Genetic, hormonal, and anatomical factors are believed to be involved in the etiology of undescended testes. Due to increased risk of infertility, testicular cancer, torsion and/or accompanying inguinal hernia (>90%) as well as cosmetic concerns, all these patients require treatment. In this review paper, we aimed to evaluate the success rates of treatment modalities used in undescended testes, beginning from 1930 to the present, and to draw attention to the possible risks and benefits and also the efficacy of hormonal therapy in the management of the disorder, which is still a controversial issue. Hormonal therapy may lead to penile growth, painful erection, and behavioral changes while on treatment. In recent years, it has been reported that human chorionic gonadotropin (hCG) treatment was associated with interstitial edema due to increased vascular permeability, inflammation-like changes, and several adverse effects on germ cells by increasing pressure and apoptotic process. It has also been reported that LHRH analogues have positive effects on germ cells by increasing fertility in patients undergoing unilateral or bilateral orchiopexy. In some studies, the success rate of hCG treatment was reported to be higher following buserelin. In some other studies, hCG treatment was recommended before orchiopexy to reduce the risk for surgical ischemia. There are a limited number of randomized controlled studies, so evidence showing the efficacy of hormonal therapy is insufficient. According to the 2007 Consensus Report of Nordic countries, it is recommended that surgery is the first-line treatment modality in undescended testes and that it should be performed by pediatric surgeons and urologists at the age of 6-12 months. Conflict of interest:None declared. Undescended testis is present in about 1-4.5% of newborns with a higher incidence in preterms 30-45%) . In infa0-45% . IUndescended testes should be differentiated from retractile, ectopic, and vanishing testes. The differential characteristics of undescended and ectopic testes are summarized in In the scope of this review paper, we aimed to evaluate the success rate of treatment modalities applied in undescended testes, beginning from 1930 to the present, with possible risks and benefits and also to assess the efficacy of hormonal therapy in the management of the disorder, which is still a controversial issue. Embryological Development of the Testes and Normal Testicular Descent Mechanismth week, Leydig cells of the fetal testis start secreting testosterone, stimulating the Wolffian duct to form the epididymis, vas deferens and seminal vesicles. During the 10-12th weeks of pregnancy, testosterone is converted into dihydrotestosterone by 5-alpha reductase, resulting in virilization of the external genital region , causing regression of Mullerian structures. By the 10l region .th and 15th weeks of pregnancy . Classification is based on testicular location, which may be either along the normal line of descent  or in an ectopic position  . ClinicaDiagnosis and Physical ExaminationThe diagnosis of undescended testes is clinical. The examination should be performed by an experienced person and should always be performed using a two-handed technique ,18. PalpThe patient should be examined in the supine position with legs abducted initially. The examination should begin with exploration of the undescended testes at the anterior superior iliac spine and sweep the groin from lateral to medial with the non-dominant hand. Once the testis is palpated, the examiner should grasp it with the dominant hand and continue to sweep the testis toward the scrotum with the other hand. Testicular mobility, size, consistency, and spermatic cord tension should be assessed. The position of the testis in the scrotum should be maintained for a minute, so that the cremaster muscle is fatigued. Then the testis is released, and if it remains in place for a short time but then retracts, it is considered retractile. In all patients, the size, location, and texture of the contralateral descended testes should also be checked. The key to distinguishing a retractile from an undescended testis is success of delivery and stability of the testis within the scrotum. The retractile testis will remain intrascrotal after overstretching of the cremaster muscle, whereas a low undescended testis will return to its undescended position after being released .Imaging Techniques and Laboratory TestsNearly 20% of undescended testes are impalpable. There are several reasons for impalpable testes, including intraabdominal, intracanalicular or ectopic location of the testes, testicular dysgenesis and absence of the testes. The use of imaging techniques in the diagnosis of impalpable testes is controversial. Today, it is recommended that impalpable testes should be examined by laparoscopic surgery with or without radiological guidance .Imaging techniques include ultrasonography (USG), computerized tomography (CT), and magnetic resonance imaging (MRI). MRI angiography has been reported to have low diagnostic accuracy ,11. CT iUSG is a useful technique in cases which are scheduled for laparoscopic or inguinal intervention due to impalpable testes. However, it has a limited diagnostic role, since 70% of palpable testes which do not move down into the scrotum can be diagnosed using USG, but only 12% of impalpable testes which have been operated on had been diagnosed by using USG (1). In a study, the sensitivity of USG for the diagnosis of inguinal undescended testis was reported to be 95-97% . Others MRI is a useful technique particularly for ectopic testes located in the abdomen, which cannot be detected by using laparoscopic or open surgery . Due to Gadolinium-enhanced MRI (Gd MRI) angiography is a reliable method in the differential diagnosis of vanishing testes from impalpable intraabdominal and intracanalicular testes. It has been emphasized that Gd MRI angiography may reduce unnecessary laparoscopic procedures and may provide insight on which surgical approach is performed. A total of 100% of intracanalicular testes and 96% of intraabdominal testes can be detected using Gd MRI angiography . HoweverIn conclusion, in patients with undescended testes who cannot be clinically diagnosed, the primary imaging technique should be USG, while MRI should be the secondary modality. Inguinal exploration or laparoscopic intervention should be considered in patients who cannot be radiologically diagnosed .Endocrinological and chromosomal investigations should be performed in cases of bilateral impalpable undescended testes accompanied by hypospadias. Anorchia should be considered in cases with bilateral impalpable testes when postnatal physiological testosterone peak or testosterone response to hCG test at >3 months postnatally are lacking. AMH and inhibin B levels may be tested to investigate whether testes are present . The posTesticular BiopsyTesticular biopsy during orchiopexy is recommended for patients with undescended testes accompanied by abnormal genital structure and chromosomal disorder .HistologyIt has been reported that in patients with undescended testes, testes are histologically normal at birth and that the histological changes occur after 6-12 months. These changes include delayed germ cell maturation, decreased germ cell number, and hyalinization of seminiferous tubules ,23.Undescended Testes and the Rationale for Treatment1- Risk for InfertilityTen percent of infertile males have a history of undescended testes. The infertility risk is sixfold higher in patients with bilateral undescended testes compared to patients with unilateral undescended testis or with a healthy population . In unilIt has been reported that the rate of azoospermia is 13.3% and 88.6% in patients with unilateral and bilateral untreated undescended testes, respectively. In bilateral undescended testes, the risk of azoospermia decreases to 32% among patients treated medically and to 46% in patients who underwent orchiopexy as a child. In unilateral cryptorchid patients, the incidence of azoospermia (13%) was found to be similar in treated and untreated patients, regardless of treatment . Tasian 2- Risk for CancerThe risk for cancer is 35 to 48 times higher in patients with undescended testes compared to the overall population (5).The risk for malignant degeneration is 3-18% in these patients . A total3- Risk for TorsionThe risk for torsion is higher in adult patients with undescended testes compared to overall population. A germ-cell tumor was reported to occur in 64% of such cases. It was also suggested that the risk for torsion was associated with the duration of the undescended testes .Undescended Testes and the Most Appropriate Age for TreatmentUndescended testes often resolve spontaneously as a consequence of the effect of luteinizing hormone (LH) and FSH peak which occurs during the mini-puberty period ,5. As a There are two treatment approaches for undescended testes: hormonal and surgical . The treUndescended Testes and Medical TreatmentAlthough the use of hormonal therapy is still controversial in the literature, it has been used in Europe since 1930s .Drugs and drug combinations used for medical treatment include androgens (testosterone), hCG, gonadotropin-releasing hormone (GnRH), hCG+GnRH, hCG+FSH, and human menopausal gonadotropin (hMG).The rationale for hormonal therapy is based on a consideration of the etiological factors in the development of undescended testes . AlthoughCG Treatment and Recommended DosesThe most frequently used hormonal therapy for undescended testes is hCG both in Turkey and worldwide; 90% of Turkish pediatric endocrinologists who suggested medical therapy preferred hCG. The success rate of this therapy ranges from 0 to 55%, while the success rate of GnRH ranges between 9 and 78% . The sucAycan et al  analyzedRecommended hCG doses for treatment of undescended testes are as follows ,38:1- According to the WHO:250 IU in boys <1 year of age twice a week for five weeks500 IU in those of ages 1-5 years twice a week for five weeks1000 IU in those of ages >5 years twice a week for five weeks2- The other recommendations are:1500 IU/m2/week twice a week for 4-9 weeks Four injections of 100 IU/kg at 4- to 5-day intervalsSeven injections of 1500 IU, every other dayIt has been also been reported that the testes return to their initial suprascrotal position in 25% of the patients who are responsive to hCG treatment .Possible side effects of hCG treatment include penile growth, appearance of pubic hair, painful erection, behavioral changes, transient inflammatory changes in the testes, germ cell apoptosis, and decreased testicular volume in adulthood ,40.Combination TherapyThere are reports of several studies investigating the success rate and efficacy of hCG in combination with hMG or GnRH analogues . In thesIn a study investigating the efficacy of combination therapy in the management of undescended testes, Bertelloni et al  reportedIn another combination therapy study, hCG was given as 500-2000 IU, twice a week for 6 weeks and FSH as 75 IU/at least once a week for 6 weeks. The success rate of this therapy may vary depending on the patient’s age. The success rate was found to be 13.3% for boys with unilateral undescended testis of ages between 1 and 2 years, 29.6% for those of ages 3-4 years, 38.2% for those of ages 5-6 years, and 50% for those of ages 7-11 years. The success rate was 16.6% for boys with bilateral undescended testes aged 1-2 years, 27.2% for those of age of 3-4 years, and 37.5% for those of ages 7-11 years (42).Hormonal Therapy and Side EffectsHormonal therapy is often a safe treatment modality; however, it may lead to penile growth, painful erection, and behavioral changes while on treatment . In receAlthough there are several publications showing that the effects of hormonal therapy on germ cells were transient (acute effect) ,48, in aIn recent years, a number of studies have been published indicating the adverse effects of medical treatment on germ cells. However, it has also been reported that preoperative and postoperative administration of LHRH analogues have positive effects on germ cells by increasing fertility in patients undergoing unilateral or bilateral orchiopexy ,45,49. ISome authors have also pointed out the paucity of randomized controlled studies with adequate sample sizes and adequate statistical power in the literature; thus, there is insufficient evidence showing the efficacy of hormonal therapy on undescended testes . AccordiUndescended Testes and SurgeryThe success of surgery is defined as presence of testes in the scrotum without testicular atrophy and/or any recurrence for ≥1 year. It has also been reported that surgery is not totally safe; the complication rate ranges from 1.5% to 12%. Surgery may be complicated and may result in higher complication rates in cases when the scrotum is undeveloped and the testis is malformed, small, and associated with short vessels . Ritzen In 64 articles analyzing 8425 patients with undescended testes, it was reported that the success rate of surgery performed by a skillful surgeon was 74% for abdominal testes, 87% for intracanalicular testes, and 92% for undescended testes in the external inguinal canal . In anotPalpable testes following surgery should not be considered as functional testes. Hormonal production and spermatogenesis should be normal to consider the testes as functional. The age of the patient during orchiopexy is also of great importance for sperm quality . DespiteTesticular retraction or atrophy has been reported to occur in a frequency of 0-2%, and postoperative hernia has been noted in 2-3% of cases after orchiopexy . In addiIn conclusion, the success rate of surgery is 90%, whereas the reported success rate of hCG treatment by randomized studies is 19-25% ,30. It i


A variety of systems have been developed to grade evidence and develop recommendations based on the available evidence. However, development of guidelines for medical tests is especially challenging given the typical indirectness of the evidence; direct evidence of the effects of testing on patient important outcomes is usually absent. We compared grading systems for medical tests on how they use evidence in guideline development.We used a systematic strategy to look for grading systems specific to medical tests in PubMed, professional guideline websites, via personal correspondence, and handsearching back references of key articles. Using the Appraisal of Guidelines for Research and Evaluation (AGREE) instrument as a starting point, we defined two sets of characteristics to describe these systems: methodological and process ones. Methodological characteristics are features relating to how evidence is gathered, appraised, and used in recommendations. Process characteristics are those relating to the guideline development process. Data were extracted in duplicate and differences resolved through discussion.Twelve grading systems could be included. All varied in the degree to which methodological and process characteristics were addressed. Having a clinical scenario, identifying the care pathway and/or developing an analytical framework, having explicit criteria for appraising and linking indirect evidence, and having explicit methodologies for translating evidence into recommendations were least frequently addressed. Five systems at most addressed these, to varying degrees of explicitness and completeness. Process wise, features most frequently addressed included involvement of relevant professional groups (8/12), external peer review of completed guidelines (9/12), and recommendations on methods for dissemination (8/12). Characteristics least often addressed were whether the system was piloted (3/12) and funder information (3/12).Five systems for grading evidence about medical tests in guideline development addressed to differing degrees of explicitness the need for and appraisal of different bodies of evidence, the linking of such evidence, and its translation into recommendations. At present, no one system addressed the full complexity of gathering, assessing and linking different bodies of evidence. Guideline panels aim to develop recommendations based on the best available evidence. In this process, panels often grade the quality of the available evidence . Such anFor intervention studies, the highest available evidence comes from high quality systematic reviews of randomized controlled trials that document the effect on patient important outcomes, such as mortality, morbidity, or functional health ,4. GuideHence, when developing recommendations for a medical test, guideline developers need to go beyond the analytical performance and the accuracy of a test to consider consequences of testing on patient outcomes, and to balance benefits versus harms of testing, taking into account patient values and preferences and resource implications .In addition, tests are never administered in isolation but as part of a testing strategy. Guideline panels therefore need to consider the evidence in context of the most likely testing strategy that includes the test that is being evaluated, and from there make judgments on the downstream patient consequences for further testing and treatment . All of Grading systems generally describe a subset of steps that are a part of the overall guideline development process. These are aspects concerned with formulating a key question, systematically searching and gathering the related evidence, and assessing its potential for bias, level of precision, and other elements of quality. The quality of the evidence, in combination with a number of other factors, guides the strength of the recommendation a guideline panel should provide. Some evidence-grading systems can go beyond these aspects and provide guidance on steps that are part of the overall guideline development process, such as those relating to stakeholder representation, dissemination and communication, and conflicts of interest. It has previously been reported that a lack of standardization in grading evidence and guideline development methodology can lead to varying quality of guideline recommendations ,11. A syOur aims were: first, to establish a comprehensive inventory of evidence-grading systems for medical tests. We wanted to compare the methods in each of these systems, with a focus on those aspects related to appraising evidence, linking different bodies of evidence, and translating evidence into recommendations; as a secondary aim, we compared the extent to which more general guideline development processes were included in these grading systems.For the purposes of this review, we defined an evidence-grading system to be a subset of the overall guideline development process. We defined a guideline development process to be one that begins by defining a topic of interest, then conducting a scoping of the literature in order to assess feasibility of the chosen topic. Once feasibility is ascertained, specific key questions that the guideline will address should be explicitly defined. This is followed by systematically gathering the available evidence and evaluating its quality; then formulating recommendations based on a number of factors such as the quality of the gathered evidence, applicability, resource issues, benefits versus harm, etc. We defined a grading system to be the subset of this series of processes: those that address aspects concerned with formulating a key question, systematically searching and gathering the related evidence, then assessing its quality and formulating recommendations Figure .Because grading systems are often described and used within the setting of a guideline development body, such as the National Institute for Health and Clinical Excellence (NICE), and are not always published in peer-reviewed journals, we felt it necessary to used a multi-staged approach that involved searching various information platforms up to March 2013  to assess the quality of the evidence and stopped there were excluded. Articles reporting a specific group process in developing a guideline, rather than a grading system that could be used as a tool for developing guidelines in general, were excluded.To be included in our review, the description of a grading system must explicitly state that it can be used for grading evidence and making recommendations for medical tests. The system must include a ‘levels of evidence’ and ‘strength of recommendations’ table. Systems that were non-English or employed only a checklist or other quality assessment tool  instrument , a tool Methodological characteristics are focused on the grading system within a guideline development process. These were defined based on how explicit a grading system was in describing how the evidence is gathered, its quality assessed and recommendations derived. Here, we defined six categories and a total of 23 subcategories Table . ProcessWe tested the applicability of each category and subcategory by extracting relevant information from a random selection of grading systems. Data extraction was done in duplicate and differences resolved through discussion between two reviewers. A third reviewer was involved when consensus could not be reached. A review protocol detailing the above methods was created by the first author , which each addressed five out of the seven subcategories listed Figure . The subHaving an explicit search methodology as part of evidence gathering was addressed in seven out of 12 systems, to varying degrees of detail. Less than half of the grading systems were explicit on the number and type of databases the search should include (5/12) Figure .The European League Against Rheumatism (EULAR), European Society of Cardiology (ESC), Institute for Clinical Systems Improvement (ICSI) and the Oxford Centre for Evidence-based Medicine (OCEMB) were not explicit on the types of evidence that needed to be collected. Half of the systems (6/12) specified the need to collect patient important outcome data of which only three  explicitly required other types of evidence to be gathered such as costs, quality of life, contextual implications of the test such as ethical, legal, and social implications and information on resource use.All systems except one (ESC) required users to grade the quality of the evidence at the individual study level, nine of which outlined specific criteria to be used. Nine systems also explicitly required the evidence to be graded collectively as a ‘body of evidence,’ and seven provided specific criteria by which this could be done. Only NICE DAP and the USPSTF provided explicit guidance on appraising different bodies of evidence. The EGAPP acknowledges in its grading system the need to link and appraise different types of evidence in the appraisal and guideline development for medical tests, given that accuracy alone is indirect evidence on patient important outcomes. However, it does not provide an explicit method by which this can be done.Methods for making recommendations were explicitly provided in most systems (9/12). Only six systems reported the inclusion of patient important data when making recommendations. Explicit methods for translating accuracy evidence to recommendations were provided in only three of the 12 systems ).Current publications on applying GRADE to diagnostic tests describe the use of a considered judgment process where the guideline panel makes an informed judgment based on presumed patient important outcomes for patients with true and false positive test results, and true and false negative test results ,18. OtheThe NHMRC’s process of moving from evidence to making recommendations is the least explicit, in comparison to the GRADE and NICE DAP processes. The guideline panel rates the evidence according to five factors: evidence base (as determined by the levels of evidence hierarchy with systematic reviews having the highest level), consistency, clinical impact, generalizability, and applicability Table . With thCharacteristics most likely to be addressed in the 12 grading systems were the need for involvement of relevant professional groups during guideline development (8/12), the need for external peer review of completed guidelines (9/12), and the inclusion of recommendations on methods for dissemination of completed guidelines to target audiences (8/12) Figure . The oveOther characteristics commonly addressed included the presence of a clear content layout and organization (7/12), the presence of a procedure for updating guidelines (7/12), and the need for guideline developers to address conflicts of interest in a guideline (7/12).Piloting of the grading system and information on funding were the least likely process characteristics reported, with only three of the 12 systems Figure  fulfilliAll 12 grading systems varied in the extent to which they addressed process and methodological characteristics. On the whole, we found a wide variation in terminologies used. Methodologically, out of the 23 subcategories defined, the EGAPP (19/23) followed by the USPSTF (18/23) and NICE (17/23) were the most comprehensive Figure a. The ScIn this review, we identified 12 eligible evidence-grading systems that could be used by guideline developers to develop guidelines for medical tests. The EGAPP, USPSTF, NICE, GRADE, and NHMRC systems addressed, to differing degrees of explicitness, the need for and appraisal of different bodies of evidence, the linking of such evidence and its translation into recommendations. However, no one system adequately addressed the complexity of gathering, assessing, and linking different bodies of evidence, which is one of the challenges guideline developers of medical tests face. All 12 varied in basic guideline development features.We have been able to include a number of grading systems available to guideline developers ,33. WhilTo describe the process characteristics, we felt adapting the domains from the AGREE instrument was the most appropriate, given that this is an instrument developed to assess the quality of clinical guidelines. However, AGREE was developed to assess the quality of the final product, whereas we looked at the guideline development process and thus we adapted the domains to fit this aim.For the methodological characteristics relating to how evidence is gathered, assessed, and recommendations derived, the AGREE instrument does not address these aspects in a manner that was specific to the issues in medical test guideline development. The domain on ‘Rigor of Development’ contains eight items relating to how the evidence is gathered, assessed, and how recommendations are formulated . While sThe objective of this review was not to make an analytical appraisal of the different grading systems available. To address that objective adequately is beyond the scope of this review. As such, the tables describing the systems in this review may not always appropriately discriminate the individual strengths and weaknesses of each system. It may also be worthwhile to note that not all of the systems included in this review may have been meant to be used independently, which may explain why they may have addressed process features poorly.et al.[Two other prominent reviews of evidence-grading systems have been reported in the literature ,2 A numbet al. did not Only three of the grading systems included in this review ,23,26 haet al. and Grilli et al. who report that guidelines produced by specialty societies tended to be of lower methodological quality compared to those produced by major guideline bodies [When it came to grading systems developed by specialty societies , these tended to be more comprehensive in addressing process characteristics related to guideline development, but were less thorough in covering features important for systematically gathering, assessing and making recommendations Figure  Figure a. For exe bodies ,36.e.g., primary care, specialty settings), how the test will be applied , and who will be tested . Both the EGAPP and USPSTF go one step further to put the clinical scenario in question into the context of an analytical framework, which essentially is an overarching key question on clinical utility, i.e., whether there is direct evidence that using the test leads to clinically meaningful improvement in outcomes.Given the complexities in medical test guideline development, we defined a number of methodological characteristics as being particularly pertinent to medical tests and different to the methods for guideline development for interventions. The definition of clearly defined key questions is a first step in any guideline development. Because medical tests are often part of a test/treatment strategy, a PICO (Patient-Intervention-Comparison-Outcome)  styled kWhile the NICE system does not contain an analytical framework, it defines a care pathway within which the clinical scenario is covered. The care pathway addresses a broader view on the test-treatment pathway that includes all aspects related to the application of the test and treatment sequences that may follow such as monitoring, retreatment, treatment for side effects and complications that may be experienced by the patient as a result of the test.‘Which of the above preparatory steps is best?’ is a difficult question to answer. The NICE, EGAPP, and USPSTF obviously go beyond the typical PICO-styled key question definition, and would make for a more comprehensive assessment of a medical test than a grading system that does not include such components in its preparatory phase. The inclusion of features such as the clinical scenario, analytical framework, and/or care pathway helps to address the point reiterated many times that an evaluation of a test in context of its test-treatment pathway is more informative than the evaluation of its accuracy alone ,38,39.Rating the quality of evidence is another aspect in grading systems that is challenging for medical tests compared to interventions. Because of the indirectness of evidence about tests relative to patient important outcomes, different bodies of evidence may need to be gathered and assessed that are relevant to the patient outcomes being considered by the guideline panel. Often these data are either lacking or when available maybe in the form of observational studies that, in the level of hierarchy of studies, is classified as low quality .Grading systems therefore need to provide explicit guidance to guideline panels on the types of evidence that need to be gathered in the absence of evidence of the effects on patient outcomes. Guidance is also needed on explicit methods on how these data can be assessed and linked to other bodies of evidence. Less than one-half of the grading systems in this review were explicit on the need for patient important data. Even fewer (three systems) mentioned the need to gather other types of data such as costs and resource utilization. EGAPP and NICE systems, both specific for medical tests, were the only two systems that were explicit on the need to gather such data, although they do not provide clear criteria on how such data should be evaluated. While we did not find this to be explicit in the current publications on GRADE for diagnostics -18, we aA considered judgment process was the most commonly used method to move from evidence to making recommendations. GRADE, NHMRC, and NICE were the only three systems that provided clear criteria that should be considered when making this transition. Although GRADE’s process was the simplest and clearest amongst the three, none of the three systems involved an explicit method by which the different bodies of evidence could be translated into recommendations. NICE’s economic modeling, which formed one aspect of the process of moving from evidence to recommendations, was the only aspect that involved an explicit, structured methodology with clear cut-off points and guidance on the different recommendations to make based on the model thresholds .Clear guidance for evaluating, linking, and making recommendations based on different bodies of evidence beyond test accuracy is lacking in grading systems available today. The EGAPP, USPSTF, NICE, GRADE, and NHMRC systems address these aspects to varying degrees of comprehensiveness. There is a clear need for closer analysis of these features in each of these systems and for more targeted user testing among medical test guideline developers.Existing grading systems for medical tests vary considerably in the extent to which they cover basic guideline quality requirements. The guideline development community can benefit from consensus and standardization regarding the basic features a grading system should cover. This could help to achieve consistency, improve transparency and, ultimately lead to the production of better quality guidelines.AGREE: Appraisal of guidelines for research and evaluation; AHAPG: American heart association practice guidelines; EGAPP: Evaluation of genomic applications in practice and prevention initiative; ESC: European society of cardiology; EULAR: European league against rheumatism; GRADE: Grading of recommendations assessment, development and evaluation; ICSI: Institute for clinical systems improvement; NHMRC: National health and medical research council; NICE: National institute for health and clinical excellence; NICE DAP: NICE Diagnostic assessment programme; OCEMB: Oxford centre for evidence-based medicine; PICO: Patient intervention comparison outcome; PIO: Patient important outcomes; QUADAS: Quality assessment of diagnostic accuracy studies; SIGN: Scottish intercollegiate guidelines network; SORT: Strength of recommendation taxonomy; USPSTF: U.S. Preventive services task force.The authors declare that they have no competing interests.GG defined the search strategy, conducted the literature search, data extraction and drafted the manuscript. MWL and MMGL carried out the data extraction each in duplicate with GG. PMMB initiated the original research idea. MWL, MMGL and PMMB participated in the definition of the data tables and figures. All authors contributed to and approved the final manuscript.Full electronic search strategy used in Pubmed.Click here for fileList of websites searched.Click here for fileReview protocol.Click here for file


The development of a research culture within the Society of Chiropodists and Podiatrists, and the research capacity building within the profession that must underpin this, is an essential element of both the ‘learn’ and ‘achieve’ themes of the conference.The role of professional bodies in developing professional practice and the maintenance of standards is unquestioned and is the main focus for the work of these bodies. However, research evidence is required to provide the evidence base for that professional practice. This need for evidence is becoming more urgent as, for example, funders of health-care services and fee-paying patients are increasingly requiring evidence of efficacy and effectiveness of interventions. In the UK, the move to commissioning of services for the National Health Service is accelerating this trend.Professional bodies should therefore have a role in developing that evidence base as a core part of their business. However, particularly for the smaller allied health professions, scarce resources and other competing priorities mitigate against this. This poster will look at how the Society of Chiropodists and Podiatrists have begun to tackle this problem and will illustrate how, in less than five years, they have moved from research being a special interest of a few, to it being a core part of the organisation, with major successes for podiatrists in prestigious, competitive national research schemes.An evidence base for the profession is essential if it is to survive. This poster describes how that evidence base is being encouraged and developed within the professional body.Participants will gain an understanding and appreciation of the role of professional bodies in general, and the UK Society of Chiropodists and Podiatrists in particular, in developing the capacity to provide the evidence base for the profession.


Evidence-based guidelines are important tools and common pathways for translating evidence into clinical practice. It is most urgently needed when significant heterogeneity in practice exist. Actively engaging opinion leaders in the process of evidence-based guidelines development is important for several reasons. These include allowing the collective views of the practice communities to be represented, resolving heterogeneity in practice through discussion, and allowing credible recommendations to be formulated. Most importantly, the process itself is a tool for facilitating dissemination and implementation. Recognizing the gap between practice pattern and guideline recommendations, and devising strategies to address it represent an important step toward maximizing concordance between guideline and practice. Evidence-based recommendations serve as important reference points, against which we can measure, debate, and innovate from. The management of curable rectal cancer has undergone significant change in recent years. Advances have been made in each of the disciplines involved in the care of patients with rectal cancer, with notable and significant improvements in surgery, radiotherapy, chemotherapy, radiology, and pathology. The strong interrelationship between these modalities means successful implementation of one strategy (or not) directly affects the readiness and appropriateness for change in another. For these reasons, strong, coordinated, and efficient process(es) are needed to optimize the uptake of evidence into practice, translating knowledge into improvement in patient outcomes.Evidence-based guidelines are important tools, as well as a strategy for translating evidence into clinical practice. The reason why they are embraced by the medical community, is the methodological rigor available supporting the creation of evidence-based guidelines. Methods for evidence synthesis and appraisal have been well described and practiced . ProcessDespite these methodological advances, the final step between guidelines and adoption into clinical practice, i.e., implementation, remains an inexact science. While it would be ideal to have a template for efficient change implementation, a single set of strategy that would apply to all clinical domains or circumstances does not exist. Rather, general principles, which can be modified based on the clinical scenario, political environment, and organizational structure, are likely to provide the blueprint in moving forward.What do we know about the best way of producing consensus and buy-in to evidence-based guidelines? In this paper, we will discuss what is known generally in this topic. Using the changing role of radiotherapy in the management of localized rectal cancer, we will describe how these principles are applied to motivate change and guideline implementation in a clinical practice environment.Multiple acceptable options, with weak evidence to guide selection between them translate into heterogeneity practice environments. The availability of multiple standards of practice makes it difficult to evaluate the quality of care, confusion for patients, and dilute the opportunity to refine excellence in selected strategies. Having clinical practice guidelines become most pressing when heterogeneity in treatment approach occurs within the practice environment.The value of evidence-based guidelines lies far beyond the resulting recommendations alone. Rather, the process of guidelines development is itself a strategy by which buy-in and acceptance is nurtured and created. Guidelines development processes share a similar core structure. First, the process begins with the provision of a forum in which evidence is systematically brought together, appraised, and debated in order to reach consensus. This consensus is further reinforced and contextualized by external consultative and review processes. Second, the network of opinion leaders brought together for the task of building consensus and creating recommendations are often the same opinion leaders charged with dissemination and implementation at a local level. Similarly, these opinion leaders are often recruited into other networks, with the mandate and ability to initiate policy changes. It is this active engagement of “networks of opinion leaders” that is the cornerstone for dissemination and implementation inherent in many evidence-based guidelines development processes.What does the literature tell us about the science of how to establish consensus among experts, and implementation strategies beyond the guideline development process itself? These questions are the subject of much research although the fields are still evolving.Even when high-quality evidence is available, our individual knowledge, interpretation of the evidence, and opinions are influenced by many factors including past experiences, peer opinions, time to learn, and critical appraisal skills to name just a few. These factors influence our recommendations and opinions even more when the available evidence is sparse. New evidence may encounter no barriers in “uptake” given its confirmatory nature to local practice, but in other contexts, be critiqued against a high threshold for acceptance when its conclusions go against standard practice. Consensus methods are called upon to narrow heterogeneity and allow the best collective opinion to be made.Within the taxonomy used within consensus methods research, the most common method of establishing consensus in clinical practice is generally referred to as an “informal” process. Groups are brought together , are free to interact with the aim of reaching an agreement. This could work well in many circumstances. Behavioral science research would highlight some disadvantages with this approach, however. Individuals often behave differently in the presence of peers. Some may feel pressured to alter their opinion especially if theirs are different from those of the group. Formal methods on the other hand are created with the basic assumption that by explicitly involving all members of a group, it is more likely that all the appropriate arguments will be considered and therefore more likely to lead to the “right” decision ••. It isThe Delphi method involves the use of questionnaires where respondents are asked to express their recommendations or choices they feel the group should consider. The results are aggregated and returned to the respondent so that his/her response is juxtaposed against the response emerging from the group. From here, the individual is invited to modify his/her response. This approach minimizes the potential of dominant characters on the final decision, employs statistics to incorporate participants’ views, but places less emphasis on direct information exchange between participants.The nominal group technique starts with each participant recording their ideas independently and privately. The ideas are then listed in a round-robin format until no new ones are expressed. The ideas are then discussed in turn. Finally, a voting process takes place and the individual judgments are synthesized statistically to arrive at the group’s final judgment.The consensus development conference method involves bringing a select group of individuals together with the objective of arriving at consensus about an issue. Evidence is presented in an open forum, and the panel deliberate before arriving at a decision.Most clinical guidelines development groups have employed informal, or versions of the consensus development conference methods. This is because of the strong parallel between achieving consensus in clinical guidelines and clinical decision-making. The validity of the recommendations hinge heavily on the breathe of the consultative process, composition of the panel, in addition to the rigor of the evidence. The best method to use would depend on the questions that need to be addressed , 12.Explicit guideline dissemination and implementation strategies should ideally be planned, for each recommendation that calls for a change in practice. Which method(s) to use depend on a number of factors including the clinical context, who and what we are trying to change, as well as resource availability. The Cochrane Effective Practice and Organization of Care (EPOC) group described a set of taxonomy to facilitate reporting and communication in this domain. Common strategies that have been studied include educational materials, educational meetings, local consensus processes, educational outreach visits, local opinion leaders, patient-mediated interventions, audit and feedback, reminders, marketing approaches, and mass media.Several systematic reviews addressing the question “which of the dissemination and implementation strategies are most effective” have been published and they share similar conclusions , 15••. CThe final step to confirm buy in and impact of guidelines is to examine the level of concordance between practice and guideline recommendations. Selecting the parameter(s) for measuring compliance is not always straight forward. The National Quality Measures Clearinghouse recommended that the parameters selected should have three core characteristics. It should be supported by evidence, have sound measurement properties, and be available and accessible within the timeframe(s) of interest .Once the metrics are selected, making an explicit judgment on what level of guideline concordance is optimal, and what key confounding factors are required for interpreting the compliance level, requires careful consideration . For exaDegree of adherence to guidelines, be it strong or weak, is seldom solely attributable to the strength or quality of the guidelines themselves. There are many systems that may influence or impede behavior aligning with the recommendations. These include the characteristics of the primary studies, training of the clinical team, and appropriate human and financial resources to name a few. Understanding the specific contribution of the guideline per se is often challenging. While concordance indicators can represent a convenient way to set bench marks, providing sufficient information to help users interpret and understand the data correctly is required.The same body of evidence should be available to answer the same question conducted by any reviewer. However, the way it is interpreted and applied can vary both at the individual and community level. How radiotherapy is used in the management of rectal cancer is a good example. Its application has evolved quite differently in Europe versus North America •. An undIn North America, the NIH consensus guideline was powerful in establishing the long course (5 weeks) postoperative pelvic radiotherapy as the standard of practice in the 1990s . Since tThe evolution in clinical practice in Europe was quite different. In Sweden, where short-course preop RT was first demonstrated to confer a survival benefit, SCRT was the dominant practice in 2001  reflectiThe evidence as described in the EORTC study in support of the use of long-course CRT preoperatively came after in 2004 . In NortThe primary evidence by Bujko et al. suggesting no difference between short-course and long-course chemoradiotherapy  was at oThe Ontario rectal cancer evidence-based guidelines were created under the auspices of the Cancer Care Ontario Program in Evidence-Based Care. The heterogeneity factor, with multiple acceptable approaches, has motivated each update to our guideline Table . The firInherent within the guidelines development process, achieving consensus hinges first on the active engagement of a “network of opinion leaders.” Within the Program in Evidence-Based Care for Cancer Care Ontario, this began with the composition of the guidelines expert panel itself. Each expert panel consists of opinion leaders, representing the relevant disciplines, the geographic diversity across the province, and methodologists. The topic formulation and prioritization is driven by the group itself to represent the needs of the community it represents. The guideline development cycle  includesAn example behind the most recent version of the rectal guideline perhaps serves to illustrate the effect of these consensus discussions. The final guideline recommended the use of radiotherapy for all patients with SII and III disease. Significant discussion occurred during the recommendation formulation as to whether there are subgroups of patients where the benefits of preoperative radiotherapy outweigh its toxicities such as in higher rectal lesions, node-negative disease, and in expert hands where high-quality TME procedures are anticipated. While the panel acknowledged that under these specific circumstances, the toxicity may outweigh the benefits, the appropriateness of articulating this within the guidelines were felt to be premature within our practice environment. The ability to incorporate these refinements within the guideline requires uniformity in reporting standards for staging MR and pathology, which was still in development across the province. The panel members acknowledged the variation in opinions but arrived at a consensus to recommend preoperative radiotherapy including these subgroups, recognizing that refinements could occur in time. A second consensus debate occurred around the use of SCPRT. This was not commonly considered across Ontario. The implementation of SCRT, while supported by evidence, represents a change from our standard practice. The rationale for change and circumstances when this should be used, relative to the standard approach was needed. The final recommendation wording of “hypofractionated (short course 25 Gy in five fractions) radiotherapy is an acceptable alternative to standard long course chemoradiotherapy” represents the panels’ adaptation of the evidence into our practice environment.Prior to formal adoption and dissemination, the draft documents go through a series of reviews including an internal and external review with the ultimate goal of maximizing its quality and credibility. The internal review panel (2–3 reviewers) is charged with the task of ensuring each PEBC document is developed in a methodologically rigorous fashion and that the recommendations were supported by the evidence in a transparent way. The external review process included soliciting opinion from oncologists within Ontario and targeted external peer reviewers . Review http://www.cancerguidelines.ca; http://www.cancerview.ca/portal/server.pt/community/sage/521/sage), and publication of the systematic review and recommendations in peer-reviewed journal [Finally, dissemination was accomplished by posting of the guidelines onto the central website , registr journal •.The multiple-step process meant that our complete guideline development cycle typically takes approximately 18 months to complete. In clinical areas where there are active changes in clinical practice processes  or where high-impact clinical trial results are released, matching response to a rapidly changing environment could be challenging. Mechanism is in place to ensure available guidelines were last updated within 5 years, however.While designing an explicit implementation plan was beyond the scope of the Program in Evidence-Based Care, the active engagement of the network of opinion leaders continues to exert its influence in promoting clinical uptake and adoption beyond the dissemination stage. At a physician level, Ontario oncologists uniformly participate in regular multidisciplinary tumor boards serving as a forum for real-time peer review. The opinion leaders serve as advocates for the provincial recommendations in these settings. The guideline recommendations became current topics and agenda items at regional conferences allowing further deliberation and alignment of practices to occur. The opinion leader network charged with creating these recommendations overlaps, and works synergistically with networks charged with creating recommendations in other related topics such as imaging , surgeryThe percentage of patients with SII and III rectal cancer receiving CRT were felt to be the most useful quality measures for the guidelines relevant to our rectal guidelines . This isThese findings cannot support a cause and effect between our guidelines and practice pattern. What is clear, however, is that the rigorous process of developing high-quality evidence-based guidelines created by a network of opinion leaders allows differences in opinion between opinion leaders to be explicitly discussed, consensus reached (or at least differences articulated), and what is needed to further advance patient outcomes described. The convergence of opinions through this process meant the availability of transparent sets of recommendations and benchmarks  for the communities, its practitioners, and patients. Evidence-based guideline recommendations serve as important references against which we measure, debate, and innovate from.Evidence guiding the best consensus building, guidelines dissemination, and implementation strategies is incomplete but growing. A network of opinion leaders built for creating evidence-based guidelines, actively engaged by an effective consensus development process, represents one of the most effective ways toward achieving excellence in quality of care. Evidence-based recommendations serve as important reference points, against which we can measure, debate, and innovate from.


A child-customized magnetoencephalography system was used to investigate somatosensory evoked field (SEF) in 3- to 4-year-old children. Three stimulus conditions were used in which the children received tactile-only stimulation to their left index finger or visuotactile stimulation. In the two visuotactile conditions, the children received tactile stimulation to their finger while they watched a video of tactile stimulation applied either to someone else’s finger (the finger-touch condition) or to someone else’s toe (the toe-touch condition). The latencies and source strengths of equivalent current dipoles (ECDs) over contralateral (right) somatosensory cortex were analyzed. In the preschoolers who provided valid ECDs, the stimulus conditions induced an early-latency ECD occurring between 60 and 68 ms mainly with an anterior direction. We further identified a middle-latency ECD between 97 and 104 ms, which predominantly had a posterior direction. Finally, initial evidence was found for a late-latency ECD at about 139–151 ms again more often with an anterior direction. Differences were found in the source strengths of the middle-latency ECDs among the stimulus conditions. For the paired comparisons that could be formed, ECD source strength was more pronounced in the finger-touch condition than in the tactile-only and the toe-touch conditions. Although more research is necessary to expand the data set, this suggests that visual information modulated preschool SEF. The finding that ECD source strength was higher when seen and felt touch occurred to the same body part, as compared to a different body part, might further indicate that connectivity between visual and tactile information is indexed in preschool somatosensory cortical activity, already in a somatotopic way. Magnetoencephalography (MEG) has become an important tool to investigate cortical activity related to sensory or cognitive processing in children of various ages  indicated that none of the preschoolers were uncomfortable with the tactile stimulation seen on video and that felt on the finger.Thirty-eight Japanese preschool children , with an average and median age of 4 years ± 1 month, participated in the experiment. All were children from staff members of Kanazawa University Hospital or recruited from nursery schools near the hospital, in Kanazawa city, Japan. The preschoolers were right-handed, as reported by their parent(s)/caregiver(s). All had normal vision and were in normal physical health. Test results from the Japanese adaptation of the Kaufman Assessment Battery for Children , was used to drive a piezo-electric pulse generator attached to the finger. The repetitive pulse caused a displacement of approximately 0.5 mm of the finger tissue. Each pulse lasted 4 ms and was presented at 2 Hz, with an average time randomization of 50%, for a period of 6 min in total. The intensity of the tactile stimulation was kept constant across participants. The pulse generator and the upper part of the magic tape used to hold the child’s finger over the pulse were decorated with a miniature stuffed butterfly made of soft cloth. This was wrapped gently around the participant’s index finger.2). The hand’s index finger was alternately and repetitively touched by one of the following six pointy objects: a tine of a metal fork, a tine of a plastic yellow fork, the tip of a black pen, and the tip of a blue pencil, a red pencil, or a yellow pencil. Visual objects were changed as to avoid the theoretical chance of interference from visually evoked magnetic field induced by too much repetition of the same visual stimulus. Movement lasted 5 s for each of the six objects, together constituting a finger-touch stimulus of 30 s. The order of the objects was randomized for each preschool child. In the toe-touch condition, the participant watched a female left toe against the same black background. In a similar vein as in the finger-touch condition, in six randomized series of 5 s, the outside of the foot just below the little toe was touched by one of the six objects. In both the finger- and the toe-touch conditions, the objects touched the human tissue with a frequency of 2 Hz, with successive touches randomly occurring within 250–750 ms after one another. Since the felt and observed stimulation occurred to the same body part in the finger-touch condition, tactile and seen stimulation were desynchronized in order to avoid the illusion that the observed body part  was part of the observer’ own body. Such a complex percept would be difficult to study reliably with preschoolers and might have been confusing to them. The two visuotactile conditions were presented with a tactile-only condition, in which the infant watched a gray screen (26.5 cd/m2) with a white fixation cross to rest his/her eyes. The fixation cross subtended 1 × 1 deg in visual angle (112.4 cd/m2) and was centered in the middle of the screen.Two visual stimulus conditions with a duration of 30 s were used Figure . In the The finger-touch, toe-touch, and the tactile-only displays were generated and controlled by a personal computer (NEC VersaPro VA9), and back-projected from a display projector (Sharp PG-B10S) through four mirrors onto a 30 cm × 21 cm screen, viewed from supine position through a mirror attached to the MEG dewar. The three stimulus conditions were each repeated four times, with the order randomized for each infant. In total, 240 visual events in the finger-touch and toe-touch conditions were displayed. The total duration of the MEG measurements was 6 min. The infant was instructed to remain in a fixed bodily position and watch the screen.F = 0.28, p = 0.75].Before MEG measurement, the infant was asked whether the tactile stimulation to his/her index finger was comfortable or not and told that MEG-recording could be abandoned any time he/she wanted. None of the preschoolers reported dislike or discomfort toward the piezo-electric stimulator and/or the tactile stimulation, which was reported as mild, painless stimulation above sensation threshold. None of the preschoolers opted out of the experiment. After the experiment a face-scale  whole-head coaxial gradiometer MEG system for children . The pick-up coils of the MEG system were 15.5 mm in diameter, the mean distance between two adjacent coils was 22 mm, and the cool-to-warm (dewar-coil) separation was 20 mm. Recordings were made in a three-layered, magnetically shielded room , installed at the MEG-research center of Yokogawa Electric Corporation . In an attempt to make the measurement environment less intimidating to the infants, the shielded room was decorated with colorful pictures of cartoon characters, familiar and liked by most Japanese preschoolers. The infant lay in a supine position on a tray-bed  adjusted to the height of the MEG dewar. One staff member (author YY) stayed in the shielded room to comfort the child and to encourage him/her to maintain a steady bodily position.Magnetoencephalography data were acquired with a sampling rate of 1000 Hz and filtered with a 200-Hz low-pass filter. Time series were segmented into windows of 250 ms (−50 to 200 ms). Around 195–214 segments were averaged for each of the 151 magnetic sensors after baseline correction (−30 to −10 ms). An average of 9.7% of the segments with a noise contamination exceeding ±4 pT was excluded from the data before principal component analysis was performed for general noise reduction. At least 195 tactile events were analyzed for each condition. We determined the position of the head within the MEG dewar by measuring the magnetic fields after passing currents through coils that were attached at three locations of the head surface as the fiduciary points, with respect to the landmarks (nasion and pre-auricular points or mastoid tips). Since magnetic resonance imaging (MRI) anatomical data of the infants were not obtained, a 3-D coordinate system based on fixed MEG sensor locations was applied to calculate the equivalent current dipoles (ECDs) by using a spherical model of the volume conductor. This was fitted to the center of the fixed MEG coordinate system, after confirmation that each infant’s head was located in the center of MEG dewar, by measuring the three locations of the head surface mentioned above  was tested with the binomial test.The single ECD model Sarvas,  was usedFigure p = 0.49), middle-latency , and the late-latency ECDs , and homogeneity of variance was met as well . The ANOVA showed that source strength did not significantly differ with latency category in the tactile-only condition . The dipole coordinates and directions of the valid ECDs in the tactile-only condition are depicted in Figure p < 0.05). Middle-latency ECDs were more often posteriorly directed (8 out of 11 ECDs), while late-latency ECDs were anteriorly directed in two-thirds of the cases (4 out of 6 ECDs). These trends in ECD direction in the middle-latency and late-latency category were not significant.In total, only five infants provided waveforms with double-peak deflections both of which obeyed the ECD criteria, whereas only four cases were found in which all three ECDs in a triple-peak waveform were valid. Paired comparisons between ECD source strengths over two or three latency categories would therefore suffer from a lack of power. Instead of repeated-measures ANOVA, one-way ANOVA for independent samples was performed between the source strengths of the ECDs in the three latency categories. Shapiro–Wilk tests showed no evidence for non-normality for the early-latency . In five children, this was the only major deflection in the waveform. In five children, it was the first of a double-peak waveform, and in six children, it was the first of a triple-peak waveform. A middle-latency deflection occurred at 101.50 ± 2.45 ms (n = 16). In four children, this was the only deflection in the waveform, in seven children, it was the second in a double-peak waveform, and in five children, it was the second in a triple-peak waveform. A late-latency deflection in the finger-touch condition occurred on average at 139.70 ± 3.38 ms (n = 10). It was the only deflection in the waveform of two children, the late second in the waveform of three children, and the third in the triple-peak waveform of five children. Only six children provided valid ECDs for both the early- and middle-latency categories, whereas only four children provided waveforms in which all ECDs in a triple-peak waveform were valid. One-way ANOVA for independent samples was therefore performed also for the finger-touch data. Shapiro–Wilk tests showed no normality violations for the early-latency , middle-latency , and the late-latency ECD groups . The variances among the three groups also did not differ significantly . One-way ANOVA showed no significant difference in source strength between the latency categories in the finger-touch condition .The finger-touch condition induced major deflections with latency clusters that were similar as those observed in the tactile-only condition. In the finger-touch condition, an early-latency deflection occurred at 67.44 ± 1.60 ms (n = 22). This deflection was the only peak in the waveform of six children, the first in a double-peak waveform observed in 12 children, and the first in a triple-peak waveform of four children. A middle-latency deflection occurred on average at 97.75 ± 2.75 ms (n = 12). This was a single deflection in the waveform of seven children, the second in a double-peak waveform in two children, and the second in a triple-peak waveform in three children. A late-latency deflection in the toe-touch condition appeared at 139.27 ± 3.88 ms (n = 15). For two children, this was the only valid major deflection. For eight children, it was the second deflection in a double-peak waveform, and for five children, it was the third in a triple-peak waveform. Four children provided valid ECDs for both the early- and middle-latency categories, and only three preschoolers provided waveforms in which all ECDs in a triple-peak waveform were valid. Shapiro–Wilk tests showed no normality violations for the early-latency , middle-latency , and the late-latency ECD groups . The variances among the three groups also did not differ significantly . One-way ANOVA for independent samples showed that source strength differed significantly between latency categories in the toe-touch condition . Post hoc Bonferroni tests showed that for the toe-touch condition the source strength in the early-latency category was higher than that in the middle-latency category (p = 0.034).In the toe-touch condition an early-latency deflection occurred at 60.82 ± 2.53 ms (p < 0.01). In the toe-touch condition, 18 out of 22 ECDs with an early-latency had an anterior direction, which was significant as well . ECDs in the middle-latency category were significantly more posteriorly than anteriorly directed. In the finger-touch condition, 14 out of 16 ECDs , and in the toe-touch condition, 10 out of 12  were posteriorly located. Late-latency ECDs again were significantly more anteriorly directed. Nine out of 10 ECDs in the finger-touch condition and 12 out of 15 ECDs in the toe-touch condition had an anterior direction .The ECDs in all three latency categories in both visuotactile conditions were located at the contralateral hemisphere. Analysis of ECD directions showed that ECDs in the early-latency category had a predominantly anterior direction. In the finger-touch condition 16 out of 17 ECDs were anteriorly directed. The binomial test showed that this difference was significant , the middle-latency , and the late-latency  ECD source strengths between stimulus conditions. In the case of unpaired comparisons, source strength between the tactile-only, the finger-touch, and the toe-touch condition did not differ for the early-latency , the middle-latency , and the late-latency  categories.For each latency category, ECD source strength between the three stimulus conditions was first compared with ANOVA for independent samples. ANOVA was performed after Levene’s tests showed no deviance from distribution normality in the early-latency  and the finger-touch condition . Under similar variances , ECD source strength did not differ between the two stimulus conditions . Eight children provided valid ECDs in the middle-latency category. Both the data in the tactile-only  and the finger-touch conditions  were normally distributed and showed similar variances . In the middle-latency category, ECD source strength in the finger-touch condition was significantly higher than in the tactile-only condition with a Bonferroni-corrected alpha-level of 0.017 for multiple paired comparisons .Paired comparisons between ECD source strengths in similar latency categories could be made with a limited number of cases. Because few children provided data for all three latency categories in all three stimulus conditions, repeated-measures ANOVA was not performed. Instead, where possible, we performed p = 0.46) and the toe-touch condition . Under similar variances , no significant difference was found between early-latency source strengths . Seven pairs could be formed with valid middle-latency ECD data. These were normally distributed in both the tactile-only condition  and the toe-touch condition  and showed no unequal variances . In the middle-latency category, ECD source strength in the tactile-only condition was higher than that in the toe-touch condition . With the Bonferroni-corrected alpha-level (p = 0.017), however, this difference would strictly be not significant.Paired comparisons between the tactile-only and the toe-touch conditions were also made just for the early-latency and the middle-latency category, since late-latency data were provided by only five children Figure . Thirteep = 0.34) and toe-touch condition . The variances in the source strengths also did not differ significantly , and neither did the source strengths themselves . For seven pairs in the late-latency category, source strength normality in the finger-touch  and the toe-touch  condition was not violated. Under homogeneity of variances , source strength in the late-latency categories did not significantly differ between the finger-touch and the toe-touch conditions . Also for the middle-latency category seven pairs could be made. Both the source strength in the finger-touch  and toe-touch conditions  was normally distributed and variances were homogeneous . The middle-latency source strength observed in the finger-touch condition was significantly higher than that in the toe-touch condition . An example of the difference in the waveforms induced by the finger-touch and toe-touch conditions is depicted in Figure Paired comparisons between the two visuotactile conditions could be made for all three latency categories Figure . In the uch df = , 0.34 anIn summary, comparisons between ECD source strengths observed in the middle-latency categories of the three stimulus conditions showed that source strength was higher in the tactile-only condition than in the toe-touch condition. With a decreased alpha-level of 0.017 to correct for multiple comparisons, however, this difference was not significant. Even with alpha-level correction, however, middle-latency ECD source strength in the finger-touch condition was significantly higher than in the toe-touch and the tactile-only conditions.The present study is the first to use a child-customized MEG system to study somatosensory responses in preschool children. Besides a tactile-only condition, in which the left index finger of the preschoolers was stimulated, two visuotactile conditions were used. In one condition, the child received tactile stimulation to the index finger and at the same time watched a video of someone else being touched at the index finger. In another condition, the child received the tactile stimulation to the finger while watching a video of someone else being touched on the toe. ECD analysis showed that all three conditions induced contralateral (right-hemispheric) activity, which enabled valid dipole estimation in about 60% of the children. For all three stimulus conditions, a first valid ECD could be identified with a latency between 60 and 68 ms. This early-latency ECD had a predominantly anterior direction. The early-latency ECD strongly resembles that reported by Pihko et al. , who anan = 7). Although paired comparisons between the source strengths observed in the visuotactile and tactile-only conditions might be inappropriate, since the tactile-only condition was a condition in which the participants could rest their eyes on the screen and arguably made less eye movements, we further found that the finger-touch condition induced a significantly higher middle-latency source strength than the tactile-only condition for n = 8. ECD source strength, by contrast, was higher in the tactile-only than in the toe-touch condition in the middle-latency category. With Bonferroni correction on the alpha-level, however, this difference was not significant.The second, middle-latency ECD occurred on average between 97 and 104 ms in all three stimulus conditions. This latency seems to correspond with the data of Gondo et al. , who repThe differences in middle-latency source strength between stimulus conditions suggest that visual information modulates preschool SEF. The difference between congruent (finger-touch) and incongruent (toe-touch) visuotactile stimulation might further suggest that somatotopic linkage for seen and felt touch already develops in early childhood. Out of behavioral necessity, children must learn to recognize congruent visual and tactile information that is behaviorally relevant to them as soon as possible. For example, they must quickly learn to recognize whether an object can cause comfort or pain – often by visuotactile inspection. The sparse literature related to somatotopy in child cortex concerns studies on phantom limb experiences in persons with congenitally absent limbs. In spite of being limb-deficient from birth, some of these persons experienced phantom limbs since early childhood Poeck, . The repBesides the early- and middle-latency ECDs, a valid ECD with a late-latency could be observed in all the stimulus conditions. The late-latency ECD occurred between 139 and 151 ms and, to our knowledge, has not been reported in preschoolers before. In the tactile-only condition, the dipole direction was anterior in four out of six children. In the two visuotactile conditions this trend was stronger: in 21 out of 25 combined ECDs the dipole direction was anteriorly directed. Significant source strength differences in the late-latency ECDs were not found between stimulus conditions.In summary, the present study with the child-customized MEG system confirmed the occurrence of an early-latency ECD connected with tactile stimulation to the finger with a latency of about 65 ms and a predominantly anterior direction. Middle-latency ECDs were observed at around 100 ms with a predominantly posterior dipole direction. Source strength differences between paired middle-latency ECDs suggest SEF modulation through visual information in general, with congruent visuotactile information (finger-touch condition) inducing a significantly larger source strength than incongruent visuotactile information (toe-touch condition). This might reflect the development of brain functional connectivity between visual and somatosensory areas, presumably in a somatotopic way. The present preschool data further indicate the occurrence of a late-latency ECD (around 145 ms), which tended to have an anterior direction. Further research on somatosensory activity in preschool cortex is necessary to test the existence and development of (somatotopic) modulation by visual information and to expand the data in general. Also with the child-customized MEG system used here, data contamination due to motion and concentration artifacts limited the quality of the data and, hence, the number of valid ECDs that could be used for statistical comparisons.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Introduction. Appropriate prevention of infection is a key area of research in natural orifice translumenal endoscopic surgery (NOTES), as identified by the Natural Orifice Surgery Consortium for Assessment and Research (NOSCAR). Methods. A review of the literature was conducted evaluating the evidence base for access orifice preparation/treatment in NOTES procedures in the context of infectious complications. Recommendations based on the Oxford Centre for Evidence-Based Medicine guidelines were made. Results. The most robust evidence includes several experimental randomised controlled trials assessing infectious complications in the transgastric approach to NOTES. Transvaginal procedures are long established for accessing the peritoneal cavity following disinfection with antiseptic. Only experimental case series for transcolonic and transvesical approaches are described. Conclusion. Grade C recommendation requiring no preoperative preparation can be made for the transgastric approach. Antiseptic irrigation is recommended for transvaginal (grade C) NOTES access, as is current practice. Further human trials need to be conducted to corroborate the current evidence base for transgastric closure. It is important that future trials are conducted in a methodologically robust fashion, with emphasis on clinical outcomes and standardisation of enterotomy closure and postoperative therapy. Natural orifice translumenal endoscopic surgery (NOTES) represents a relatively recent development in the continuing evolution of minimal access surgery and minimally invasive surgery. Since its first published description in 2004 by Kalloo , NOTES hNOTES access to the peritoneal cavity has been variously described via transgastric, transcolonic, transvaginal, and transvesical approaches. There is a lack of consensus regarding the most appropriate approach; the transvaginal and transgastric are the approaches currently most commonly reported in existing literature. It is worth noting that the concept of colpotomy and transvaginal approach to intraperitoneal organs is an old one, first described by Langenbeck in 1813 for transvaginal hysterectomy . One potAt present there exist a lack of consensus and a paucity of data regarding disinfection and the prevention of infection in NOTES, and most current NOTES, research is based on experimentation in the porcine model. Experience of NOTES in humans is steadily increasing, and several case series of appendectomies via transvaginal or transgastric approaches , 5 and pThe aim of this paper was to evaluate the current evidence base relating to the preparation or treatment of the access route for NOTES procedures in specific relation to postoperative infectious complications. A review of all the published literature on NOTES procedures reporting on infectious outcomes of access was undertaken. A comprehensive search strategy was used to identify relevant evidence according to the inclusion and exclusion criteria specified below using the following search terms: natural orifice, transgastric, transvaginal, transvesical, transcolonic, disinfection, infection, and NOTES. The search was broadened using the “related articles” function. The following mesh terms were used: “endoscopy”, “gastrointestinal”, “gastroenterostomy”, “infection”, “disinfection”, “colpotomy”, “colotomy”, and “gastrotomy”. The bibliographies of all publications were manually searched for any relevant references. The following electronic databases were searched: PubMed, MEDLINE (Ovid); EMBASE; Google Scholar. The endpoints considered for evaluation of the evidence were: (1) route of access, (2) operative intervention, (3) method of disinfection, and (4) infectious outcomes of the intervention including method of assessment.Inclusion criteria included all studies considering infectious outcomes following a NOTES procedure in human or animal subjects using the transvaginal, transcolonic, transvesical, and transgastric access routes. No language restrictions were considered for review. All articles which did not refer to infectious sequelae of NOTES were excluded. Only publications relating to the highest level of evidence for each access route were described in this paper. All articles were independently reviewed as to whether they fulfilled the above-mentioned criteria.Levels of evidence were assessed according to the Oxford Centre for Evidence-Based Medicine. Levels of Evidence guidance and recommendations were based on these levels of evidence . A total of 22 publications were included in this paper. There were 5 comparative studies and 17 case series as illustrated in Tables The transgastric approach to NOTES is the most commonly investigated approach and the only one to have experimental randomised controlled trials assessing methods of infection prevention. The methods and evaluation of these trials are rather heterogeneous. Ramamoorthy et al. demonstrate in the rat model that use of PPIs can be associated with a greater rate of infection , in agreWhilst many studies use the bacterial culturing of intraperitoneal lavage fluid as the basis of determining the presence and severity of infection, it must be noted that a positive culture result did not necessarily correlate with clinical findings in many studies , 18. n = 40), or NOTES staging peritoneoscopy (n = 10), using disinfected but not sterilised endoscopes and no stomach preparation or irrigation. They report that in their series they found evidence of gastric to peritoneum cross-contamination  in 10% of laparoscopic RYGB, 21% of NOTES RYGB, and 0% of NOTES peritoneoscopy; however, this did not correlate to clinical findings and did not affect patient management [Level 3 evidence is available in the assessment of infectious complications following transgastric NOTES access. The case-controlled study by Nau et al. compared 50 patients who underwent a laparoscopic Roux-en-Y gastric bypass (RYGB) with endoscopic gastrotomy, with 50 patients who underwent laparoscopic guided NOTES RYGB (nagement . These fnagement  who reponagement  report aThe colon as a route of access for NOTES presents with a greater and more diverse bacterial flora than the stomach, vagina, or bladder and as a result a theoretically greater risk of peritonitis following a transcolonic procedure. Several case series have demonstrated the feasibility of this approach for procedures including laparoscopic cholecystectomy  and periColpotomy and the transvaginal approach to the intraperitoneal viscera have been performed for almost two centuries. NOTES represents an endoscopic extension of this technique. Disinfection of the vagina through irrigation with antiseptic such as povidone-iodine is known to produce good bactericidal results with great reduction in positive vaginal bacterial cultures . As a reInitial investigations have demonstrated the feasibility of this approach in the porcine model, including an initial series of transvesical NOTES peritoneoscopy , 30 withThe current experimental and human evidence base is on a whole limited and methodologically not robust enough to allow us to draw concrete and meaningful conclusions regarding most adequate preparation and treatment of the access orifice to prevent postoperative infectious complications. It is obvious that evaluation of postoperative infectious complications of NOTES access as currently described in the literature are significantly related to the method of closure, and therefore studies that use different closure modalities have limited comparability. There is currently no single gastrotomy closure modality supported in the literature , and theIt is also not known which optimal postoperative treatment of these viscerotomies is to avoid infectious complications. There is no data currently available to suggest the need for PPI or specific antibiotic cover following NOTES enterotomy, and this is likely to have an effect on infectious complication rate. For these reasons the interpretation of these data is complex, further complicated by the lack of controlled human trials. It is clear that for gastrotomy closure, further trials are needed to assess various modalities of prophylaxis on an individual basis. Furthermore, evaluation of the choice of equipment must also be considered—is sterile equipment required or is decontamination sufficient and is the use and further development of sterile overtubes to facilitate sterile intubation of stomach or colon indicated? These results must therefore be interpreted with care. It is difficult to draw concrete conclusions, exemplified by the study by Eickhoff et al. which does not differentiate between the individual effects of the various components of the transgastric trial therapy given and the therapy package as a whole , or the As the transcolonic route presents perhaps the greatest potential source of bacterial translocation into the peritoneum, further study along similar lines of investigation as have been pursued for the transgastric route would be desirable. As well, the shorter route of access, compared to the traversing of oropharynx and oesophagus for transgastric access, may mean that the further development of sterile overtube devices as well as instrumentation to isolate individual colonic segments for disinfection will emerge as feasible and the most efficient way forward. Current evidence is based on animal models, and no formal recommendation can be made to recommend antiseptic irrigation for transcolonic NOTES. It is logical; however, due to the nature of the cavity that some method of disinfection is going to be necessary for this approach.Although the transvaginal approach does not have any high level evidence supporting the most appropriate method of disinfection of the vagina preoperatively, there are large case series in the gynaecological literature which indicate that postoperative complication rates of colpotomy for tubal ligation using preoperative vaginal disinfection result in a <2% risk of infection , 35. EviAs the urinary tract is under normal circumstances sterile, theoretically no special preparation is required for the transvesical approach. The study by McGee et al.  suggestsIt is important that further evaluation is conducted in a methodologically appropriate fashion. This involves specific comparisons of individual treatments/preparations of the orifice, using a standardized and identical closure modality, with objective evaluation of infectious sequelae in blinded randomised controlled trials. The results of this paper suggest that there is still a lack of experimental evidence pertaining to transrectal or transvesical access to justify implementation of human trials. Further animal evaluation is necessary for the transrectal route; however, due to the sterility of the urinary tract, it seems logical that efforts need to focus on disinfecting the external urethral orifice and surrounding areas which come into contact with operative instrumentation or the use of a sterile overtube to aid deployment of instrumentation. Due to the diameter of the urethra, current human application of this natural orifice approach has been limited.Based on the results of this paper, we suggest that it is appropriate to embark on human randomised controlled trials in the assessment of infectious complications of transgastric access. The operative intervention must be appropriate and safe, which will likely involve a hybrid approach with closure of the gastrotomy performed laparoscopically. Outcome measures have to be objective and clinically relevant, and the levels of disinfection/sterilisation of the transgastric instrumentation or overtubes have to be standardised and clearly described as well as the postoperative treatment. As with all NOTES research, it is of vital importance that trials are carried out under IRB-approved protocols and that favourable as well as unfavourable results are disseminated through expedient publication in peer-reviewed journals as well as established NOTES registries.


Sialorrhea or excessive drooling is a major issue in children with cerebral palsy and adults with neurodegenerative disorders. In this review, we describe the clinical features, anatomy and physiology of sialorrhea, as well as a review of the world literature on medical treatment using Yale University’s search engine; including but not limited to Medline and Erasmus. Level of drug efficacy is defined according to the guidelines of American Academy of Neurology. Current medical management is unsatisfactory. Topical agents (scopolamine and tropicamide) and oral agents (glyccopyrolate) combined render a level B evidence (probably effective); however, this treatment is associated with troublesome side effects. Double-blind and placebo-controlled studies of botulinum toxin (BoNT) provide a level A evidence for type B  and both overall and individual B level of evidence for OnabotulinumtoxinA (A/Ona) and AbobotulinumtoxinA (A/Abo); these are probably effective. For IncobotulinumtoxinA (A/Inco), the level of evidence is U (insufficient) due to lack of blinded studies. Side effects are uncommon; transient and comparable between the two types of toxin. A clinical note at the end of this review comments on fine clinical points. Administration of BoNTs into salivary glands is currently the most effective way of treating sialorrhea. Sialorrhea, also known as drooling or ptyalis, is a debilitating symptom which occurs when there is excess saliva in the mouth beyond the lip margin . DroolinThe major salivary glands include parotid, submandibular, and sublingual glands; the largest being the parotid gland. These glands secrete saliva which has a major role in lubrication, digestion, immunity and maintenance of homeostasis in the human body . The parIn the unstimulated state, 70% of saliva is secreted by submandibular and sublingual glands. Conversely, in the stimulated state the parotids glands provide most of the saliva. The flow of saliva is five times greater in the stimulated state than in the resting state [Sialorrhea can be either due to increased production of saliva (idiopathic or drug-induced) or related to failure of mechanisms that clear and remove saliva from the oral cavity. Disturbance in the coordination of orofacial and palate—lingual musculature is one mechanism that can lead to pooling of saliva in anterior portion of mouth. Ultimately, muscle incoordination inhibits the initiation of the swallow reflex, thereby further disrupting the path of saliva from the mouth to the oropharynx . SalivarSialorrhea occurring with neurologic illnesses is usually due to impaired swallowing as a result of impaired neuromuscular function. Neuromucular activity of swallowing involves efficient coordination of several structures including the oral cavity, pharynx, larynx, and esophagus . These sThe objective of this paper is to provide a comprehensive review of sialorrhea and its various neurologic presentations, thus providing information on anatomy, physiology, and current treatment methods with an emphasis on the role of botulinum neurotoxins (BoNTs). The evidence for treatment efficacy is presented according to the guidelines of the American Academy of Neurology  Table 1Table 1. Information for this paper was collected by searching the Yale Medical Library Database, which utilizes a wide range of scholarly search engines including, but not limited to, Pubmed, Erasmus, Ovid, EBSCO and Cochrane databases. Literature was searched from the time line 1960 to present, including literature ahead of print and articles not in English. Terms used for search included “saliva”, “drooling”, “sialorrhea”, “hypersalivation”, “ptyalis”, “double-blind”, “therapy”, “treatment”, “botulinum toxin”, and “botulinum neurotoxin” in various combinations.Sialorrhea is known to be difficult to treat. Management can be conservative or more invasive. Conservative treatments include changes in diet or habits, oral-motor exercises, intra-oral devices such as palatal training devices, and medical treatments such as medication or botulinum toxin injections. Behavior modification has been advocated for many decades but results are inconsistent and time consuming . More inOral therapy for sialorrhea encompasses the use of anticholinergic agents such as glycopyrrolate, benztropine, scopalamine and tropicamide. Biperiden has also been implicated for use in the literature but was found in one study to have an adverse effect on cognition, thus limiting its use . GlycopySix double-blind studies investigated the efficacy of oral agents in sialorrhea . The majp < 0.05); however, four patients dropped out due to side effects and minor adverse events were noted in three others. It was concluded that though scopolamine can be useful to control drooling in severely disabled patients, it is not free from adverse effects, thus requiring careful patient selection [One double-blind study of 30 patients handicapped by debilitating illnesses  is described in the literature using transdermal scopolamine. Moderate or severe mental retardation was present in 80% of patients. Severity of drooling was quantified using a modified Thomas-Stonell and Greenberg visual scale and frequency of drooling was monitored by number of bibs used each day. A significant drooling reduction was noted (election . This class II study justifies a C level of evidence (possibly effective) Various surgical procedures have been suggested for treatment of drooling. These procedures all encompass an alteration in the anatomy of the salivary glands and include salivary gland excision, denervation of the salivary glands, and transposition or ligation of the salivary ducts . These pThe effect of Botulinum toxin (BoNT) on drooling was first noted in PD patients . BoNT, avs. placebo  agents   placebo , Botulin placebo  and comp) agents . BoNT inWe have determined the level of evidence for BoNT efficacy based on reviewed studies , Table 6As implied from this data, there is now strong evidence that both A and B types of BoNTs are effective in treatment of sialorrhea and both have a low profile of side effects. Despite the strong level of evidence collectively, the cited studies are not without limitations. One such limitation is that of outcome measures. There is significant heterogeneity of outcome measures among the studies. In some studies outcome measures were poorly defined. Some studies measured only qualitative clinical scales (drooling and activity of daily living) ,37,38,39Another limitation is variability of injection technique. A recent review paper stated that factors affecting diffusion and spread of BoNT include dose, concentration and volume of injectate, number of injections, injection site, rate of injection, gauge of needle, and distance of needle tip from the neuromuscular junction . The tabIn regards to duration of effect, one study suggested a length of duration up to six months , whereasFor location of injection, the studies presented focus on injections into the salivary glands (parotid and submandibular). Only one study discussed experience with direct injection into sublingual glands under the tongue with BoNT-B which lead to occurrence of dysphagia in two of four patients without any improvement in sialorrhea, thus discouraging this approach .A lack of correlation between reduction in salivary secretion and improvement in drooling has been observed in some studies and is probably related to the fact that factors influencing the severity of drooling and reduction of saliva secretion are variable . Side effects in general were few and mild. Among them, transient dysphagia was the most worrisome, resolving in two weeks and affecting a small number of patients. vs. side effects.One comparator study suggested better efficacy for type B toxin. Another indicated more side effects with type B. These need to be further investigated with weighing the efficacy A recent meta-analysis study (2012) , which rAs of now, level of evidence and low rate of adverse side effects indicate that administration of BoNT-A and BoNT-B into salivary glands is the most effective way of treating sialorrhea . Injections are simple and when executed by experienced hands, side effects are uncommon and manageable. Overall, efficacy of both toxins and their side effect profiles are comparable . Specialet al. is a review on the subject from a European team using the evidence criteria of the American Academy of Neurology (AAN). Due to differences in interpretation of AAN criteria, the evidence depicted in this report gives a level of evidence which is higher than levels depicted in our paper, as evidenced by the high number of class I studies in their report compared to ours. Several reviews on sialorrhea and management have been published recently ,48,49,50Our review covers the published literature on prospective and controlled studies (with placebo arm or comparator) until December 2012. It covers BoNTs, as well as oral and topical agents. The level of evidence is provided with adherence to the AAN guidelines.Defining the correct technical approach for botulinum toxin injections in sialorrhea is still an evolving issue. Many studies which have not used ultrasound for guiding injections report good results using anatomical landmarks. Particularly, the optimum number of injections into parotid glands is still a subject of debate. Since parotid gland anatomy is variable (sometimes extending anteriorly over masseter or posteriorly and inferiorly below the angle of the jaw), we at Yale practice using a larger number of subcutaneous injections and have been doing so for the past decade. Injections are done in a grid-like pattern using three rows, with three sites injected in each row . The top