRV), randomized controlled trial (RCT), and meta-analysis (MA) articles may take longer to publish because of the time needed for establishing study design, data collection and analysis, as well as for peer review –57. ThesThe overall slightly positive value of annual percent change (APC) for SRV and the negative APC in the proportion of SRV to All PubMed publication (APP) suggested that SRV has had a long period of slow growth and a decrease in popularity in the scientific world. However, since 1970, the APCs for SRV and the APCs in the proportion SRV/APP have increased dramatically. This increment might reflect a regain of interest in SRV among scientists. This may have been due to the reconsideration of the role of SRV as a critical contributor to Evidence-based Medicine (EBM) ,62.The marked increase in the APCs for MA, as well as the APCs for the proportion of MA to APP, suggests that MA is a popular methodology for publication in modern EBM. As a subset of SRV, MA uses a method that aims at combining results from several studies mathematically and hence create a larger sample size ,56. CombFor PGL, the growth was initially very strong (APC = 48.6%), but for the most recent 20 years, the growth rate has been slow (APC = 5.6%). As mentioned above, the recorded period for PGL was relatively short, and PGL currently has the lowest total number of publications. In the initial phase of growth, PGL appeared with a very small number of publications. Many questions have been raised about the quality of PGL. Initially some PGLs were assembled on consensus of expert committees rather than based on research derived evidence –66. ClinThis study found a slight increase in growth in the number of published clinical trials (CTs) ((APC = 7.4% for CT). As mentioned earlier, CT is still important for generating hypothesis and creating data for further in-depth studies, namely SRV and MA. We hypothesize that as APP continues to grow in number, the aforementioned article types will continue to increase, as the scientific community will continue to face new issues and open up to new perspectives.RCTs are more prevalent than controlled clinical trial (CCTs), as shown by their respective total absolute quantities , the staThe aim of this study was to assess the tendency of changes in quantities of publication types which are used in evidence-based medicine, and thus to partly show researchers’ interest in various publication types. We considered some publication types such as MA, SRV, RCT as providing high level of evidence; however, according to OCEBM 2011 , the levIn conclusion, quantitative growth was found across all publication types. The growth of all, rather than only some publication types, is necessary for the development of EBM, because evidence-based medicine develops in a step-by-step manner: evidence from low-quality studies serve as data points for conducting larger/better designed studies which provide stronger evidence. Current trends may predict that SRV and MA will continue to grow in the future. RCT is getting priority over the other subset of CT; and although the proportion of RCT to CT has recently shown a stable but significantly increasing trend, RCT is still important in order to gain valuable robust evidence needed for better health care outcomes. This current study provides the first large scale quantitative analysis of EBM publication trends.


Orthopedic oncology or the art and science of management of musculoskeletal tumors is one of the relatively newer sub specialties in orthopedics.The last few decades have seen rapid strides in the field of musculoskeletal oncology with amputation no longer remaining the only option to achieve local control in malignant bone tumors. Function preserving alternatives in these lesions have now become the norm without compromising on overall disease survival and have resulted in a documented improvement in overall quality of life of patients . As surgAdditionally, there is also a pressing need to create awareness about these uncommon lesions, rapidly disseminate and propagate current information and techniques, train care givers from diverse geographical backgrounds, set up collaborative networks to gain further insight into these rare lesions and help develop evidence based protocols.More than 80% of the population of the world is located in developing countries where there exists considerable diversity in terms of resource and expertise availability when it comes to managing musculoskeletal lesions . The gamVarious exchange initiatives where experienced surgeons travel to resource challenged areas to share their knowledge and expertise serves as an excellent example of a symbiotic relationship . The “exEarly diagnosis helps in achieving improved outcomes for patients with cancer . Delays The illiterate of the 21st century will not be those who cannot read and write, but those who cannot learn, unlearn, and relearn.” Over the years, many beliefs and practices become entrenched as tried and tested, and we believe they are based on scientific evidence (Alvin Toffler hits the nail on the head when he says “evidence . While tevidence .While the importance of clinical expertise and experience is unquestionable, we do need to combine this with the judicious integration of best available scientific evidence to facilitate rational “informed” clinical decision making. The issue of antibiotic prophylaxis and post treatment surveillance in bone tumors highlight just two examples in orthopedic oncology where guidelines based on evidence are lacking.In a systematic review to determine infection rates following endoprosthetic reconstruction in long bone tumors the duration of antibiotic prophylaxis ranged from “intraoperative dosing only” to “ >72 h.” Current clinical practice is highly varied with respect to antibiotic duration and there is a need to have evidence based guidelines, not only to stream line escalating healthcare costs but also prevent antibiotic misuse and overuse, which lead to antibiotic resistance, an issue of increasing clinical importance. The multicentre randomized control trial coordinated by the Center for Evidence Based Orthopaedics at McMaster University to determine the optimal dosing regimen among patients undergoing surgical excision and endoprosthetic reconstruction of bone tumors is a commendable step to try and fill this lacuna .Modern multimodality therapy has improved patient survival; hence, follow-up surveillance strategies are becoming increasingly important with significant clinical and fiscal implications. Whether an increased frequency of follow-up visits and the use of various expensive imaging modalities for screening and early detection of recurrence actually results in improving overall survival of patients with sarcomas is a question that remains as yet unanswered. The financial costs incurred by surveillance are considerable and this includes both the cost to the health service and to the patient in terms of hospital visits and lost working days. Ideally, any follow-up program should be able to prove that its benefits and savings exceed its risks and costs. Although guidelines have been suggested for follow-up of patients with sarcomas, there is a paucity of data in medical literature on the effectiveness of these recommendations. There is reasonable evidence in literature from other solid tumor types, i.e., breast cancer, colorectal cancer, endometrial cancer, and melanoma that challenges the usefulness of multiple follow-up imaging tests in terms of efficacy, cost-effectiveness, and survival benefit and recent publications seem to support the same surmise for bone and soft tissue sarcomas , 17.In an increasingly “cost conscious” health care scenario, allocation of limited health funding is best guided by these newer evidence based recommendations rather than empirical beliefs. We need to rapidly develop the ability to “unlearn and relearn” or else risk being condemned as “illiterate.”It is this ability to question, reason, continually innovate, and find sustainable solutions that distinguishes us from our primate ancestors. These are qualities that we must encourage and inculcate in our colleagues and trainees. We need to stimulate them to break free from the constraints of hierarchical acceptance of practices steeped in convention without solid scientific merit. That would be one of the best legacies that we could bestow on future generations.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Authors from the Barrow Neurological Institute at Phoenix Children’s Hospital present a narrative overview of preventive treatment for pediatric and adolescent migraine. Authors from the Barrow Neurological Institute at Phoenix Children’s Hospital present a narrative overview of preventive treatment for pediatric and adolescent migraine. Tricyclic antidepressants (TCAs) were thought to have the most evidence for pediatric migraine prevention, particularly amitriptyline and to a lesser extent nortriptyline. Serotonin selective reuptake inhibitors (SSRIs) have conflicting evidence for use in pediatric migraine. Selective serotonin and norepinephrine reuptake inhibitors (SSNRIs) including venlafaxine and duloxetine were thought to have more evidence for pediatric use. Antihypertensives including beta blockers, calcium channel blockers and angiotensin receptor blockers were discussed. The one with the most evidence in pediatric migraine was thought to be flunarizine, although it is not easily available in the U.S.. Propranolol, metoprolol, and candesartan may also be effective, however it is noted that the evidence is greater in adult studies. The anticonvulsant medications with the most support for use include topiramate and valproic acid. The antihistamine cyproheptadine was also recommended for preventive use. Finally, the authors review the evidence for botulinum toxin A injections. The authors admit the difficulty in drawing firm conclusions on its use in pediatrics based on the small, limited studies performed. They emphasize the need for effective migraine preventive measures in reducing headache-related disability and improving patients’ quality of life. COMMENTARY. Pediatric migraine is a common and potentially debilitating disorder. Migraine preventive treatment is commonly prescribed for young people affected by migraine at least 4 days per month or those who have experienced a significant impact on quality of life. This review proposes that preventive treatment can be considered successful when the patient has fewer than 4 migraine attacks per month which also subside with abortive therapy. In practical use, this definition of treatment success may be a bit stringent. A migraineur with 24 days of headache per month may be very satisfied if they are able to reduce this to 8 headache days per month. Alternatively, patients may also be satisfied with treatment if they are able to perform more routine daily activities even without a reduction in headache days. Data on what pediatric migraineurs, and their families, desire from preventive migraine treatment is a current gap in the literature.This review has nicely summarized many of the typical migraine preventives used, common side effects, pertinent studies, and provides a concise list with starting dosage and dose range. To date there is no clinically available medication that was developed for the purpose of migraine prevention. However, there are promising recently completed phase IIb trials involving calcitonin gene related peptide (CGRP) antibodies for migraine prevention in adults  and hopeNutraceuticals including riboflavin, coenzyme Q10 and magnesium were not reviewed. Although the current evidence is limited, neutraceuticals may be an appropriate option for some patients. There is also increasing evidence in the adult literature for use of memantine, an NMDA antagonist . Memanti


Up to 62% of severe injuries in British patients include Traumatic Brain Injury (TBI) . 48% of Post-graduate students constructed a current optimal patient pathway following brainstorming exercises. A comprehensive literature review of current and promising new treatments was performed. A new care pathway based on the direction of current research was predicted for 2020, which we believe could improve outcomes.Best-practice TBI care is expensive and complex, requiring extensive infrastructure at all stages. Overall, there is weak evidence for much of TBI care. There are several reasons for this. TBI is often addressed as a single entity, rather than individual injury patterns with variable pathophysiology. Monitoring in the acute setting is difficult, with multiple options but no single modality with consistent evidence of benefit. Long-term outcome assessment is expensive with common tools providing little detailed information.Large improvements in TBI care can be made by consistently and effectively applying treatments with known benefits. Funding is required to secure infrastructure required for optimal TBI care and evidence is required to secure this. A shift in thinking from ‘TBI’ to the assessment and treatment of individual injury patterns is important. Multimodal monitoring with computerised analysis of large registries shows promise in guiding treatment and research. Functional imaging and Patient-Reported Outcome Measurements can facilitate better evidence for aftercare. Research into tools such as novel biomarkers or drugs is important long-term, but a higher-quality evidence base is needed first as a foundation towards minimising gaps in care.